The Drugs and Cosmetics Act and Rules

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0. Preamble

Statutory text

GOVERNMENT OF INDIA

MINISTRY OF HEALTH AND FAMILY WELFARE

(Department of Health)

THE DRUGS AND COSMETICS ACT AND RULES

THE DRUGS AND COSMETICS ACT, 1940

(23 OF 1940)

(As amended up to the 30th June, 2005)

and

THE DRUGS AND COSMETICS RULES, 1945

Statutory text

11.1 All containers and closures intended for use shall comply with the pharmacopoeial and other specified requirements. Suitable samples sizes, specifications, test methods, cleaning procedures and sterilization procedures, shall be used to assure that containers, closures and other component parts of drug packages are suitable and are not reactive, additive, adsorptive or leachable or presents the risk of toxicity to an extent that significantly affects the quality or purity of the drug. No second hand or used containers and closures shall be used.

11.2 Plastic granules shall also comply with the pharmacopoeial requirements including physio-chemical and biological tests.

11.3. All containers and closures shall be rinsed prior to sterilization with Water for Injection according to written procedure.

11.4. The design of closures, containers and stoppers shall be such as to make cleaning, easy and also to make airtight seal when fitted to the bottles.

11.5 It shall be ensured that containers and closures chosen for a particular product are such that when coming into contact they are not absorbed into the product and they do not affect the product adversely. The closures and stoppers should be of such quality substances as not to affect the quality of the product and avoid the risk of toxicity.

11.6. Whenever glass bottles are used, the written schedule of cleaning shall be laid down and followed. Where bottles are not dried after washing, these shall be finally rinsed with distilled water or pyrogen free water, as the case may be, according to written procedure.

11.7. Individual containers of parenteral preparations, ophthalmic preparations shall be examined against black/white background fitted with diffused light after filling so as to ensure freedom from foreign matters.

12. The Drugs and Cosmetics (Amendment) Act, 1995 (71 of 1995).

Statutory text

(2) Without prejudice to the generality of the forgoing power, such rules may— (a) specify the drugs or classes of drugs or cosmetics or classes of cosmetics for the import of which a licence is required, and prescribe the form and conditions of such licences, the authority empowered to issue the same, the fees payable therefor and provide for the cancellation, or suspension of such licence in any case where any provision of this Chapter or the rules made thereunder is contravened or any of the conditions subject to which the licence is issued is not complied with; (b) prescribe the methods of test or analysis to be employed in determining whether a drug or cosmetic is of standard quality; (c) prescribe, in respect of biological and organometallic compounds, the units or methods of standardization; (cc) prescribe under clause (d) of section 9A the colour or colours which a drug may bear or contain for purposes or colouring; (d) specify the diseases or ailments which an imported drug may not purport or claim to prevent, cure or mitigate and such other effects which such drug may not purport or claim to have; (e) prescribe the conditions subject to which small quantities of drugs, the import of which is otherwise prohibited under this Chapter, may be imported for the purpose of examination, test or analysis or for personal use; (f) prescribe the places at which drugs or cosmetics may be imported, and prohibit their import at any other place; (g) require the date of manufacture and the date of expiry of potency to be clearly and truly stated on the label or container of any specified imported drug or class of such drug, and prohibit the import of the said drug or class of drug after the expiry of a specified period from the date of manufacture; (h) regulate the submission by importers, and the securing, of samples of drugs or cosmetics for examination, test or analysis by the Central Drugs Laboratory, and prescribe the fees, if any, payable for such examination, test or analysis; (i) prescribe the evidence to be supplied, whether by accompanying documents or otherwise, of the quality of drugs or cosmetics sought to be imported, the procedure of officers of Customs in dealing with such evidence, and the manner of storage at places of import of drugs or cosmetics detained pending admission; (j) provide for the exemption, conditionally or otherwise, from all or any of the provisions of this Chapter and the rules made thereunder of drugs or cosmetics imported for the purpose only of transport through, an export from, India; (k) prescribe the conditions to be observed in the packing in bottles, packages or other containers, of imported drugs or cosmetics including the use of packing material which comes into direct contact with the drugs; (l) regulate the mode of labeling drugs or cosmetics imported for sale in packages, and prescribe the matters which shall or shall not be included in such labels; (m) prescribe the maximum proportion of any poisonous substance which may be added to or contained in any imported drug, prohibit the import of any drug in which that proportion is exceeded, and specify substances which shall be deemed to be poisonous for the purposes of this Chapter and the rules made thereunder; (n) require that the accepted scientific name of any specified drug shall be displayed in the prescribed manner on the label or wrapper of any imported, patent or proprietary medicine containing such drug; (o) provide for the exemption, conditionally or otherwise, from all or any of the provisions of this Chapter or the rules made thereunder, of any specified drug or class of drugs or cosmetic or class of cosmetics.

Statutory text

From such date as may be fixed by the State Government by notification in the Official Gazette in this behalf, no person shall himself or by any other person on his behalf—

(a) manufacture for sale or for distribution, or sell, or stock or exhibit or offer for sale or distribute—

(i) any drug which is not of a standard quality, or is misbranded, adulterated or spurious;

(ii) any cosmetic which is not of a standard quality or is misbranded or spurious;

(iii) any patent or proprietary medicine, unless there is displayed in the prescribed manner on the label or container thereof the true formula or list of active ingredients contained in it together with the quantities thereof;

(iv) any drug which by means of any statement, design or device accompanying it or by any other means, purports or claims to prevent, cure or mitigate any such disease or ailment, or to have any such other effect as may be prescribed;

(v) any cosmetic containing any ingredient which may render it unsafe or harmful for use under the directions indicated or recommended;

(vi) any drug or cosmetic in contravention of any of the provisions of this Chapter or any rule made thereunder;

(b) sell, or stock or exhibit or offer for sale, or distribute any drug or cosmetic which has been imported or manufactured in contravention of any of the provisions of this Act or any rule made thereunder;

(c) manufacture for sale or for distribution, or sell, or stock or exhibit or offer for sale, or distribute any drug or cosmetic, except under, and in accordance with the conditions of, a licence issued for such purpose under this Chapter :

Provided that nothing in this section shall apply to the manufacture, subject to prescribed conditions, of small quantities of any drug for the purpose of examination, test or analysis:

Provided further that the Central Government may, after consultation with the Board, by notification in the Official Gazette, permit, subject to any conditions specified in the notification, the manufacture for sale, or for distribution, sale, stocking or exhibiting or offering for sale or distribution of any drug or class of drugs not being of standard quality.

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18A. Disclosure of the name of the manufacturer, etc.

23. Procedure of Inspectors.

Statutory text

(1) Where an Inspector takes any sample of a drug or cosmetic under this Chapter, he shall tender the fair price thereof and may require a written acknowledgment therefor. (2) Where the price tendered under sub-section (1) is refused, or where the Inspector seizes the stock of any drug or cosmetic under clause (c) of section 22, he shall tender a receipt therefor in the prescribed form. (3) Where an Inspector takes a sample of a drug or cosmetic for the purpose of test or analysis, he shall intimate such purpose in writing in the prescribed form to the person from whom he takes it and, in the presence of such person unless he wilfully absents himself, shall divide the sample into four portions and effectively seal and suitably mark the same and permit such person to add his own seal and mark to all or any of the portions so sealed and marked: Provided that where the sample is taken from premises whereon the drug or cosmetic is being manufactured, it shall be necessary to divide the sample into three portions only: Provided further that where the drug or cosmetic is made up in containers of small volume, instead of dividing a sample as aforesaid, the Inspector may, and if the drug or cosmetic be such that it is likely to deteriorate or be otherwise damaged by exposure shall, take three or four, as the case may be, of the said containers after suitably marking the same and, where necessary, sealing them. (4) The Inspector shall restore one portion of a sample so divided or one container, as the case may be, to the person from whom he takes it, and shall retain the remainder and dispose of the same as follows:— (i) one portion or container he shall forthwith send to the Government Analyst for test or analysis; (ii) the second he shall produce to the Court before which proceedings, if any, are instituted in respect of the drug or cosmetic; (iii) the third, where taken, he shall send to the person, if any, whose name, address and other particulars have been disclosed under section 18A. (5) Where an Inspector takes any action under clause (c) of section 22,— (a) he shall use all despatch in ascertaining whether or not the drug or cosmetic contravenes any of the provisions of the section 18 and, if it is ascertained that the drug or cosmetic does not so contravene, forthwith revoke the order passed under the said clause or, as the case may be, take such action as may be necessary for the return of the stock seized; (b) if he seizes the stock of the drug or cosmetic, he shall as soon as may be inform a Judicial Magistrate and take his orders as to the custody thereof; (c) without prejudice to the institution of any prosecution, if the alleged contravention be such that the defect may be remedied by the possessor of the drug or cosmetic, he shall, on being satisfied that the defect has been so remedied, forthwith revoke his order under the said clause.

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24. Persons bound to disclose place where drugs or cosmetics are manufactured or kept.

Statutory text

(1) An application for an import licence shall be made to the licensing authority in Form 8 for drugs excluding those specified in Schedule X, and in Form 8-A for drugs specified in Schedule X, either by the manufacturer himself having a valid wholesale licence for sale or distribution of drugs under these Rules, or by the manufacturer’s agent in India either having a valid licence under the Rules to manufacture for sale of a drug or having a valid wholesale licence for sale or distribution of drugs under these Rules, and shall be accompanied by a licence fee of Rs. 1,000 for a single drug and an additional fee at the rate of Rs. 100 for each additional drug and by an undertaking in Form 9 duly signed by or on behalf of the manufacturer:

Provided that in the case of any subsequent application made by the same importer for import licence for drugs manufactured by the same manufacturer, the fee to accompany each such application shall be Rs. 100 for each drug:

(2) Any application for import licence in Form 8 or Form 8-A, as the case may be, shall be accompanied by a copy of Registration Certificate issued in Form 41 under Rule 27-A:

Provided that in case of emergencies the licensing authority may, with the approval of the Central Government, issue an import licence in Form 10 or 10-A, as the case may be, without the issuance of Registration Certificate under Rule 27-A, for reasons to be recorded in writing.

Provided further that Registration certificate shall not be required to be accompanied with an application for an import licence under the Rules for the import of in-vitro diagnostic kits and regents, except for the diagnostic kits notified from time to time under sub-clause (iv) of clause (b) of section 3.

(3) A fee of Rs. 250 shall be paid for a duplicate copy of the licence issued under this Rule, if the original is defaced, damaged or lost.

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25. Reports of Government Analysts.

Statutory text

(1) The Government Analyst to whom a sample of any drug or cosmetic has been submitted for test or analysis under sub-section (4) of section 23, shall deliver to the Inspector submitting it a signed report in triplicate in the prescribed form.

(2) The Inspector on receipt thereof shall deliver one copy of the report to the person from whom the sample was taken and another copy to the person, if any, whose name, address and other particulars have been disclosed under section 18A, and shall retain the third copy for use in any prosecution in respect of the sample.

(3) Any document purporting to be a report signed by a Government Analyst under this Chapter shall be evidence to the facts stated therein, and such evidence shall be conclusive unless the person from whom the sample was taken or the person whose name, address and other particulars have been disclosed under section 18A has, within twenty-eight days of the receipt of a copy of the report, notified in writing the Inspector or the Court before which any proceedings in respect of the sample are pending that he intends to adduce evidence in controversion of the report.

(4) Unless the sample has already been tested or analysed in the Central Drugs Laboratory, where a person has under sub-section (3) notified his intention of adducing evidence in controversion of a Government Analyst’s report, the Court may, of its own motion or in its discretion at the request either of the complainant or the accused, cause the sample of the drug or cosmetic produced before the Magistrate under sub-section (4) of section 23 to be sent for test or analysis to the said Laboratory, which shall make the test or analysis and report in writing signed by, or under the authority of, the Director of the Central Drugs Laboratory the result thereof, and such report shall be conclusive evidence of the facts stated therein.

(5) The cost of a test or analysis made by the Central Drugs Laboratory under sub-section (4) shall be paid by the complainant or accused as the Court shall direct.

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26. Purchaser of drug or cosmetic enabled to obtain test or analysis.

Statutory text

An import licence shall be subject to the following conditions: (i) the manufacturer shall at all times observe the undertaking given by him or on his behalf in Form 9; (ii) the licensee shall allow any Inspector authorised by the licensing authority in that behalf to enter with or without notice any premises where the imported substance is stocked, to inspect the means, if any, employed for testing the substance and to take samples; (iii) the licensee shall on request furnish to the licensing authority from every batch of each substance or from such batch or batches as the licensing authority may from time to time specify a sample of such amount as the licensing authority may consider adequate for any examination required to be made, and the licensee shall, if so required, furnish full protocols of the tests, if any, which have been applied; (iv) if the licensing authority so directs the licensee shall not sell or offer for sale any batch in respect of which a sample is or protocols are furnished under the last preceding sub-rule until a certificate authorising the sale of the batch has been issued to him by or on behalf of the licensing authority; (v) the licensee shall, on being informed by the licensing authority that any part of any batch of the substance has been found by the licensing authority not to conform with the standards of strength, quality and purity prescribed by Chapter III of the Act, or the rules thereunder and on being directed so to do, withdraw the remainder of that batch from sale and, so far as may in the particular circumstances of the case be practicable, recall the issues already made from that batch; (vi) the licensee shall maintain a record of all sales by him of substances for the import of which a licence is required, showing particulars of the substance and of the person to whom sold and such further particulars, if any, as the licensing authority may specify and such record shall be open to the inspection of any Inspector authorised in that behalf by the licensing authority: Provided that in respect of the sale or distribution of drugs specified in Schedule X, the licensee shall maintain a separate record or register showing the following particulars, namely: 1. Name of the Drug, 2. Batch number, 3. Name and address of the manufacturer, 4. Date of transaction, 5. Opening stock on the business day, 6. Quantity of drug received, if any, and the source from which received, 7. Name of the purchaser, his address and licence number, 8. Balance quantity of drug at the end of the business day, 9. Signature of the person under whose supervision the drugs have been supplied. (vii) the licensee shall comply with such further requirements, if any, applicable to the holders of import licenses, as may be specified in any Rules, subsequently made under Chapter III of the Act and of which the licensing authority has given to him not less than four months’ notice.

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26A. Power of Central Government to prohibit manufacture, etc., of drug and cosmetic in public interest.

Statutory text

Without prejudice to any other provision contained in this Chapter, if the Central Government is satisfied, that the use of any drug or cosmetic is likely to involve any risk to human beings or animals or that any drug does not have the therapeutic value claimed or purported to be claimed for it or contains ingredients and in such quantity for which there is no therapeutic justification and that in the public interest it is necessary or expedient so to do, then, that Government may, by notification in the Official Gazette, prohibit the manufacture, sale or distribution of such drug or cosmetic.

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27. Penalty for manufacture, sale, etc., of drugs in contravention of this Chapter.

Statutory text

Whoever, himself or by any other person on his behalf, manufactures for sale or for distribution, or sells, or stocks or exhibits or offers for sale or distributes, —

(a) any drug deemed to be adulterated under section 17A or spurious under section 17B or which when used by any person for or in the diagnosis, treatment, mitigation, or prevention of any disease or disorder is likely to cause his death or is likely to cause such harm on his body as would amount to grievous hurt within the meaning of section 320 of the Indian Penal Code (45 of 1860), solely on account of such drug being adulterated or spurious or not of standard quality, as the case may be, shall be punishable with imprisonment for a term which shall not be less than five years but which may extend to a term of life and with fine which shall not be less than Rs. 10,000;

(b) any drug—

(i) deemed to be adulterated under section 17A, but not being a drug referred to in clause (a), or

(ii) without a valid licence as required under clause (c) of section 18,

shall be punishable with imprisonment for a term which shall not be less than one year but which may extend to three years and with fine which shall not be less than Rs. 5,000:

Provided that the Court may, for any adequate and special reasons to be recorded in the judgment, impose a sentence of imprisonment for a term of less than one year and of fine of less than Rs. 5,000;

(c) any drug deemed to be spurious under section 17B, but not being a drug referred to in clause (a) shall be punishable with imprisonment for a term which shall not be less than three years but which may extend to five years and with fine which shall not be less than Rs. 5,000:

Provided that the Court may, for any adequate and special reasons, to be recorded in the judgment, impose a sentence of imprisonment for a term of less than three years but not less than one year;

(d) any drug, other than a drug referred to in clause (a) or clause (b) or clause (c), in contravention of any other provision of this Chapter or any rule made thereunder, shall be punishable with imprisonment for a term which shall not be less than one year but which may extend to two years and with fine:

Provided that the Court may, for any adequate and special reasons, to be recorded in the judgment impose a sentence of imprisonment for a term of less than one year.

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27A. Penalty for manufacture, sale, etc., of cosmetics in contravention of this Chapter.

Statutory text

Whoever himself or by any other person on his behalf manufactures for sale or for distribution, or sells, or stocks or exhibits or offers for sale—

(c) under clause (d) of section 27, is again convicted of an offence under that clause shall be punishable with imprisonment for a term which shall not be less than two years but which may extend to four years or with fine which shall not be less than Rs. 5,000, or with both.

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31. Confiscation.

Statutory text

(1) Where any person has been convicted under this Chapter for contravening any such provision of this Chapter or any rule made thereunder as may be specified by rule made in this behalf, the stock of the drug or cosmetic in respect of which the contravention has been made shall be liable to confiscation and if such contravention is in respect of—

(i) manufacture of any drug deemed to be misbranded under section 17, adulterated under section 17A or spurious under section 17B; or

(ii) manufacture for sale, or for distribution, sale, or stocking or exhibiting or offering for sale, or distribution of any drug without a valid licence as required under clause (c) of section 18;

any implements or machinery used in such manufacture, sale or distribution and any receptacles, packages or coverings in which such drug is contained and the animals, vehicles, vessels or other conveyances used in carrying such drug shall also be liable to confiscation.

(2) Without prejudice to the provisions contained in sub-section (1) where the Court is satisfied, on the application of an Inspector or otherwise and after such inquiry as may be necessary that the drug or cosmetic is not of standard quality misbranded, adulterated or spurious drug or misbranded or spurious cosmetic, such drug or, as the case may be, such cosmetic shall be liable to confiscation.

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31A. Application of provisions to Government departments.

Statutory text

The provisions of this Chapter except those contained in section 31 shall apply in relation to the manufacture, sale or distribution of drugs of any department of Government as they apply in relation to the manufacture, sale or distribution of drugs by any other person.

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32. Cognizance of offence.

Statutory text

(1) No prosecution under this Chapter shall be instituted except by an Inspector or by the person aggrieved or by a recognised consumer association whether such person is a member of that association or not.

(2) No court inferior to that of a Metropolitan Magistrate or of a Judicial Magistrate of the first class shall try an offence punishable under this Chapter.

(3) Nothing contained in this Chapter shall be deemed to prevent any person from being prosecuted under any other law for any act or omission which constitutes an offence against this Chapter.

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32A. Power of Court to implead the manufacturer, etc.

Statutory text

Where, at any time during the trial of any offence under this Chapter alleged to have been committed by any person, not being the manufacturer of a drug or cosmetic or his agent for the distribution thereof, the Court is satisfied, on the evidence adduced before it, that such manufacturer or agent is also concerned in that offence, then, the Court may, notwithstanding anything contained in sub-sections (1), (2) and (3) of section 319 of the Code of Criminal Procedure,1973 (2 of 1974) proceed against him as though a prosecution had been instituted against him under section 32.

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33. Power of Central Government to make rules.

Statutory text

(1) The Central Government may after consultation with, or on the recommendation of, the Board and after previous publication by notification in the Official Gazette, make rules for the purpose of giving effect to the provisions of this Chapter:

Provided that consultation with the Board may be dispensed with if the Central Government is of opinion that circumstances have arisen which render it necessary to make rules without such consultation, but in such a case the Board shall be consulted within six months of the making of the rules and the Central Government shall take into consideration any suggestions which the Board may make in relation to the amendment of the said rules.

(2) Without prejudice to the generality of the foregoing power, such rules may—

(a) provide for the establishment of laboratories for testing and analysing drugs or cosmetics;

(b) prescribed the qualifications and duties of Government Analysts and the qualifications of Inspectors;

(c) prescribe the methods of test or analysis to be employed in determining whether a drug or cosmetic is of standard quality;

(d) prescribe, in respect of biological and organometallic compounds, the units or methods of standardisation;

(dd) prescribe under clause (d) of section 17A the colour or colours which a drug may bear or contain for purposes of colouring;

(e) prescribe the forms of licences for the manufacture for sale or for distribution, for the sale and for the distribution of drugs or any specified drug or class of drugs or of cosmetics or any specified cosmetic or class of cosmetics, the form of application for such licences, the conditions subject to which such licences may be issued, the authority empowered to issue the same, the qualification of such authority and the fees payable therefor and provide for the cancellation or suspension of such licences in any case where any provision of this Chapter or the rules made thereunder is contravened or any of the conditions subject to which they are issued is not complied with;

(ee) prescribe the records, registers or other documents to be kept and maintained under section 18B;

(eea) prescribe the fees for the inspection (for the purposes of grant or renewal of licence) of premises, wherein any drug or cosmetic is being or is proposed to be manufactured;

(eeb) prescribe the manner in which copies are to be certified under sub-section (2A) of section 22;

(f) specify the diseases or ailments which a drug may not purport or claim to prevent, cure or mitigate and such other effects which a drug may not purport or claim to have;

(g) prescribe the conditions subject to which small quantities of drugs may be manufactured for the purpose of examination, test or analysis.

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33A. Chapter not to apply to

Statutory text

Small quantities of new drug, as defined in Rule 122-E, the import of which is otherwise prohibited under section 10 of the Act, may be imported for treatment of patients suffering from life threatening diseases, or diseases causing serious permanent disability, or such disease requiring therapies for unmet medical needs, by a Medical Officer of a Government Hospital or an Autonomous Medical Institution providing tertiary care, duly certified by the Medical Superintendent of the Government Hospital, or Head of the Autonomous Medical Institution, subject to the following conditions, namely:- (a) no new drug shall be imported for the said purpose except under a licence in Form 11-A, and the said drug has been approved for marketing in the country of origin; (b) the licensee shall use the substances or drugs imported under the licence exclusively for the purpose of treatment of patients suffering from life threatening diseases, or diseases causing serious permanent disability, or such diseases requiring therapies for unmet medical needs, under the supervision of its own Medical Officers at the place, specified in the licence or at such other places, as the licensing authority, may from time to time authorise; (c) the licensee shall allow an Inspector authorised by the licensing authority in this behalf to enter, with or without prior notice, the premises where the substances or drugs are stocked, and to inspect the premises and relevant records and investigate the manner in which the substances or drugs are being used and to take, if necessary, samples thereof; (d) the licensee shall keep a record of, and shall submit the said report half yearly to the licensing authority, the substances or drugs imported under the licence, together with the quantities imported and issued to the patients, the date of importation, the name of the manufacturer, the name and address of the patient for whom the drug is prescribed and the name of disease; (e) the licensee shall comply with such other requirements, if any, applicable to the holders of import licences for import of new drugs for treatment of patients by Government Hospitals, as may be specified from time to time in any rule subsequently made under Chapter III of the Act and of which the licensing authority has given to him not less than one month’s notice; (f) the drug shall be stocked under proper storage conditions and shall be dispensed under the supervision of a registered pharmacist; (g) the quantity of any single drug so imported shall not exceed 100 average dosages per patient: Provided that the licensing authority may, in exceptional circumstances, sanction the import of drug of a larger quantity.

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33B. Application of Chapter IVA.

Statutory text

This Chapter shall apply only to

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33C. Ayurvedic, Siddha and Unani] drugs.

Statutory text

12[Ayurvedic, Siddha and Unani Drugs Technical Advisory Board].—(1) The Central Government shall, by notification

in the Official Gazette and with effect from such date as may be specified therein, constitute a Board (to be called the

12[Ayurvedic, Siddha and Unani Drugs Technical Advisory Board]) to advise the Central Government and the State Governments on technical matters arising out of this Chapter and to carry out the other functions assigned to it by this Chapter.

(2) The Board shall consist of the following members, namely:— ____________________________________________________________________________________________________________

¹ Ins. by Act 21 of 1962, s. 22 (w.e.f. 27-7-1964).

² Ins. by Act 68 of 1982, s. 29 (w.e.f. 1-2-1983).

⁴ Subs. by Act 35 of 1960, s. 10, for cl. (n) (w.e.f. 16-3-1961).

⁵ Ins. by Act 68 of 1982, s. 29 (w.e.f. 15-9-1965).

⁶ Subs. by Act 21 of 1962, s. 22, for “the drugs or class of drugs” (w.e.f. 27-7-1964).

⁷ Subs. by Act 13 of 1964, s. 24, for cl. (p) (w.e.f. 15-9-1964).

⁹ Ins. by Act 13 of 1964, s. 25 (w.e.f. 1-2-1969).

¹⁰ Subs. by Act 68 of 1982, s. 2, for “

¹¹ Ins. by Act 13 of 1964, s. 26 (w.e.f. 1-2-1969).

¹² Subs. by Act 68 of 1982, s. 30, for certain words (w.e.f. 1-2-1983).

Drugs and Cosmetics Act, 1940

(i) the Director General of Health Services, ex officio;
(ii) the Drugs Controller, India, ex officio;

1[(iii) the principal officer dealing with Indian systems of medicine in the Ministry of Health, ex officio;]

(iv) the Director of the Central Drugs Laboratory, Calcutta, ex officio;
(v) one person holding the appointment of Government Analyst under section 33F, to be nominated by the Central Government;
(vi) one Pharmacognocist to be nominated by the Central Government;
(vii) one Phyto-chemist to be nominated by the Central Government; 2[(viii) four persons to be nominated by the Central Government, two from amongst the members of the Ayurvedic Pharmacopoeia Committee, one from amongst the members of the Unani Pharmacopoeia Committee and one from amongst the members of the Siddha Pharmacopoeia Committee;]
(ix) one teacher in Dravyaguna and Bhaishajya Kalpana, to be nominated by the Central Government;
(x) one teacher in ILM-UL-ADVIA and TAKLIS-WA-DAWA-SAZI, to be nominated by the Central Government; 3[(xi) one teacher in Gunapadam, to be nominated by the Central Government;
(xii) three persons, one each to represent the Ayurvedic, Siddha and Unani drug industry, to be nominated by the Central Government;
(xiii) three persons, one each from among the practitioners of Ayurvedic, Siddha and Unani Tibb system of medicine, to be nominated by the Central Government.]

(3) The Central Government shall appoint a member of the Board as its Chairman.
(4) The nominated members of the Board shall hold office for three years but shall be eligible for renomination.
(5) The Board may, subject to the previous approval of the Central Government, make bye-laws fixing a quorum and regulating its own procedure and conduct of all business to be transacted by it.
(6) The functions of the Board may be exercised notwithstanding any vacancy therein.
(7) The Central Government shall appoint a person to be Secretary of the Board and shall provide the Board with such clerical and other staff as the Central Government considers necessary.

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33D. The Ayurvedic, Siddha and Unani Drugs Consultative Committee.

Statutory text

(1) The Central Government may constitute an Advisory Committee to be called the Ayurvedic, Siddha and Unani Drugs Consultative Committee to advise the Central Government, the State Governments and the Ayurvedic, Siddha and Unani Drugs Technical Advisory Board on any matter for the purpose of securing uniformity throughout India in the administration of this Act in so far as it relates to Ayurvedic, Siddha or Unani drugs.
(2) The Ayurvedic, Siddha and Unani Drugs Consultative Committee shall consist of two persons to be nominated by the Central Government as representatives of that Government and not more than one representative of each State to be nominated by the State Government concerned.
(3) The Ayurvedic, Siddha and Unani Drugs Consultative Committee shall meet when required to do so by the Central Government and shall regulate its own procedure.

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33E. Misbranded drugs.

Statutory text

¹ Ins. by Act 13 of 1964, s. 26 (w.e.f. 1-2-1969).

² Subs. by Act 68 of 1982, s. 30, for cl. (viii) (w.e.f. 1-2-1983).

³ Subs. by s. 30, ibid., for cls. (xi) and (xii) (w.e.f. 1-2-1983).

⁴ Subs. by s. 31, ibid., for ss. 33D and 33E (w.e.f. 1-2-1983).

For the purposes of this Chapter, an Ayurvedic, Siddha or Unani drugs shall be deemed to be misbranded— __________________________________________________________________________________________________________________________________________________________________________________________________

Drugs and Cosmetics Act, 1940

(a) if it is so coloured, coated, powered or polished that damage is concealed, or if it is made to appear of better or greater therapeutic value than it really is; or
(b) if it is not labelled in the prescribed manner; or
(c) if its label or container or anything accompanying the drug bears any statement, design or device which makes any false claim for the drug or which is false or misleading in any particular.

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33EE. Adulterated drugs.

Statutory text

For the purposes of this Chapter, an Ayurvedic, Siddha or Unani drug shall be deemed to be adulterated,—

(a) if it consists, in whole or in part, of any filthy, putrid or decomposed substance; or
(b) if it has been prepared, packed or stored under insanitary conditions whereby it may have been contaminated with filth or whereby it may have been rendered injurious to health; or
(c) if its container is composed, in whole or in part, of any poisonous or deleterious substance which may render the contents injurious to health; or
(d) if it bears or contains, for purposes of coloring only, a colour other than one which is prescribed; or
(e) if it contains any harmful or toxic substance which may render it injurious to health; or
(f) if any substance has been mixed therewith so as to reduce its quality or strength. Explanation.—For the purpose of clause (a), a drug shall not be deemed to consist, in whole or in part, of any decomposed substance only by reason of the fact that such decomposed substance is the result of any natural decomposition of the drug: Provided that such decomposition is not due to any negligence on the part of the manufacturer of the drug or the dealer thereof and that it does not render the drug injurious to health.

Chapter IV Chapter IV

33EEA. Spurious drugs.

Statutory text

For the purposes of this Chapter, an Ayurvedic, Siddha or Unani drug shall be deemed to be spurious—

(a) if it is sold, or offered or exhibited for sale, under a name which belongs to another drug; or
(b) if it is an imitation of, or is a substitute for, another drug or resembles another drug in a manner likely to deceive, or bears upon it or upon its label or container the name of another drug, unless it is plainly and conspicuously marked so as to reveal its true character and its lack of identity with such other drug; or
(c) if the label or container bears the name of an individual or company purporting to be the manufacturer of the drug, which individual or company is fictitious or does not exist; or
(d) if it has been substituted wholly or in part by any other drug or substance; or
(e) if it purports to be the product of a manufacturer of whom it is not truly a product.

Chapter IV Chapter IV

33EEB. Regulation of manufacture for sale of Ayurvedic, Siddha and Unani drugs.

Statutory text

No person shall

manufacture for sale or for distribution any Ayurvedic, Siddha or Unani drug except in accordance with such standards, if any, as may be prescribed in relation to that drug.

Chapter IV Chapter IV

33EEC. Prohibition of manufacture and sale of certain Ayurvedic, Siddha and Unani drug.

Statutory text

From such date as the State Government may, by notification in the Official Gazette, specify in this behalf, no person, either by himself or by any other person on his behalf, shall—

(a) manufacture for sale or for distribution—
- (i) any misbranded, adulterated or spurious Ayurvedic, Siddha or Unani drugs;
- (ii) any patent or proprietary medicine, unless there is displayed in the prescribed manner on the label or container thereof the true list of all the ingredients contained in it; and Drugs and Cosmetics Act, 1940
- (iii) any Ayurvedic, Siddha or Unani drug in contravention of any of the provisions of this Chapter or any rule made thereunder;
(b) sell, stock or exhibit or offer for sale or distribute, any Ayurvedic, Siddha or Unani drug which has been manufactured in contravention of any of the provisions of this Act, or any rule made thereunder;
(c) manufacture for sale or for distribution, any Ayurvedic, Siddha or Unani drug, except under, and in accordance with the conditions of, a licence issued for such purpose under this Chapter by the prescribed authority: Provided that nothing in this section apply to Vaidyas and Hakims who manufacture Ayurvedic, Siddha or Unani drug for the use of their own patients:

Chapter IV Chapter IV

33EED. Provided further that nothing in this section shall apply to the manufacture, subject to the prescribed conditions, of small quantities of any Ayurvedic, Siddha or Unani drug for the purpose of examination, test or analysis.

Statutory text

Without prejudice to any other provision contained in this Chapter, if the Central Government is satisfied on the basis of any evidence or other material available before it that the use of any Ayruvedic, Siddha or Unani drug is likely to involve any risk to human beings or animals or that any such drug does not have the therapeutic value claimed or purported to be claimed for it and that in the public interest it is necessary or expedient so to do then, that Government may, by notification in the Official Gazette, prohibit the manufacture, sale or distribution of such drug.

Chapter V Chapter V

34. Offences by companies.

Statutory text

(1) Where an offence under this Act has been committed by a company, every person who at the time the offence was committed, was in charge of, and was responsible to the company for the conduct of the business of the company, as well as the company shall be deemed to be guilty of the offence and shall be liable to be proceeded against and punished accordingly:

Provided that nothing contained in this sub-section shall render any such person liable to any punishment provided in this Act if he proves that the offence was committed without his knowledge or that he exercised all due diligence to prevent the commission of such offence.

(2) Notwithstanding anything contained in sub-section (1), where an offence under this Act has been committed by a company and it is proved that the offence has been committed with the consent or connivance of, or is attributable to any neglect on the part of, any director, manager, secretary or other officer of the company, such director, manager, secretary or other officer shall also be deemed to be guilty of that offence and shall be liable to be proceeded against and punished accordingly:

Statutory text

Notwithstanding anything contained in the Code of Criminal Procedure, 1973 (2 of 1974), all offences under this Act, punishable with imprisonment for a term not exceeding three years, other than an offence under clause (b) of sub-section (1) of section 33-I, shall be tried in a summary way by a Judicial Magistrate of the first class specially empowered in this behalf by the State Government or by a Metropolitan Magistrate and the provisions of sections 262 to 265 (both inclusive) of the said Code shall, as far as may be, apply to such trial:

70 Agasthiyar Kanma Soothiram 71 18 Siddar’s Chillarai Kovai 72 Yog Vatha Kaviyam 73 Therayar Tharu 74 Agasthiyar Vaidya Kaviyam (1500) 75 Bala Vagadam 76 Chimittu Rathna (Rathna) Churukkam 77 Nagamuni (200) 78 Agasthiyar Chillarai Kovai 79 Chikicha Rathna Deepam 80 Agasthiyar Nayana Vidhi 81 Yugi Karisal (151) 82 Agasthiyar Vallathi (600) 83 Therayar Thaila Varkam

1[84 Siddha Formulary of India (Part I)]

2[B.—UNANI TIBB SYSTEM]

Serial No. Name of book

6 Biaz Kabir Vol. II 7 Karabadin Jadid 8 Kitab-ul-Taklis 9 Sanat-ul-Taklis 10 Mifta-ul-Khazain 11 Madan-ul-Aksir 12 Makhzan-ul-murabhat

1[13 National Formulary of Unani Medicine (Part I)]

¹ Ins. by Notifn. No. G.S.R. 735 (E), dated the 28th August, 1987.

² Ins. by Notifn. No. G.S.R. 423 (E), dated the 11th June, 2002.

³ Ins. by Notifn. No. G.S.R. 735 (E), dated the 28th August, 1987.

⁴ Subs. by Act 68 of 1982, s. 41 (w.e.f. 1-2-1983).

_________________________________________________________________________________________________________________________

Drugs and Cosmetics Act, 1940

THE SECOND SCHEDULE

(See sections 8 and 16)

TANDARDS TO BE COMPLIED WITH BY IMPORTED DRUGS AND BY DRUGS MANUFACTURED FOR SALE, SOLD,

STOCKED OR EXHIBITED FOR SALE OR DISTRIBUTED

Class of drug

Standard to be complied with 1 2 1. Patent or proprietary medicines

1[other than

Homoeopathic medicines]

2[Substances commonly known as vaccines, sera toxins, toxoids, antitoxins and antigens and biological products of like nature, for human use or for veterinary use.

3* * *

4. Substances (other than food) intended to affect the structure or any function of the human body or intended to be used for the destruction of vermin or insects which cause disease in human beings or animals.

1[4-A. Homoeopathic Medicines.

The formula of list of ingredients displayed in the prescribed manner on the label of the container and such other standards as may be prescribed.

The standards maintained at the International Laboratory for Biological Standards, Stantans Serum Institute, Copenhagen and at the Central Veterinary Laboratory, Weybridge Surrey, U.K., and such other laboratories recognized by the World Health Organization from time to time, and such further standards of strength, quality and purity, as may be prescribed.]

• * Such standards as may be prescribed.

(1) The Standards specified from time to time in the Homoeopathic Pharmacopoeia of the United States

of America or the United Kingdom or Germany for

the medicines included therein.

(2) For the Homoeopathic medicines not included in the Homoeopathic Pharmacopoeia of the United States of America or the United Kingdom or Germany, the standards approved by the Central Government and displayed in the prescribed manner on the label of the container.] _________________________________________________________________________________________________

¹ Ins. by Notifn. No. S.O. 887, dated the 19th March 1966, Gazette of India , Pt. II, Sec. 3 (ii), p. 819.

² Subs. by Notifn. No. G.S.R. 299(E), dated the 23rd April 1984.

3. Entry 3 omitted by Notifn. No. G.S.R. 299(E), dated the 23rd April, 1984.

Drugs and Cosmetics Act, 1940

1[5. Other drugs:

(a) Drugs included in the Indian Pharmacopoeia
(b) Drugs not included in the Indian Pharmacopoeia but which are included in the official Pharmacopoeia of any other country. Standards of identity, purity and strength specified in the edition of the Indian Pharmacopoeia for the time being in force and such other standards as may be prescribed. In case the standards of identity, purity and strength for drugs are not specified in the edition of the Indian Pharmacopoeia for the time being in force but are specified in the edition of the Indian pharmacopoeia immediately preceding, the standards of identity, purity and strength shall be those occurring in such immediately preceding

edition of the Indian Pharmacopoeia and such other

standards as may be prescribed.

Standards of identity, purity and strength specified for drugs in the edition of such official Pharmacopoeia of any other country for the time being in force and such other standards as may be prescribed.

In case the standards of identity, purity and strength for drugs are not specified in the edition of such official Pharmacopoeia for the time being in force, but are specified in the edition immediately preceding, the standards of identity, purity and strength shall be those occurring in such immediately preceding of such official

Pharmacopoeia and such other standards as may be

prescribed.] Class of drug Standard to be complied with

1 2

¹ Subs. by Notifn. No. G.S.R. 885, dated the 4

_____________________________________________________________________________________________ th August, 1973, Gazette of India, Pt. II, s. 3(i), p. 1643.

DEPARTMENT OF HEALTH NOTFICATION

New Delhi, the 21st December 1945

No. F. 28-10/45-H (1). _ In exercise of the powers conferred by

1[sections 6(2), 12, 33 and 33N] of the Drugs and Cosmetics Act, 1940 (XXIII of 1940), the Central Government is pleased to make the following Rules: __ RULES

Part V GOVERNMENT ANALYSTS, INSPECTORS, LICENSING AUTHORITIES AND CONTROLLING AUTHORITIES

54A. Prohibition of sale.

Statutory text

__ No person in possession of a

2[drug or cosmetic] in

respect of which an Inspector has made an order under clause (c) of sub-section (1) of section 22 of the Act shall in contravention of that order sell or otherwise dispose of any stock of such

2[drug or cosmetic].

Part V GOVERNMENT ANALYSTS, INSPECTORS, LICENSING AUTHORITIES AND CONTROLLING AUTHORITIES

55. Forms of receipts for seized drug, cosmetic, record register, document or

Statutory text

any other material object.-- A receipt by an Inspector for the stock of any drug or cosmetic or for any record, register, document or any other material object seized by him under clause (c) or clause (cc) of sub-section (1) of section 22 of the Act shall be in Form 16.

Part V GOVERNMENT ANALYSTS, INSPECTORS, LICENSING AUTHORITIES AND CONTROLLING AUTHORITIES

55A. Manner of certifying copies of seized documents.

Statutory text

The Drugs Inspector

shall return the documents , seized by him under clause (cc) or produced before him under clause (cca), of sub-section (1) of section 22 of the Act, within a period of twenty days of the date of such seizure or production, to the person from whom they have seized or, as the case may be, the person who produced them, after copies thereof of extracts therefrom have been signed by the concerned Drug Inspector and the person from whom they have seized , or, as the case may be , who produced such records.]

Part V GOVERNMENT ANALYSTS, INSPECTORS, LICENSING AUTHORITIES AND CONTROLLING AUTHORITIES

56. Form of intimation of purpose of taking samples.

Statutory text

__ When an Inspector takes a sample of a drug for the purpose of test or analysis, he shall intimate such purpose in writing in Form 17 to the person from whom he takes it.

Part V GOVERNMENT ANALYSTS, INSPECTORS, LICENSING AUTHORITIES AND CONTROLLING AUTHORITIES

56A. Form or receipt for samples of drugs where fair price tendered is refused

Statutory text

Where the fair price, for the samples of drugs taken for the purpose of test or analysis, tendered under sub-section (1) of section 23 has been refused, the Inspector shall tender a receipt therefor to the person from whom the said samples have been taken as specified in Form 17-A.]

Part V GOVERNMENT ANALYSTS, INSPECTORS, LICENSING AUTHORITIES AND CONTROLLING AUTHORITIES

57. Procedure for despatch of sample to Government Analyst.

Statutory text

(1) The portion of sample or the container sent by an Inspector to the Government Analyst for test or analysis under sub-section (4) of section 23 of the Act shall be sent by registered post or by hand in a sealed packet, enclosed together with a memorandum in Form 18, in an outer cover addressed to the Government Analyst.
(2) A copy of the memorandum and a specimen impression of the seal used to seal the packet shall be sent to the Government Analyst separately by registered post or by hand. _________________________________________________________________

² Subs. by G.S.R 850(E), dt. 07-12-1994.

⁴ Ins. by G.S.R 89 (E), dt. 16-2-1981.

⁵ Ins. by G.S.R 292 (E), dt. 29-5-1997.

Drugs and Cosmetics Rules, 1945 56

Part V GOVERNMENT ANALYSTS, INSPECTORS, LICENSING AUTHORITIES AND CONTROLLING AUTHORITIES

58. Confiscation of drugs, implements, machinery etc.

Statutory text

(1) Where any person has been convicted for contravening any of the provisions of Chapter IV of the Act or any Rule made thereunder, the stock of the drug in respect of which the contravention has been made shall be liable to confiscation.
(2) Where any person has been convicted for the manufacture of any drug deemed to be misbranded under clause (a), clause (b), clause (c), clause (d), clause (f) or clause (g) of section 17 of the Act, or adulterated drug under section 17B of the Act, or for manufacture for sale, or stocking or exhibiting for sale or distribution of any drug without a valid licence as required under clause (c) of section 18 of the Act, any implements or machinery used in such manufacture, sale or distribution and any receptacle, packages, or coverings in which such drug is contained and the animals, vehicles, vessels or other conveyances used in carrying such drug shall also be liable to confiscation.] 2[58-A. Procedure for disposal of confiscated drugs. __
(1) The Court shall refer the confiscated drugs to the Inspector concerned for report as to whether they are of standard quality or contravene the provisions of the Act or the Rules in any respect.
(2) If the Inspector, on the basis of Government Analyst’s report finds the confiscated drugs to be not of standard quality or to contravene any of the provisions of the Act or the Rules made thereunder, he shall report to the Court accordingly. The Court shall thereupon order the destruction of the drugs. The destruction shall take place under the supervision of the Inspector in the presence of such authority, if any, as may be specified by the Court.
(3) If the Inspector finds that the confiscated drugs are of standard quality and do not contravene the provisions of the Act or the Rules made thereunder, he shall report to the Court accordingly. 3[The Court may then order the Inspector to give the stocks of confiscated drugs to hospital or dispensary maintained or supported by the Government or by Charitable Institutions.] ____________________________________________________________________

63B. Certificate of renewal of licence.

Statutory text

Part VI Part VI

64. A certificate of renewal of a licence in Form 20BB or Form 21BB shall be issued in Form 21-CC.

Statutory text

Conditions to be satisfied before a licence in Form

3[20, 20-B, 20-F,20-G,

21 or 21-B] is granted . __ (1)A licence in Form

3[20, 20-B, 20-F, 20-G, 21 or 21-B]

6[to sell, stock, exhibit or offer for sale or distribute] drugs shall not be

7[granted or

renewed] to any person unless the authority empowered to grant the licence is satisfied that the premises in respect of which the licence is to be

7[granted or

renewed] are adequate, equipped with proper storage accommodation for preserving the properties of the drugs to which the licence applies and are in charge of a person competent in the opinion of the licensing authority to supervise and control the sale, distribution and preservation of drugs :

Provided that in the case of a pharmacy a licence in Form 20 or 21 shall not be

7[granted or renewed] unless the licensing authority is satisfied that the requirements prescribed for a pharmacy in Schedule N have been complied with:

3[Provided further that licence in Form 20-F shall be

7[granted or renewed] only

to a pharmacy and in areas where a pharmacy is not operating, such licence may be

7[granted or renewed] to a chemist and druggist.]

Explanation. __ For the purpose of this rule the term ‘Pharmacy’ shall be held to mean to include every store or shop or other place : (1) where drugs are dispensed, that is, measured or weighed or made up and supplied ; or (2) where prescriptions are compounded; or (3) where drugs are prepared; or (4) which has upon it or displayed within it, or affixed to or used in connection with it, a sign bearing the word or words “Pharmacy”, “Pharmacist”, “Dispensing Chemist” or “Pharmaceutical Chemist”; or

(5) which, by sign, symbol or indication within or upon it gives the impression that the operations mentioned at (1), (2) and (3) are carried out in the premises; or (6) which is advertised in terms referred to in (4) above. ____________________________________________________________________

³ Ins. by G.S.R 462 (E), dt. 22-6-1982.

⁶ Subs. by G.S.R 788 (E), dt. 10-10-1985.

⁷ Subs. by No. G.S.R 681(E), dt. 6-6-1988.

Drugs and Cosmetics Rules, 1945 62

(2) In 1[granting or renewing]a licence under sub-rule (1) the authority empowered to grant it shall have regard ____

1[(i) to the average number of licences granted during the period of 3 years

immediately preceding, and

(ii) to the occupation, trade or business ordinarily carried on by such applicant during the period aforesaid :] Provided that the licensing authority may refuse to grant or renew a licence to any applicant or licensee in respect of whom it is satisfied that by reason of his conviction of an offence under the Act or these rules, or the previous cancellation or suspension of any licence granted thereunder, he is not a fit person to whom a licence should be granted under this rule. Every such order shall be communicated to the licensee as soon as possible: 2[Provided further that in respect of an application for the grant of a licence in Form 20-B or Form 21-B or both, the licensing authority shall satisfy himself that the premises in respect of which a wholesale licence is to be granted are:-
(i) of an area of not less than ten square meters; and] 3[(ii) in the charge of a competent person, who—

(a) is a Registered Pharmacist, or
(b) has passed the matriculation examination or its equivalent examination from a recognised Board with four years’ experience in dealing with sale of drugs, or
(c) holds a degree of a recognised University with one year’s experience in dealing with drugs:] 4[Provided also that,⎯
- (i) in respect of an application for the grant of a licence in Form 20 or Form 21 or both, the licensing authority shall satisfy itself that 5[the premises are of an area] of not less than 10 square meters, and
- (ii) in respect of an application for the grant of a licence⎯
(A) In Form 20 or Form 21 or both, and
(B) In Form 20 B or Form 21B or both,

the licensing authority shall satisfy itself that the premises are of an area not less than

¹ Subs. by G.S.R 681(E), dt. 6.6.1988.

15 square meters: ____________________________________________________________________

³ Ins. by G.S.R 681(E), dt. 6.6.1988.

⁵ Ins. by G.S.R 91(E), dt. 25-2-1997.

Statutory text

(1) Application for grant or renewal of licence to manufacture for sale or for distribution of drugs, other than those specified in Schedules C and C (1) shall be made to the licensing authority appointed by the State Government for the purpose of this Part (hereinafter in this Part referred to as the licensing authority) and shall be made—

(a) in the case of repacking of drugs excluding those specified in Schedule X for sale or distribution in, Form 24-B;

(b) in the case of manufacture of drugs included in Schedule X, in Form 24-F;

(2)(a) Every application in Form 24-B shall be made up to ten items for each category of drugs categorised in Schedule M and shall be accompanied by a licence fee of Rs. 500 plus and an inspection fee of Rs. 200 for every inspection or for the purpose of renewal of the licence. (b) Every application in Form 24B shall be made up to ten items for each category of drugs categorised in Schedule M and shall be accompanied by a licence fee of Rs. 6,000 and an inspection fee of Rs. 1,500 for every subsequent inspection or for the purpose of renewal of licence. (c) Every application in Form 24 shall be made up to ten items for each category of drugs catogarised in Schedule M and Schedule M-III and shall be accompanied by a licence fee of Rs. 6,000 and an inspection fee of Rs. 1,500 for every inspection or for the purpose of renewal of the licence.

(3) If a person applies for the renewal of a licence after the expiry thereof but within six months of such expiry the fee payable for the renewal of such licence shall be— (i) in the case of Form 24-B a licence fee of Rs. 500 plus an additional fee at the rate of Rs. 250 per month or part thereof in addition to an inspection fee of Rs. 200; (ii) in the case of Form 24-F a licence fee of Rs. 6,000 plus an additional fee at the rate of Rs. 1,000 per month or part thereof in addition to an inspection fee of Rs. 1,000; (iii) in the case of Form 24 a licence fee of Rs. 6,000 plus an additional fee at the rate of Rs. 1,000 per month or part thereof in addition to an inspection fee of Rs. 1,500.

(4) A fee Rs. 1,000 shall be paid for a duplicate copy of the licence issued under clause (a), clause (b) or clause (c) of sub-Rule (1) if the original is defaced, damaged or lost.

(5) Applications by licensees to manufacture additional items of drugs shall, in the case of a licence to manufacture for sale and distribution for repacking and other than those specified in Schedule C and Schedule C (I), be made to the Licensing Authority. Such applications shall, if the additional items of drugs applied for belong to categories which are not already included in the licence, be accompanied by an additional fee at the rate of Rs. 100 for each additional item of drug for repacking and Rs. 300 per additional item of drugs categorised in Schedule M and Schedule M-III.

(6) Where an application under this Rule is for the manufacture of drug formulations falling under the purview of new drug as defined in rule 122-E, such application shall also be accompanied with approval, in writing in favour of the applicant, from the licensing authority as defined in clause (b) of rule 21.

Explanation.— For the purpose of these Rules, the term ‘repacking’ means the process of breaking up any drug from a bulk container into small packages and the labelling of each such package with a view to its sale and distribution, but does not include the compounding or dispensing or the packing of any drug in the ordinary course of the retail business.

Part VII Part VII

70. Form of licence to repack or manufacture drugs other than those specified

Statutory text

Licences for repacking of drugs against application in Form 24-B shall be granted in Form 25-B, licences for manufacture of drugs included in Schedule X and against application in Form 24-F shall be granted in Form 25-F and licences for manufacture of drugs against application in Form 24 shall be granted in Form 25.

Part VII Part VII

71. Schedules C, C(1) and X] shall be issued in Form 25-A.

Statutory text

Before a licence in Form 25 or Form 25-F is granted or renewed, the following conditions shall be complied with by the applicant.-

(1) The manufacture shall be conducted under the active direction and personal supervision of competent technical staff consisting at least of one person who is a whole-time employee and who is—

Statutory text

Amobarbital • * * Amphetamine Methylphenidate Barbital Methylphenobarbital Cyclobarbital Pentobarbital Dexamphetamine Phencyclidine Ethclorvynol Phenometrazine Glutethimide • * * Meprobamate Secobarbital Methamphetamine Note: 1. Any stereoisometric form of the substance specified in this Schedule, any salt of the substance and preparation containing such substances are also covered by this Schedule. 2. Preparations containing the above substances are also covered by this Schedule. Provided, however, preparations containing Meprobamate • * * in combination with other drugs may be exempted by the Licensing Authority specified in clause (b) of rule 21, from the provisions of this Schedule, if satisfactory evidence is adduced that these preparations are not liable to be misused.] ____________________________________________________________________________ 1. Schedule W ins. by. G.S.R. 27(E) ,dt. 17.1.1981 and omitted by. G.S.R. 94(E) ,dt. 8..2. 2000. 3. Omitted by G.S.R. 647(E) ,dt. 28.10.1998. 4. Omitted by. G.S.R. 673(E) ,dt. 27.10.1993. 2 Ins. by G.S.R. 462(E) ,dt. 22.6.1982. Drugs and Cosmetics Rules, 1945 503

Some statutory text is still being prepared for this language version.

PDF: pending for this language.

A

FORM 1 (See rule 4) Memorandum to the Central Drugs Laboratory Serial Number .................................. To the Director, Central Drugs Laboratory ...................................................... From...................................... I send herewith, under the provisions of section 25 (4) of the Drugs and Cosmetics Act, 1940, sample(s) of a drug purporting to be....................for test or analysis and request that a report of the result of the test or analysis may be supplied to this Court.

(2) The distinguishing number on the packet is............................................
(3) Particulars of offence alleged ...................................................................
(4) Matter on which opinion is required .......................................
(5) A fee of Rs ................. has been deposited in Court.

Date .................... ...................

Magistrate

FORM 2 (See rule 6) Certificate of test or analysis by the Central Drugs Laboratory Certified that the sample bearing number ....................................... ....................

............................................... has been tested/analysed and that the result of such test / analysis is as stated below. 2. The condition of the seals on the packet on receipt was as follows: — *3. In the opinion of the undersigned the sample is of standard quality as defined_ is not of standard quality as defined

in the Drugs and Cosmetics Act, 1940 and Rules thereunder for the reasons given below:–

in the Drugs and Cosmetics Act, 1940, and Rules thereunder

Date.............. Director

Central Drugs Laboratory or other authorised officer

Details of results of test or analysis with protocols of test applied

Date.................. Director

Central Drugs Laboratory or other authorised officer

• If opinion is required on any other matter, the paragraph should be suitably amended.

Drugs and Cosmetics Rules, 1945 177

FORMS 3-7 (Omitted)

1[FORM 8 (See rule 24)

Application for licence to import drugs (excluding those specified in Schedule X) to the Drugs and Cosmetics Rules, 1945 I/We* ......................................................... (full address with telephone number, fax number and e-mail address) hereby apply for a licence to import drugs specified below manufactured by M/s ........................................... (full address with telephone no, fax and e- mail no.). 2. Names of the drugs to be imported: (1) (2) (3) 3. I/We* ..................................................... enclose herewith an undertaking in Form 9 dated ............signed by the manufacturer as required by rule 24 of the Drugs and Cosmetics Rules, 1945. 4. I/We* ................................................... enclose herewith a copy of Registration Certificate concerning the drugs to be imported in India, issued under Form 41 of the rules, vide Registration Certificate No .....................dated .................. issued through M/s. ............................. (name and full address) ................................valid up to ................................ 5 I/We* .................................................... hold a valid wholesale licence for sale or distribution of drugs or valid licence to manufacture drugs, under the provisions of the Act and rules made thereunder. A copy of the said licence is enclosed.

6. A fee of ..................has been credited to Government under the Head of Account "0210-

Medical and Public Health, 04-Public Health, 104-Fees and Fines" under the Drugs and

Cosmetics Rules, 1945 - Central vide Challan No......................... dated ................(attached in

original)

Signature ....................... Name.............................. Designation ................... Seal/Stamp of Manufacturer's agent in India.

*Delete whichever is not applicable.] ___________________________________________________________________________________________ __________________________

² Subs. by G.S.R. 604(E) , dt. 24.8.2001.

1. Forms 3 to 7 omitted by Notfn. No. F. 1-16/57-D, dt. 15-6-1957.

1[FORM 8A (See rule 24) Application for licence to import drugs specified in Schedule X to the Drugs and Cosmetics Rules, 1945 I/We* ............................... (full address with telephone number, fax number and e-mail

2. Name of the drugs to be imported:

Drugs and Cosmetics Rules, 1945 178

(1) (2) (3)

3. I/We* ........................................ enclose herewith an undertaking in Form 9

dated...............signed by the manufacturer as required by rule 24 of the Drugs and Cosmetics Rules, 1945.

4. I/We* ........................................... enclose herewith a copy of Registration Certificate

concerning the drugs to be imported in India, issued under Form 41 of the rules, vide Registration Certificate No dated issued through M/s.

5. I/We* ............................. hold a valid wholesale licence for sale or distribution of drug or

licence to manufacture drugs, under the provisions of the Act and rules made thereunder. A copy of the said licence is enclosed.

6. A fee of ..........................has been credited to Government under the Head of Account

"0210 - Medical and Public Health, 04- Public Health, 104- Fees and Fines" under the

Drugs and Cosmetics Rules 1945 - Central vide Challan No ....................... dated .................

(attached in original). Signature ................................. Name ..................................... Designation............................. Seal/Stamp of Manufacturer's agent in India.]

¹ Subs. by G.S.R. 604(E), dt.24.8.2001.

*Delete whichever is not applicable. _____________________________________________________________________________

FORM 9 (See rule 24) Form of undertaking to accompany an application for an import licence

Whereas .............................. of............................. intends to apply for a licence under the

Drugs and Cosmetics Rules, 1945, for the import into India, of the drugs specified below manufactured by us, we.................................of................................hereby give this undertaking that for the duration of the said licence—

(1) the said applicant shall be our agent for the import of drugs into India;
(2) we shall comply with the conditions imposed on a licence by 1[rules 74 and 78] of the Drugs and Cosmetics Rules, 1945; (3)we declare that we are carrying on the manufacture of the drugs mentioned in this undertaking at the premises specified below, and we shall from time to time report any change of premises on which manufacture will be carried on and in cases where manufacture is carried on in more than one factory any change in the distribution of functions between the factories;
(4) we shall comply with the provisions of Part IX of the Drugs and Cosmetics Rules,

Drugs and Cosmetics Rules, 1945 179

1945;

(5) every drug manufactured by us for import under licence into India shall as regards strength, quality and purity conform with the provisions of Chapter III of the Drugs

and Cosmetics Act, 1940, and the Drugs and Cosmetics Rules, 1945;

(6) we shall comply with such further requirements, if any, as may be specified by Rules, by the Central Government under the Act and of which the licensing authority has given to the licensee not less than four months' notice. Names of drugs and classes of drugs Particulars of premises where manufacture is carried on. Date....................... 2[Signature, Name, Designation Seal/Stamp of manufacturer or on behalf of the manufacturer.] ________________________________________________________________________________________________________________________________________ 1[FORM 10 (See rules 23 and 27) Licence to import drugs (excluding those specified in Schedule X) to the Drugs and Cosmetic Rules, 1945

¹ Subs. by. G.S.R. 462(E), dt. 22.6.1982.

² Subs. by G.S.R. 604(E), dt. 24.8.2001.

Licence Number .............. Date... ..............

........................................................................................ (Name and full address of the importer)

address) and any other drugs manufactured by the said manufacturer as may from time to time be endorsed on this licence.

2. This licence shall be in force from ........................... to ............. unless it is sooner

suspended or cancelled under the said rules. 3. Names of drugs to be imported. Place : ..........

Date : .......... Licensing Authority

Seal/Stamp

• Delete whichever is not applicable. Conditions of Licence. 1. A photocopy of licence shall be displayed in a prominent place in a part of the premises, and the original licence shall be produced, whenever required. 2. Each batch of drug imported into India shall be accompanied with a detailed batch test report and a batch release certificate, duly signed and authenticated by the manufacturer with date of testing, date of release and the date of forwarding such reports. The imported batch of each drug shall be subjected to examination and testing as the licensing authority deems fit prior to its marketing. 3. The licensee shall be responsible for the business activities of the manufacturer in India along with the registration holder and his authorised agent. 4. The licensee shall inform the licensing authority forthwith in writing in the event of

Drugs and Cosmetics Rules, 1945 180

¹ Subs. by G.S.R. 604(E) ,dt. 24.8.2001.

any change in the constitution of the firm operating under the licence. Where any change in the constitution of the firm takes place, the current licence shall be deemed to be valid for a maximum period of three months from the date on which the change takes place unless, in the meantime, a fresh licence has been taken from the licensing authority in the name of the firm with the changed constitution. ___________________________________________________________________________________

1[FORM 10A (See rules 23 and 27)

Licence to import drugs specified in Schedule X to the Drugs and Cosmetics Rules, 1945

Licence Number ............................. Date.........................

...............................................................................................................(Name and full address of the importer) is hereby licensed to import into India during the period for which the licence is

in force, the drugs specified below, manufactured by M/s ...................................... (name and

full address) and any other drugs manufactured by the said manufacturer as may from time to time be endorsed on this licence.

2. This licence shall be in force from............................. to .......................... unless it is

sooner suspended or cancelled under the said rules.

3. N a m e s o f d r u g s t o b e i m p o r t e d .

Place:......................

Date: .....................

Licensing Authority Seal/Stamp. *Delete whichever is not applicable.

¹ Subs. by G.S.R. 604(E), dt. 24.8.2001.

Conditions of Licence 1. A photocopy of licence shall be displayed in a prominent place in a part of the premises, and the original licence shall be produced, whenever required. 2. Each batch of drug imported into India shall be accompanied with a detailed batch test report and a batch release certificate, duly signed and authenticated by the manufacturer with date of testing, date of release and the date of forwarding such reports. The imported batch of each drug shall be subjected to examination and testing as the licensing authority deems fit prior to its marketing. 3. The licensee shall be responsible for the business activities of the manufacturer in India along with the registration holder and his authorised agent. 4. The licensee shall inform the licensing authority forthwith in writing in the event of any change in the constitution of the firm operating under the licence. Where any change in the constitution of the firm takes place, the current licence shall be deemed to be valid for a maximum period of three months from the date on which the change takes place unless, in the meantime, a fresh licence has been taken from the licensing authority in the name of the firm with the changed constitution.] _______________________________________________________________________

Drugs and Cosmetics Rules, 1945 181

FORM 11 (See rule 33) Licence to import drugs for the purposes of examination, test or analysis

1 ..................of .......................... is hereby licensed to import from ................................ the

drugs specified below for the purposes of examination, test or analysis at ...............................or in such other places as the licensing authority may from time to time authorise. 2. This licence is subject to the conditions prescribed in the Rules under the Drugs and Cosmetics Act, 1940. 3. This licence shall, unless previously suspended or revoked, be in force for a period of

one year from the date specified below:–

Names of drugs Quantities which may be imported Date............................. Licensing Authority

1[FORM 11A (See rule 33A) Licence to import drugs by a Government Hospital or Autonomous Medical Institution for the treatment of patients

Licence No ................ Date...................

Dr. ........................................................... ...................................................Designation .................................................................................................................of ................................................................................................................... (Name of College/Hospital/Autonomous Institution)

is hereby licenced to import from M/s ..............................(name and full address) the drugs specified below for the purpose of treatment of patients for the disease (name of the disease) .................... at ............................. or in such other places as the licensing authority may from time to time authorise. 2. This licence shall, unless previously suspended or revoked, be in force for a period of one year from the date of issue specified above.

3. Names of drugs to be imported:

Names of drugs Quantity which may be imported

Place : ............ Date :.............

Drugs and Cosmetics Rules, 1945 182

¹ Subs. by G.S.R.. 604(E), dt. 24.8.2001.

Licensing Authority Seal / Stamp Conditions of Licence 1. The licence shall be displayed in the Office of the Medical Superintendent of Government Hospital / Head of Institution of Autonomous Medical Institution. 2. The licensee shall store the drugs imported under this licence under proper storage conditions. 3. The drugs imported under this licence shall be exclusively used for the treatment of patients, and a record shall be maintained in this regard, by a registered pharmacist giving the full name(s) and address(es) of the patients, diagnosis, dosage schedule, total quantity of drugs imported and issued, and shall be countersigned by the Medical Superintendent of the Government Hospital or Head of the Autonomous Medical Institution which shall be produced, on demand by an Inspector appointed under the Act.] ___________________________________________________________________________ FORM 12 (See rule 34) Application for licence to import drugs for purpose of examination, test or analysis

the purposes of examination, test or analysis at .............................. from ..........................and I undertake to comply with the conditions applicable to the licence.

1[A fee of rupees ...................... has been credited to Government under the head of

Account “0210-Medical and Public Health, 04-Public Health, 104-Fees and Fines” under the Drugs and Cosmetics Rules, 1945—Central vide Challan No.......dated.........(attached in original).]

Names of drugs and classes of drugs: Quantities:

Date.......... Signature.................

¹ Subs. by G.S.R. .604(E), dt. 24.8.2001.

______________________________________________________________________________________________________________________________________

1[FORM 12A (See rule 36, Second Proviso) Application for the issue of a permit to import small quantities of drugs for personal use

I, ......................................... resident of ..............................................................by

occupation................................................. hereby apply for a permit to import the drugs specified below for personal use from ....................................................................

I attach a prescription from a registered medical practitioner in regard to the need for the said drugs.

1. Added by S.O. 903, dt. 28.2.1976.

Drugs and Cosmetics Rules, 1945 183

1[FORM 12AA (See rule 34A) Application for licence to import small quantities of new drugs by a Government Hospital or Autonomous Medical Institution for the treatment of patients.

I, .................. ............... (name and designation) ............................... .................

of ....................................... (name of the Hospital/Autonomous Medical Institution) hereby apply for a licence to import small quantities of new drugs specified below for the purpose of treatment of patients for the disease ..................................................... (name of the disease)...... ... ............ at.....................................(name and place of the hospital) and I undertake to comply with the conditions applicable to the licence and other provisions of the Drugs and Cosmetics Act, 1940 and the rules made thereunder, from time to time. 1. A fee of rupees ............. has been credited to Government under the Head of Account "0210-Medical and Public Health, 04- Medical and Public Health, 104- Fees and Fines" under the Drugs and Cosmetics Rules, 1945 - Central vide Challan

No.................dated ...................... (attached in original).

2. Name of new drugs to be imported:

Name of drugs Quantity which may be imported

: Place: ........... Signature.......................... Date: ........... Name.............................. Seal/Stamp......................

Certificate Certified that the drugs specified above for import are urgently required for the

treatment of patients suffering from and that the said drug(s) is/are not available in India.

¹ Subs. by. G.S.R. 604(E), dt. 24.8.2001.

Autonomous Medical Institution Seal / Stamp.] _____________________________________________________________________________

FORM 12B (See rule 36, Second Proviso) Permit for the import of small quantities of drugs for personal use 1. ..............................of ............................................... is hereby permitted to import from......................................... the drugs specified below for personal use. 2. This permit is subject to the conditions prescribed in the Rules under the Drugs and

Drugs and Cosmetics Rules, 1945 184

Cosmetics Act, 1940. 3. This permit shall, unless previously suspended or revoked, be in force for a period of six months from date specified below.

Names of drugs Quantities which may be imported

Date................. Licensing Authority.

FORM 13 (See rule 46) Certificate of test or analysis by Government Analyst under section 25 (1) of the Drugs and Cosmetics Act, 1940

In the opinion of the undersigned the sample referred to above is of standard quality as defined in the Drugs and Cosmetics Act, 1940 and Rules thereunder is not of standard quality as defined in the Drugs and Cosmetics Act, 1940 and Rules thereunder for the reasons given below:-

Date................... Government Analyst.

¹ Subs. by G.S.R. 59(E), dt. 7.2.1995.

________________________________________________________________________________________________________________________

1[FORM 13A [See rule 163 (5)] Certificates of tests or analysis by Government Analyst under section 33H of the Drugs and Cosmetics Act, 1940

4. Date of receipt .................................................................

5. Names of ingredients purporting to have been used in the preparation of the sample.....

6. Condition of seals on the package ...................................................................... 7. Results of test or analysis ..............................................................

Date................... Government Analyst..

___________________________________________________________________________

1. Added by Notfn. No. F 1-23/67-D, dt. 2.2.1970.

Drugs and Cosmetics Rules, 1945 185

FORM 14A (See rule 47) Application from a purchaser for test or analysis of a drug under Section 26 of the Drugs and Cosmetics Act, 1940

1[7. A fee of rupees ............................................................vide Schedule B of the Drugs and

Cosmetics Rules, 1945, has been credited to Government under the head of account "080— Medical—Miscellaneous—Fees under the Drugs and Cosmetics Rules, 1945— Central/State"—vide treasury receipt attached.] I hereby declare that the drug being submitted for test was purchased by or for me. I further declare that the sample of the drug being sent for test or analysis is exactly as it was purchased and has not been tampered with in any way to reduce its potency.

Date.............................. Signed.... .......

_____________________________________________________________________________ 1. Added by Notfn. No. F. 1-3/51-D.S., dt. 15-10-1954

FORM 14-B (See rule 47) Certificate of test or analysis by Government Analyst under Section 26 of the Drugs and Cosmetics Act, 1940

4. Opinion of the Government Analyst—The sample referred to above is/is not of standard quality as defined in the Drugs and Cosmetics Act, 1940 and Rules thereunder.

Date................... Government Analyst.............

1[FORM 15 (See rules 54 and 145C) Order under section 22 (1)(c) of the Drugs and Cosmetics Act, 1940 requiring a person not to dispose of stock in his possession Whereas, I have reasons to believe that the stocks of drugs/cosmetics in your possession, detailed below contravene the provisions of section 18 of the Drugs and Cosmetics Act, 1940; Now, therefore, I hereby require you under clause (c) of sub-section (1) of section 22 of the said Act not to dispose of the said stock for a period of .................. days from the date of this order.

Drugs and Cosmetics Rules, 1945 186

Date..................... Inspector...............

Details of stock of drugs/ cosmetics

Date........................... Inspector...................]

___________________________________________________________________________________________________________________________

1. Amended by G.S.R. 1594, dt. 13-11-1976.

1[FORM 16 (See rules 55 and 145-B) Receipt for stock of drugs or cosmetics for record, register, document or material object seized under section 22 (1) (c) or (cc) of the Drugs and Cosmetics Act, 1940. The stock of drugs or cosmetics for records, registers, documents or material objects detailed below has / have this day been seized by me under the provisions of clause (c) or clause (cc) of sub-section (1) of section 22 of the Drugs and Cosmetics Act. 1940 (23 of 1940) from the premises of............................................ situated at............................................

Date......................... Inspector. .......................

Details of drugs, cosmetics, records, registers, documents or material objects seized.

Date........................... Inspector. ..........................]

¹ Subs. by. G.S.R. 926 , dt. 16-7-1977.

___________________________________________________________________________________________________________________________________

1[ FORM 17

(See rules 56 and 145A) Intimation to person from whom sample is taken To. I have this day taken from the premises of ............................... situated at............................................ samples of the drugs / cosmetics specified below for the purpose of test or analysis.

Date......................... Inspector. .......................

Details of samples taken

Date......................... Inspector. ................]

¹ Subs. by S.O. 2139, dt. 12.8.1972.

______________________________________________________________________________________________________________________________

1[FORM 17A (See rules 56A and 145AA) Receipt for samples of drugs or cosmetics taken where fair price tendered thereof under sub- section (I) of Section 23 of the Drugs and Cosmetics Act, 1940 is refused To ...................................

Details of Samples..............................

samples of drugs/cosmetics taken: And whereas, you have refused to accept the fair price tendered thereof.

Now, therefore, I give you the receipt as the fair price tendered for the samples of the drugs/cosmetics taken by me.

Date: ..................... Inspector ..... .....]

¹ Ins. by G.S.R. 292(E) , dt. 29.5.1977.

______________________________________________________________________________________________________________________ FORM 18 (See Rule 57) Memorandum to Government Analyst Serial No. of Memorandum ................................................................................... From: To The Government Analyst .............................. .............................. The portion of sample / container described below is sent herewith for test or analysis under the provisions of clause (i) of sub-section (4) of Section 23 of the Drugs and Cosmetics Act, 1940. The portion of sample/container has been marked by me with the following mark. Details of portion of sample or container with

1[name of drug/cosmetic] which it purports to contain—

Date..................... Inspector. ....................

¹ Subs. by G.S.R. 370(E), dt. 7.4.1994.

____________________________________________________________________________________________________________________

1[FORM 18A [See rule 163 (1)] Memorandum to Government Analyst Serial No. From : To The Government Analyst .............................. .............................. The portion of sample / container described below is sent herewith for test or analysis under the provisions of Section 33H of the Drugs and Cosmetics Act, 1940. The portion of sample / container has been marked by me with the following mark. Details of portion of sample or container with name of ingredients from which it is claimed to be made.

Date......................... Inspector. .........................

___________________________________________________________________________

1. Added by Notfn. No. F 1-23/67-D, dt. 2-2-1970.

FORM 19 [See rule 59 (2)] Application for grant or renewal of a

2[licence to sell, stock or exhibit or offer for sale, or distribute] of drugs other than those specified in Schedule

Drugs and Cosmetics Rules, 1945 188

1 . I / We* ...................................hereby apply for licence to sell by wholsesale/retail drugs

specified in Schedules C and C(1) excluding those specified in Schedule X *and/or drugs other than those specified in Schedules C, C(1) and X to the Drugs and Cosmetics Rules, 1945 *and also to operate a pharmacy on the premises situated at........................................................ 2. ** The sale and dispensing of drugs will be made under the personal supervision of the registered pharmacists namely:-

(Name) ..............................................(Qualification)................................................
(Name) ................................................(Qualification)................................................... 3. Categories of drugs to be sold .................................................................................... 4. *** Particulars of special storage accommodation .................................................................

5. A fee of rupees ......................................... has been credited to the Government account under

the head of account ......................................

Date........................................ Signature .........................]

• Delete whichever is not applicable. ** To be deleted if drugs will be sold only by wholesale. *** Required only if products requiring special storage are to be sold. ____________________________________________________________________________ FORM 19A [See rule 59 (2)] Application for the grant or renewal of a restricted 1[licence to sell, stock or exhibit or offer for sale, or distribute] drugs by retail by
• * * dealers who do not engage the services of a registered pharmacist

¹ Subs. by G.S.R. 462(E), dt. 22.6.1982.

² Subs. by G.S.R. 788(E), dt. 10.10.1985.

3[Drugs other than those specified in Schedule C, C1

• * *

and X] on the premises situated at .......................................................................

or (ii)

5[Drugs specified in Schedule C(1)] on the premises situated at

.....................

5[Drugs specified in Schedule C(1)] as vendor in the area........................ 2. Sales shall be restricted to such drugs as can be sold without the supervision of a

*4. Particulars of the storage accommodation for the storage of

5[Schedule C(1)] on the

premises referred to above. **5. The drugs for sale will be purchased from the following dealers and such other dealers as may be endorsed on the licence by the Licensing Authority from time to time. Name of the dealers........................................Licence No.................................... 6. A fee of rupees

• * * has been credited to Government under the head of + twenty account........................................................................................................................

Date............................... Signature ........................

Drugs and Cosmetics Rules, 1945 189

*Delete whichever is not required. **Applies only to an itinerant vendor. + Rupees five for itinerant vendors and

¹ Subs. by G.S.R. 788(E) ,dt. 10.10.1985.

applicant from a village or town having a population of 5000 or less, and rupees twenty for other restricted licence. ____________________________________________________________________________________________________________________________

³ Subs. by G.S.R. 462(E), dt. 22.6.1982.

2. The words “itinerants vendors and other” omitted by. G. S. R. 231(E) , dt. 4.6.1996.

⁵ Subs. by.G.S.R. 487(E) , dt. 2.7.1984.

4. The word “five” omitted by. G. S. R. 231(E) , dt. 4.6.1996.

1[FORM 19AA (See rule 62C) Application for grant or renewal of a

2[licence to sell, stock or exhibit or offer for sale by

2[licence to sell, stock or exhibit or offer for sale by wholesale, or distribute] drugs specified in Schedules C and C (1) and /or drugs other than those specified in Schedules C and C (1) from the vehicle bearing registration no._______________assigned under the Motor Vehicles Act, 1939.

2. Categories of drugs to be sold / distributed ___________________________

3. A fee of rupees ___________________________has been credited to Government under the head of account _________________________________ *4.Particulars of the storage accommodation for the storage of drugs specified in Schedules C and C (1) on the vehicle referred to above.

Date ______________________ Signature ____________

¹ Ins. by. Notfn.No.X.11013/7/76-DandMS, dt. 25.1.1979.

² Subs. by.G.S.R. 788(E), dt. 10.10.1985.

*Delete if not required. _____________________________________________________________________________

FORM 19B (See rule 67A) Application for

1[licence to sell, stock or exhibit or offer for sale, or distribute]

Homoeopathic medicines 1 . 1 / We* ....................... of................................. hereby apply for a licence to sell by *wholesale/*retail Homoeopathic medicines on the premises situated at ....................................... **2. The sale and dispensing of Homoeopathic medicines shall be made under the personal supervision of the following competent person in -charge. Name ..........................

3. A fee of rupees ................has been credited to Government under the head of

account.......................................................

Date......................... Signature ......................

¹ Subs. By G.S.R. 788(E), dt.10.10.1985.

*Delete whichever is not required. ** To be deleted if Homoeopathic medicines will be sold by wholesale. ________________________________________________________________________________________________________________________________

Drugs and Cosmetics Rules, 1945 190

1[FORM 19C [See rule 59(2)] Application for grant or renewal of a

2[licence to sell, stock, exhibit or offer for sale, or distribute] of drugs specified in Schedule .

1. I/We* ........................................ of................................hereby apply for a licence to

sell by *wholesale/*retail drugs specified in Schedule X to the Drugs and Cosmetics Rules, 1945. We operate a pharmacy on the premises, situated at ...................... 2. ** The sale and dispensing of drugs will be made under the personal supervision of the registered pharmacists mentioned below:-

(Name) ............................................... (Qualification)
(Name) ................................................(Qualification)

under the head of account....................................

Date ................ Signature ...........................

• Delete whichever is not applicable. ** To be deleted if drugs will be sold only by wholesale. ***Required only if products requiring special storage are to be sold.] ___________________________________________________________________________ FORM 20 [See rule 61(1)] 1[Licence to sell, stock or exhibit or offer for sale, or distribute] drugs by retail other than those specified in 2[Schedules C, C(1) and X]

¹ Subs. by G.S.R. 462(E), dt. 22.6.1982.

² Subs. by G.S.R. 788(E), dt. 10.10.1985.

1. ................................................ is hereby

1[licensed to sell, stock or exhibit or offer for sale, or distribute] by retail drugs other than those specified in

2[Schedules C, C (1) and X] of the Drugs and Cosmetics Rules 1945, *and to operate a pharmacy on the premises situated at.......................... subject to the conditions specified below and to provisions of the Drugs and Cosmetics Act, 1940 and the Rules thereunder.

2 The licence shall be in force from ........................................ to ...........................

3. Name (s) of registered pharmacist(s) in charge .................................................... 4. Categories of drugs..................................................

Date.................................... Licensing Authority ....... ..........

• Delete whichever is applicable Conditions of Licence 1. This licence shall be displayed in a prominent place in a part of the premises open to the public. 2. The licensee shall comply with the provisions of the Drugs and Cosmetics Act, 1940 and the Rules thereunder for the time being in force. 3. The licensee shall report to the Licensing Authority any change in the qualified staff in charge within one month of such change.

Drugs and Cosmetics Rules, 1945 191

¹ Subs. by G.S.R. 788(E), dt. 10.10.1985

² Subs. by.G.S.R. 462(E), dt. 22.6.1982

4. No drug shall be sold unless such drug is purchased under cash or credit memo from a duly licensed dealer or a duly licensed manufacturer. 5. The licensee shall inform the Licensing Authority in writing in the event of any change in the constitution of the firm operating under the licence. Where any change in the constitution of the firm takes place, the current licence shall be deemed to be valid for a maximum period of three months from the date on which the change takes place unless, in the meantime, a fresh licence has been taken from the Licensing Authority in the name of the firm with the changed constitution. ________________________________________________________________________

FORM 20A [See rule 61 (1)]

Restricted

1[Licence to sell, stock or exhibit or offer for sale, or distribute] drugs by retail other than those specified in

2[Schedules C, C (1) and X] for

• * * dealers who do not engage the

services of a registered pharmacist

1. ......................................is hereby

1[licensed to sell, stock or exhibit or offer for sale, or Distribute] on the premises situated at

• * * .......................the following drugs being drugs other than those specified in 2[Schedules C, C (1) and X] of the Drugs and Cosmetics Rules, 1945, subject to the conditions specified below and to the provisions of the Drugs and Cosmetics Act, 1940 and the Rules made thereunder. 2. The licence shall be in force from ........................................ to .......................... 3 The licensee can deal only in such drugs as can be sold without the supervision of qualified person under the Drugs and Cosmetics Rules, 1945.
• * * * *

Conditions of Licence 1. This licence shall be displayed in a prominent place in a part of the premises open to the public . 3

• * *. 2. The licensee shall comply with the provisions of the Drugs and Cosmetics Act, 1940 and the Rules thereunder for the time being in force. 3. No drug shall be sold unless such drug is purchased under a cash or credit memo from a duly licensed dealer or a duly licensed manufacturer. 4. The licensee shall inform the Licensing Authority in writing in the event of any change in the constitution of the firm operating under the licence. Where any change in the constitution of the firm takes place, the current licence shall be deemed to be valid for a maximum period of three months from the date on which the change takes place unless, in the meantime, a fresh licence has been taken from the Licensing Authority in the name of the firm with the changed constitution. ___________________________________________________________________________ 3. Omitted by G.S.R. 231 (E) , dt. 4.6.1996

¹ Subs. by.G.S.R. 788(E) , dt. 10.10.1985

² Subs. by G.S.R. 462(E)< dt. 22.6.1982.

4 Sl. No. 4 omitted by G.S.R. 504(E) dt. 18.7.2002.

Drugs and Cosmetics Rules, 1945 192

FORM 20B [See rule 61 (1)]

1[Licence to sell, stock or exhibit or offer for sale, or distribute] by wholesale, drugs other than those specified in

1[licensed to sell, stock or exhibit or offer for sale, or distribute] by wholesale drugs other than those specified in

1[Schedules C, C(1) and X] on the premises situated at ............... subject to the conditions specified below and to the provisions of the Drugs and Cosmetics Act, 1940, and the Rules thereunder. 2. The licence shall be in force from ................................to ...............................

3[3. The sale shall be made under the personal supervision of a competent person (Name of the competent person.)]

Date............................... Licence No..................

Licensing Authority. Conditions of Licence 1. This licence shall be displayed in a prominent place in part of the premises open to the public. 2. The licensee shall comply with the provisions of the Drugs and Cosmetics Act, 1940 and the Rules thereunder for the time being in force.

4[3 (i) No drug shall be sold unless such drug is purchased under a cash or credit

memo from a duly licensed dealer or a duly licensed manufacturer.

(ii) No sale of any drug shall be made to a person not holding the requisite 1[licence to sell, stock or exhibit for sale, or distribute] the drug. Provided that this condition shall not apply to the sale of any drug to—

(a) an officer or authority purchasing on behalf of Government, or
(b) a hospital, medical, educational or research institution or a registered medical practitioner for the purpose of supply to his patients, or 5[(c) a manufacturer of beverages, confectionery biscuits and other non-medicinal products, where such drugs are required for processing these products.] 4. The licensee shall inform the Licensing Authority in writing in the event of any change in the constitution of the firm operating under the licence. Where any change in the constitution of the firm takes place, the current licence shall be deemed to be valid for a maximum period of three months from the date on which the change takes place unless, in the meantime, a fresh licence has been taken from the Licensing Authority in the name of the firm with the changed constitution. ___________________________________________________________________________ 5. Added by Notfn. F. No. 1-113/69-D, dt. 23.12.1969. 1[FORM 20BB (See rule 62-D) 2[Licence to sell, stock or exhibit or offer for sale by wholesale, or distribute] drugs other than those specified in Schedule C and Schedule C (1) to the Drugs and Cosmetics Rules, 1945 from a motor vehicle 1. ............ is hereby

¹ Subs. by.G.S.R. 788(E), dt. 10.10.1985.

² Subs. by G.S.R. 462(E) , dt. 22.6.1982.

³ Ins. by G.S.R 681(E), dt. 6.6.1988.

⁴ Subs. by Notfn. No. F. 1/63/61-D, dt. 17.7.1963.

2[l i c e n s e d to sell, stock or exhibit or offer for sale by

wholesale, or distribute] drugs other than those specified in Schedule C and Schedule

C(1) from the vehicle bearing registration no.____________________ assigned under

under Motor Vehicles Act, 1939, subject to the conditions specified below and to the

Drugs and Cosmetics Rules, 1945 193

provisions of the Drugs and Cosmetics Act, 1940 and the Rules made thereunder.

Conditions of Licence

1. This licence shall be displayed in a prominent place on the vehicle.

2. The licensee shall comply with the provisions of the Drugs and Cosmetics Act, 1940 and the Rules made thereunder for the time being in force.

3 (i) No drugs shall be sold by wholesale or distributed unless such drug is purchased under

a cash or credit memo from a duly licensed dealer or a duly licensed manufacturer.

(ii) No sale by wholesale or distribution of any drug shall be made to a person not holding the requisite

2[l i c e n s e d to sell, stock or exhibit or offer for sale by wholesale,

or distribute] the drug: Provided that this condition shall not apply to the sale of any drug to— ( a) an officer or authority purchasing on behalf of the Government, or

(c) a manufacturer of beverages, confectionery, biscuits and other non-medical products, where such drugs are required for processing these products. 4. The licensee shall inform the Licensing Authority in writing in the event of change in the

constitution of the firm operating under the licence. Where any change in the constitution

of the firm takes place, the current licence shall be deemed to be valid for a maximum period of three months from the date on which the change takes place unless, in the meantime, a fresh licence has been taken from the Licensing Authority in the name of the firm with the changed constitution.

5. The licensee shall inform the Licensing Authority in writing in the event of any change in

ownership of the vehicle specified in this licence within seven days of such change. ____________________________________________________________________________ 1. Added by Notfn. No. X. 11013/7/76-D&MS, dt. 25.1.1979. 2.

Subs. by G.S.R .788(E), dt.10.10.1985

1[FORM 20-C (See rule 67-C)

2[Licence to sell, stock or exhibit or offer for sale, or distribute] Homoeopathic medicines by retail 1. ........................is hereby

2[l i c e n s e d to sell, stock or exhibit or offer for sale

by wholesale, or distribute]by retail Homoeopathic medicines on the premises situated at ......................subject to the conditions specified below and to the

Conditions of Licence 1. The licence shall be displayed in a prominent place in a part of the premises open to the public. 2. The licensee shall comply with the provisions applicable to homoeopathic

Drugs and Cosmetics Rules, 1945 194

medicines under the Drugs and Cosmetics Act, 1940 and the Rules made thereunder for the time being in force. 3. The licensee shall report to the Licensing Authority any change in the competent staff within one month of such change.

3[4. This licence authorises the sale of Homoeopathic medicines made from one earlier potency up to a quantity of 30 ml at a time.]

4[5. Where any change in the constitution of the firm takes place, a licensee shall inform the Licensing Authority in writing about the same and the current licence shall be valid only for a period of three months from the date on which the change takes place unless, in the meantime, name of the firm with the changed constitution.] ______________________________________________________________________________________________________________________________ 1. Added by Notfn. No. F. 1-35/64-D, dt. 18.8.1964. . Subs. by.G.S.R. 788(E), dt. 10.10.1985. 3. Added by.Notfn. No. F. 1-59/68-D, dt. 19.11.1969. 4. Added. G.S.R. 665, dt. 28-5-1977.

1[FORM 20D (See rule 67-C)

2[Licence to sell, stock or exhibit or offer for sale, or distribute] Homoeopathic medicines by wholesale

1. .......................................... is hereby

3[licensed to sell, stock or exhibit or offer for sale, or distribute] by wholesale Homoeopathic medicines on the premises situated at..........................................................subject to the conditions specified below and to the provisions of the Drugs and Cosmetics Act,. 1940 and the Rules made thereunder.

2. The licence shall be in force from.............................................to..........................

Date............................. Licensing Authority.

Conditions of Licence

1. This licence shall be displayed in a prominent place on the premises.

2. The licensee shall comply with the provisions as applicable to Homoeopathic medicines under the Drugs and Cosmetics Act, 1940 and the Rules made thereunder for the time being in force.

3. No sale of any drug shall be made to a person not holding the requisite

2[licensed to

sell, stock or exhibit or offer for sale, or distribute] the drug. Provided that this conditions

hall not apply to the sale of any drug to (a) an authority purchasing on behalf of Government, or (b) a hospital, medical, educational or research institute or a Homoeopathic medical practitioner for the purpose of supply to his patients.

² Subs. by.G.S.R. 788(E), dt. 10.10.1985.

3[4 The licensee shall inform the Licensing Authority in writing in the event of any change in the constitution of the firm operating under the licence and the current licence shall be valid only for a period of three months from the date on which the change takes place unless, in the meantime, a fresh licence has been taken from the Licensing Authority in the name of the firm with the changed constitution.] ____________________________________________________________________________ 1. Added by Notfn. No. F.1-35/64-D, dt. 18.8.1964.

3. Added by G.S.R. 665, date 28.5.1977.

1[FORM 20E (See rule 67 EE) Certificate of renewal of

2[Licence to sell, stock or exhibit or offer for sale, or distribute]

Homoeopathic medicines

1. Number of licence and date of issue ...............................................................

Drugs and Cosmetics Rules, 1945 195

Certified that licence no ..... in Form 20-C / 20D granted on the ..................... to................. for sale of Homoeopathic medicines at the premises situated at ...................has been renewed for a period from ......... to............................. 2. Name of competent persons in-charge.

Date........................... Licensing Authority.

______________________________________________________________________________________________________________________________

1. Added by Notfn. No. F. 1-14/67-D, dt. 3.2.1969.

Subs. by G.S.R. 788 (E), dt. 10.10.1985

1[FORM 20F [See rule 61(3)] Licence to sell, stock or exhibit for sale or distribute by retail drugs specified in Schedule X

1. ...........is hereby licensed to sell, stock or exhibit for sale or distribute by retail drugs specified in Schedule X to the Drugs and Cosmetics Rules, 1945 on the premises situated at.................................................................

2. Names of drugs.

3. This licence shall be in force from............ ................to........ ............... 4. Name(s) of registered pharmacist in-charge. 5. The licence is subject to the conditions stated below and the provisions of the

Drugs and Cosmetics Act, 1940 and the Rules made thereunder.

Date:.......................... Licence No........... Licensing Authrotity. Conditions of the licence.

1. This licence shall be displayed in a prominent place in a part of the premises open to the

public. 2. The licensee shall report to the licensing authority any change in the qualified staff in charge within one month of such change. 3. No drug shall be stocked or sold unless such drug has been purchased under cash/credit memo from a duly licensed dealer or a duly licensed manufacturer. 4. The licensee shall inform the licensing authority in writing in the event of any change in the constitution of the firm operating under the licence. Where any change in the constitution of the firm takes place, the current licence shall be deemed to be valid for a maximum period of three months from the date on which the change takes place unless in the meantime, a fresh licence has been taken from the licensing authority in the name of the firm with the changed constitution. .__________________________________________________________________________________ 1.

Ins. by G.S. R. 462(E) , dt. 22.6.1982.

1[FORM 20G [See rule 61(3)]

2[Licence to sell, stock or exhibit or offer for sale, or distribute] by wholesale drugs specified in Schedule X 1. ......................is hereby

2[licensed to sell, stock or exhibit or offer for sale, or distribute] by wholesale drugs specified in Schedule X to the Drugs and Cosmetics Rules,

3. This licence shall be in force from................. to............................. 4. The licence is subject to the conditions stated below and the provisions of the Drugs and Cosmetics Act, 1940 and the Rules made thereunder. Date:.......................... Licence No........... Licensing Authority. Conditions of the licence. 1. This licence shall be displayed in a prominent place in a part of the premises open to the public. 2. The licensee shall comply with the provisions of the Drugs and Cosmetics Act, 1940 and the rules made thereunder. 3. No drug shall be stocked or sold unless such drug has been purchased under a cash or credit memo from a duly licensed dealer or a duly licensed manufacturer. 4. The licensee shall forward to the licensing authority copies of the invoices of sales made to the retail dealers. 5. No sale of any drug by wholesale shall be made to a person not possessing the requisite

2[licence to sell, stock or exhibit or offer for sale, or distribute] drugs specified in Schedule X : Provided that this condition shall not apply to the sale of any drug to -

(a) an officer or authority purchasing on behalf of Government;
(b) a hospital, medical, educational or research institution, nursing home, Registered Medical Practitioner for the purpose of supply to its/his patients or manufacturer holding a licence in Form 25-E or 28-B to manufacture the drugs containing drugs included in Schedule X. 3[The licensee shall inform the licensing authority in writing in the event of any change in the constitution of the firm operating under the licence, where any change in the constitution of the firm takes place, the current licence shall be deemed to be valid for a maximum period of three months from the date on which the change takes place unless in the meantime, a fresh licence has been taken from the licensing authority in the name of the firm with the changed constitution.]] ________________________________________________________________________ 1.

² Ins. by. G.S..R. 788(E) , dt. 10.10.1985.

³ Ins. by 370(E), dt. 7.4.1994.

Ins. by. G..S. R. 462(E) , dt. 22.6.1982.

FORM 21 [See rule 61 (2)]

1[Licence to sell, stock or exhibit or offer for sale,or distribute] by retail drugs specified in Schedules C and C (1)

2[excluding those specified in Schedule X]

3[1. ....................................................... is hereby

1[licensed to sell, stock or exhibit or offer for sale, or distribute] by retail the following categories of drugs specified in Schedules C and C (1)

2[excluding those specified in Schedule X] to the Drugs and Cosmetics Rules, 1945 and to operate a pharmacy on the premises situated at ..................... subject to the conditions specified below and to the provisions of the Drugs and Cosmetics Act, 1940 and the Rules thereunder.

Drugs and Cosmetics Rules, 1945 197

3[4. Categories of drugs .......................................................................]

Date........................................ Licensing Authorit.y

Licence No ....................... *Delete if not applicable. Conditions of Licence 1. This licence shall be displayed in a prominent place in a part of the premises open to the public. 2. The licensee shall report to the Licensing Authority any change in the qualified staff in charge within one month of such change.

• * * * * 4. If the licensee wants to sell, stock or exhibit for sale, or distribute, during the currency of the licence, additional categories of drugs listed in Schedules C and C(I) 2[excluding those specified in Schedule X] but not included in this licence, he should apply to the Licensing Authority for the necessary permission. This licence will be deemed to extend to the categories of drugs in respect of which such permission is given. This permission shall be endorsed on the licence by the Licensing Authority. 6[5 No drug shall be sold unless such drug is purchased under a cash or credit memo from a duly licensed dealer or a duly licensed manufacturer.] 6. The licensee shall inform the Licensing Authority in writing in the event of any change in the constitution of the firm operating under the licence. Where any change in the constitution of the firm takes place, the current licence shall be deemed to be valid for a maximum period of three months from the date on which the change takes place, unless in the meantime, a fresh licence has been taken from the Licensing Authority in the name of the firm with the changed constitution. __________________________________________________________________________

¹ Subs. by G.S.R.788(E), dt. 10.10.1985.

² Subs. by G.S.R. 462(E), dt. 22.6.1982

⁵ Omitted by. G.S.R. 17(E) , dt. 7.1.1986.

FORM 21A [See rule 61 (2)]

1[Licence to sell, stock or exhibit or offer for sale, or distribute] by retail drugs specified in

2[Schedule C (1)]

3[excluding those specified in Schedule X]

• * * for dealers who do not engage the services of a registered pharmacist 1. ........................is hereby 1[licensed to sell, stock or exhibit or offer for sale, or distribute] by retail on the premises situated at
• * * the following drugs being drugs specified in 2[Schedule C (1)] 3[excluding those specified in Schedule X] to the Drugs and Cosmetics Rules, 1945, subject to the conditions specified below and to the provisions of the Drugs and Cosmetics Act, 1940 and the Rules thereunder. 2. The licence will be in force from......................................... .

3. Particulars of

2[Schedule C (1)]

3[excluding those specified in Schedule X] drugs to be sold.

• * * * * Name of dealer(s)................... Licence No...........

Date............................. Licensing Authority

Drugs and Cosmetics Rules, 1945 198

Conditions of Licence. 1. This licence shall be displayed in a prominent and conspicuous place in a part of the premises open to the public

• * *.
• * * * * 3. The licensee shall deal only in such drugs as can be sold without the supervision of a "registered pharmacist" as defined in the Explanation to sub-rule (15) of rule 65 of the Drugs and Cosmetics Rules, 1945. 4. No drug shall be sold unless such drug is purchased under cash or credit memo from duly licensed manufacturer. 5. The licensee shall inform the Licensing Authority in writing in the event of any change in the constitution of the firm operating under the licence. Where any change in the constitution of the firm takes place, the current licence shall be deemed to be valid for a maximum period of three months from the date on which the change takes place unless, in the meantime, a fresh licence has been taken from the Licensing Authority in the name of the firm with the changed constitution. _________________________________________________________________________

1 Subs. by G.S.R.788(E), dt. 10.10.1985.

³ Ins. by G.S.R. 462(E), dt. 22.6.1982.

⁴ Omitted by G.S.R. 231 (E), dt. 4.6.1996

FORM 21B [See rule 61(2)]

1[Licence to sell, stock or exhibit or offer for sale, or distribute] by wholesale drugs specified in Schedules C and C (1)

2[excluding those specified in Schedule X

1. .....................is hereby

1[licensed to sell, stock or exhibit or offer for sale, or

distribute] by wholesale on the premises situated at the following categories of drugs specified

in Schedule. C and C (1)

2[excluding those specified in Schedule X] to the Drugs and Cosmetics Rules, 1945. Categories of drugs 2. This licence shall be in force from................................. to............................

3[2A. The sale shall be made under the personal supervision of a competent person. (Name of the competent person)]. 3. This licence is subject to the conditions stated below and to the provisions of the Drugs and Cosmetics Act, 1940 and the rules thereunder. Licence No ...........

Date............................ Licensing Authority.

Conditions of Licence 1. This licence shall be displayed in a prominent place in a part of the premises open to the public.

• * * * * 3. If the licensee wants to sell, stock or exhibit for sale or distribute during the currency of the licence additional categories of drugs listed in Schedules C and C (1) 2[excluding those specified in Schedule X] but not included in this licence, he should apply to the Licensing Authority for the necessary permission. This licence will be deemed to extend to the categories of drugs in respect of which such permission is given. This permission shall be endorsed on the licence by the

Drugs and Cosmetics Rules, 1945 199

Licensing Authority.

5[4. (i) No drug shall be sold unless such drug is purchased under a cash or credit memo

from a duly licensed dealer or a duly licensed manufacturer.

(ii) No sale of any drug shall be made for purposes of resale to a person not holding the requisite licence to sell, stock or exhibit for sale or distribute the drug: Provided that this condition shall not apply to the sale of any drug to —

(a) an officer or authority purchasing on behalf of Government, or
(b) a hospital, medical, educational or research institute or a registered medical practitioner for the purpose of supply to his patients, or 6[(c) a manufacturer of hydrogenated vegetable oils, beverages, confectionary and other non-medicinal products, where such drugs are required for processing these products.]
- • * * * * 6. The licensee shall inform the Licensing Authority in writing in the event of any change in the constitution of the firm operating under the licence. Where any change in the constitution of the firm takes place, the current licence shall be deemed to be valid for a maximum period of three months from the date on which the change takes place unless, in the meantime, a fresh licence has been taken from Licensing Authority in the name of the firm with the changed constitution. _________________________________________________________________________ 1 Subs. by. G.S.R.788(E), dt. 10.10.1985. 4. Omitted by.G.S.R. 17(E), dt. 7.1.1980 5 Added by. Notfn. No. F. 1-63/61 -D, dt. 17.7.1963. 6.Added by Notfn. No. F. 1-113/69-D, dt. 23.12.1969. 7. Condition 5 omitted by S.O. 289, dt 20.12.1973 (w.e.f. 3.2.1973) FORM 21BB [See Rule 62-D] Licence to sell by wholesale or to distribute drugs specified in Schedule C and Schedule C (1) to the Drugs and Cosmetics Rules, 1945 from a motor vehicle.

² Subs. by.G.S.R.462(E), dt. 22.6.1982

³ Ins. by.G.S.R. 681(E), dt. 6.6.1988.

..................................... assigned under Motor Vehicles Act, 1939, subject to the conditions specified below and to the provisions of the Drugs and Cosmetics Act, 1940 and the Rules made thereunder.

Conditions of licence

the precautions as are published by the Licensing Authority from time to time in the

Official Gazette have been observed throughout the period during which it has been in the

possession of the licensee. 3. If the licensee wants to sell by wholesale or distribute during the currency of the licence, additional categories of drugs listed in Schedules C and C (1) not included

Drugs and Cosmetics Rules, 1945 200

in this licence, he shall apply to the Licensing Authority for necessary permission. This licence shall be deemed to extend to the categories of drugs in respect of which such permission is given. This shall be endorsed on the licence by the Licensing Authority. 4. (i) No drugs shall be sold by wholesale or distributed unless such drug is purchased under a cash or credit memo from a duly licensed manufacturer.

(ii) No sale for wholesale or distribution of any drug shall be made for the purpose of resale to a person, not holding the requisite licence to sell, stock or exhibit for sale or distribute the drug: Provided that this condition shall not apply to the sale of any drug to—

(a) an officer or authority purchasing on behalf of the Government, or
(b) a hospital, medical, educational or research institution or a registered medical practitioner for the purpose of supply to his patients, or
(c) a manufactures of hydrogenated vegetable oils, beverages, confectionery and other non-medical products, where such drugs are required for processing their products. 5. The licensee shall inform the Licensing Authority in writing in the event of any change in the constitution of the firm operating under the licence. Where any change in the constitution of the firm takes place, the current licence shall be deemed to be valid for a maximum period of three months from the date on which the change takes place unless, in the meantime, a fresh licence has been taken from the Licensing Authority in the name of the firm with the changed constitution. 6. The licensee shall inform the Licensing Authority in writing in the event of any change in the ownership of the vehicle specified in this licence within seven days of such change. _____________________________________________________________________

(See rule 63A)

Certificate of renewal of

1[licence to sell, stock or exhibit or offer for sale, or distribute] drugs Number of licence and date of issue........................................................................ 1. Certified that licence No ......................... in

2[Form 20, 20A, 20-B, 20-F, 20G, 21, 21A or 21B], granted on the.....................to ................ for sale of the following drugs at the premises situated at................... has been renewed for a period from ............................to ............

¹ Subs. by G.S.R. 788(E),dt. 10.10.1985.

² Subs. by .S.R. 462(E),dt. 22.6.1982.

______________________________________________________________________________

FORM 21CC (See rule 63B) Certificate of renewal of

1[licence to sell, stock or exhibit or offer for sale by wholesale, or distribute] drugs from a motor vehicle Number of licence and date of issue....................................................................... 1. Certified that licence no...................in Form 20-BB or Form 21-BB granted on the ..................................to..................................................for sale by wholesale or

Drugs and Cosmetics Rules, 1945 201

distribution of the following drugs from the vehicle bearing registration No..................................... assigned under the Motor Vehicles Act, 1939 has been renewed for a period from...................................to ................................................

2. Categories of the drugs:

............................ ............................

Date................. Licensing Authority.

¹ Subs. by G.S.R. 788(E), dt.10.10.1985.

____________________________________________________________________________

FORM 22 (See rule 67) (Omitted by S.O. 289, dt. 20.12.1972) FORM 23 (See rule 67) (Omitted by S.O. 289, dt. 20.12.1972) FORM 24 (See rule 69) Application for the grant of or renewal of a

1[licence to manufacture for sale or for distribution]

of drugs other than those specified in

2[Schedules C and C (1) and X]

following drugs being drugs other than those specified in

2[Schedules C and C (1) and X] of the Drugs and Cosmetics Rules, 1945. 2. Names of drugs categorized according to Schedule M. 3. Names, qualifications and experience of technical staff employed for manufacture and testing.

4. A fee of rupees ...................................................... has been credited to Government

under the head of account .......................................................................

Date.................................... Signature ....................

² Subs. by G.S.R. 462(E), dt. 22.6.1982.

Note: The application should be accompanied by a plan of the premises. ______________________________________________________________________________________________________________________________________ 1. Subs. by. G.S.R. 788(E), dt. 10.10.1985.

FORM 24A (See rule 69A) Application for grant or renewal of a loan

1[licence to manufacture for sale or for distribution] of drugs other than those specified in

for the grant / renewal of a loan licence to manufacture on the premises situated

at................................................................... C /o§ ................................................ the under-

mentioned drugs, other than those specified in

2[Schedules C and C (1) and X] to the Drugs and Cosmetics Rules. Names of drugs (each substance to be separately specified).

Drugs and Cosmetics Rules, 1945 202

2. The names, qualifications and experience of the expert staff actually connected with the manufacture and testing of the specified products in manufacturing premises.

3. I/We enclose–

(a) A true copy of a letter from me/us to the manufacturing concern whose manufacturing capacity is intended to be utilized by me/us.
(b) A true copy of a letter from the manufacturing concern that they agree to lend the services of their expert staff, equipment and premises for the manufacture of each item required by me/us and that they will analyse every batch of finished product and maintain the registers of raw materials, finished products and reports of analysis separately in this behalf.
(c) Specimens of labels, cartons of the products proposed to be manufactured. 4. A fee of rupees ........................................................................has been credited to Government under the head of account ....................................................................

Date...................................................... Signature .............................

• Enter here the name of the proprietor, partners of Managing Director as the case may be. #Enter here the name of the applicant firm and the address of the principal place of business. § Enter here the name and address of the manufacturing concern where the manufacture will be actually carried out and also the Licence number under which the latter operates. __________________________________________________________________________________ FORM 24B (See rule 69) Application for grant or renewal of licence to repack for sale or distribution of drugs, being drugs other than those specified in Schedules C and C (1) 1[excluding those specified in Schedule X] 1 . 1 / We ..................of............................hereby apply for grant/renewal of a licence to repack the following drugs at the premises situated at............... 2. Names of the drugs to be repacked ....................................................................... ....

¹ Subs. by G.S.R. 788(E), dt. 10.10.1985.

² Subs. by G.S.R. 462(E), dt. 22.6.1982.

¹ Subs. by G.S.R. 462(E), dt. 22.6.1982.

NOTE :—The application shall be accompanied by a plan of the premises. _________________________________________________________________________

1[FORM 24C (See rule 85B)

Application for the grant or renewal of a

2[licence to manufacture for sale or for distribution of] Homoeopathic medicines or a licence to manufacture potentised preparations from back potencies by licensees holding licence in Form 20-C

Drugs and Cosmetics Rules, 1945 203

3[1. I / We* ....................................... of ........................................ holder of licence

no ....................................................... in Form 20-C hereby apply for the grant/renewal of licence to manufacture the undermentioned Homoeopathic mother tinctures/potentised preparations on the premises situated at.............................. ........................................ Name of the Homoeopathic preparations .................................................. ...................... ....

(E a c h i t e m t o b e separately specified)].

2. Names, qualifications and experience of technical staff employed for manufacture and testing of Homoeopathic medicines. 3. A fee of rupees ......................................... has been credited to Government under head of account...............................................................................................................

Date..................................... Signature...............................

Note 1. Delete whichever portion is not applicable.

2. The application should be accompanied by a plan of the premises. _______________________________________________________________________

² Subs. by. G.S.R.788(E) dt. 10.10.1985.

³ Subs. by. G.S.R. 13(E) dt. 7.1.1983.

1. Amended by Notfn. No. F. 1-598-D, dt. 19.11.1969

1[FORM 24D (See rule 153) Application for the grant / renewal of a licence to manufacture for sale of Ayurvedic/ Siddha or Unani drugs

1 . I / W e ........................................... of.....................................................hereby apply for the

grant / renewal of a licence to manufacture Ayurvedic (including Siddha) or Unani drugs on the premises situated at.......................................................... .................................. 2. Names of drugs to be manufactured (with details) 3. Names, qualifications and experience of technical staff employed for manufacture and testing of Ayurvedic (including Siddha) or Unani drugs ............................................. 4. A fee of rupees ............................... has been credited to the Government under the head of account .................................... and the relevant Treasury Challan is enclosed herewith.

Date............................................ Signature......................................

(applicant) Note—The application should be accompanied by a Plan of the premises.] ______________________________________________________________________________________________________________________________

1. Added by Notfn. No. 1-23/67-D,dt. 2.2.1970.

1[FORM 24E

(See rule 154A)

Application for grant or renewal of a loan licence to manufacture for sale Ayurvedic (including Siddha) or Unani Drugs

1. I / We* ...........................................................................of**................................ hereby

apply for the grant / renewal of a loan licence to manufacture Ayurvedic (including Siddha) or

Unani Drugs on the premises situated at.....................................................................

Drugs and Cosmetics Rules, 1945 204

C/o*** ............................................................................................................................ 2. Names of drugs to be manufactured (with details). 3. The names, qualifications and experience of technical staff actually connected with the manufacture and testing of Ayurvedic (including Siddha) or Unani drugs in the manufacturing premises. 4. I / We* enclose,

(a) A true copy of a letter from me/us to the manufacturing concern whose manufacturing capacity is intended to be utilized by me / us.
(b) A true copy of a letter from the manufacturing concern that they agree to lend the services of their competent technical staff, equipment and premises for the manufacture of each item required by me/us and that they shall maintain the registers of raw materials and finished products separately in this behalf.
(c) Specimen of labels, cartons of the drugs proposed to be manufactured. 5. A fee of Rs ...................................................... has been credited to Government under the head of account .................................... and the relevant Treasury Challan is enclosed herewith.

Date ...................................... Signature ...................... .........]

(applicant)

• Enter here the name of the proprietor, partners or Managing Director as the case may be. **Enter here the name of the applicant firm and the address of the principal place of business. *** Enter here the name and address of the manufacturing concern where the manufacture will be actually carried out and also the licence number under which the letter operates. ______________________________________________________________________

1. Added by G.S.R. 376 (E), dt. 20.7.1978.

1[FORM 24F (See rule 69) Application for the grant or renewal of a

2[licence to manufacture for sale or for distribution of] drugs specified in Schedule X and not specified in Schedules C and C(1)

1. I/We ...................... of ....................................hereby apply for the grant/renewal

of licence to manufacture on premises situated at ............................ the undermentioned drugs, specified in Schedule X to the Drugs and Cosmetics Rules, 1945. 2. Names of drugs. 3. Names, qualifications and experience of technical staff employed for manufacture and testing. 4. A fee of rupees...... has been credited to Government account under the head of account.................................................... Signature ................ ..........

Date:.......... Designation ........................]

¹ Subs. by .G.S.R. 462(E) ,dt. 22.6.1982.

² Subs. by G.S.R. 788(E) dt. 10.10.1985.

_____________________________________________________________________________

(See rule 70)

1[Licence to manufacture for sale or for distribution of] drugs other than those specified in

2[Schedules C and C(1) and X]

Number of Licence and date of issue ................................................................ 1 ........................................................................ is hereby licensed to manufacture the following categories of drugs being drugs other than those specified in

2[Schedules C

and C (1) and X] to the Drugs and Cosmetics Rules, 1945, on the premises situated at.................................................................................under the direction and supervision of the following

3[competent technical staff]:

(a)

2[Competent technical staff].(Names)...................................................

(b) Names of Drugs (each item to be separately specified)......................................

2. The licence authorises the sale by way of wholesale dealing and storage for sale by the

licensee of the drugs manufactured under the licence, subject to the conditions applicable to licence for sale.

3. The licence shall be in force from................................................ to ...................

4. The licence is subject to the conditions stated below and to such other conditions as may be specified in the Rules for the time being in force under the Drugs and Cosmetics Act, 1940.

¹ Subs. by. G.S.R. 788(E) ,dt. 10.10.1985

² Subs. by G.S.R. 462(E), dt. 22.6.1982.

³ Subs. by G.S.R. 231(E), dt. 4.6..1996.

4[Date ..................................... Signature ............ Designation .......... *Licensing Authority_____________ *Central Licence Appoving Authority.] *Delete whichever is not applicable. Conditions of Licence 1. This licence and any certificate of renewal in force shall be kept on the approved premises and shall be produced at the request of an Inspector appointed under the Drugs and Cosmetics Act, 1940. 2. Any change in the expert staff named in the licence shall be forthwith reported to the Licensing Authority. 3. If the licensee wants to manufacture for sale additional items of drugs not included above he should apply to the Licensing Authority for the necessary endorsement as provided in Rule 69(5). This licence will be deemed to extend to the categories so endorsed. 4. The licensee shall inform the Licensing Authority in writing in the event of any change in the constitution of the firm operating under the licence. Where any change in the constitution of the firm takes place, the current licence shall be deemed to be valid for a maximum period of three months from the date on which the change takes place unless, in the meantime, a fresh licence has been taken from the Licensing Authority in the name of the firm with the changed constitution. ____________________________________________________________________________

4 Subs. by G.S.R. 923(E), dt. 14.12.1992.

Drugs and Cosmetics Rules, 1945 206

FORM 25A (See rule 70A) Loan

1[licence to manufacture for sale or for distribution of] drugs other than those specified In

2[Schedules C and C (1) and X]

1. Number of licence and date of issue ............................................................

2..................................................... of ................................. is hereby granted a loan licence to manufacture the following drugs other than those specified in

2[Schedules C and C(1)

and X] to the Drugs and Cosmetics Rules, 1945, on the premises

situated at C/o under the direction and supervision of the following

2[competent technical

staff]: (a)

2[competent technical staff]. (Names):.........................

(c) Names of drugs .................................. 3. The licence authorises the sale by way of wholesale dealing and storage for sale by the licensee of the drugs manufactured under the licence subject to the conditions applicable to licences for sale. 4. The licence is subject to the conditions stated below and to such other conditions as may be specified in the Rules for the time being in force under the Drugs and Cosmetics Act, 1940.

Date............................... Signature ... .........

Designation.. ..... Conditions of Licence 1. This licence and any certificate of renewal in force shall be kept on the approved premises and shall be produced at the request of an Inspector appointed under the Drugs and Cosmetics Act, 1940. 2. Any change in the

¹ Subs. by G.S.R. 788(E) , dt.10.10.1985.

² Subs. by G.S.R. 462(E), dt. 22.6.1982.

³ Subs. by. G.S.R. 231(E) ,dt. 4.6.1996.

3[competent technical staff] named in the licence shall be forthwith reported to the Licensing Authority. 3. If the licensee wants to undertake during the currency of the licence the manufacture for of sale additional drugs he should apply to the Licensing Authority for the necessary endorsement to the licence as provided in Rule 69-A. This licence will be deemed to extend to the drugs so endorsed. 4. The licensee shall inform the Licensing Authority in writing in the event of any change in the constitution of the firm operating under the licence. Where any change in the constitution of the firm takes place, the current licence shall be deemed to be valid for a maximum period of three months from the date on which the change takes place unless, in the meantime, a fresh licence has been taken from the Licensing Authority in the name of the firm with the changed constitution. _________________________________________________________________________________________________________________________

1[ FORM 25B

(See rule 70) Licence to repack for sale or distribution of drugs being drugs other than those specified in Schedules C and C (1)

2[excluding those specified in Schedule X] Number of licence and date of issue.

1. ........ ................................... of .....................................is hereby granted a licence to

repack the following drugs for sale or distribution on the premises situated at................................. under the supervision of the following competent staff.

Drugs and Cosmetics Rules, 1945 207

(a) Names of drugs to be repacked.
(b) Names of competent staff.

2. The licence shall be in force from ......................................... to............................

3. The licence authorises the sale by way of wholesale dealing by the licensee and storage for sale by the licensee of the drugs repacked under the licence subject to conditions applicable to licences for sale. 4. The licence is subject to the conditions stated below and to such other conditions as may be specified in the Rules for the time being in force under the Drugs and Cosmetics Act, 1940.

Date...................................... Signature ... ..............

Conditions of Licence 1. This licence and any certificate of renewal in force shall be kept on the approved premises and shall be produced at the request of an Inspector appointed under the Drugs and Cosmetics Act, 1940. 2. Any change in the expert staff named in the licence shall be forthwith reported to the Licensing Authority. 3. If the licensee wants to repack for sale or distribution additional items he should apply to the Licensing Authority for the necessary endorsement to this licence. This licence will be deemed to extend to only those items so endorsed. 4. The drugs repacked under this licence shall bear on their label, apart from other particulars required by these Rules, the name and address of the licensee and the number of the licence under which the drug is repacked preceded by the words "Rpg. Lic. No.". 5. The licensee shall inform the Licensing Authority in writing in the event of any change in the constitution of the firm operating under the licence. Where any change in the constitution of the firm takes place, the current licence shall be deemed to be valid for a maximum period of three months from the date on which the change takes place unless, in the meantime, a fresh licence has been taken from the Licensing Authority in the name of the firm with the changed constitution. _______________________________________________________________________________________________________________________

² Subs. by G.S.R. 462(E), dt. 22.6.1992.

1. Added by Notfn. No. F. 1-22/59-D, dt. 9-4-1960.

FORM 25C (See rule 85-D)

1[Licence to manufacture for sale or for distribution of] Homoeopathic medicines Number of Licence and date of issue .....................................................................

1[*1. .................... of.................... who holds a licence in Form 20-C is hereby licensed to manufacture undermentioned Homoeopathic Mother Tinctures/ potentised and other preparations on the premises situated at ....under the direction and supervision of the following technical staff:

Names of the Homoeopathic preparations. (Each item to be separately specified).

Names of the Technical Staff.................................................... ]

2. The licence shall be in force from ............................................ to ...................

3. The licence is subject to the conditions stated below and to such other conditions as may be specified in the Rules for the time being in force under the Drugs and Cosmetics Act, 1940.

Drugs and Cosmetics Rules, 1945 208

Date...................................... Signature.......

Designation....

3[3. The licensee shall inform the Licensing Authority in writing in the event of any change in the constitution of the firm operating under the licence. Where any change in the constitution of the firm takes place, the current licence shall be deemed to be valid for a maximum period of three months from the date on which the change takes place unless, in the meantime, a fresh licence has been taken from the Licensing Authority in the name of the firm with the changed constitution.]

*Delete the words “who holds a licence in Form 20C” in case this is not applicable.

¹ Subs. by.. G.S.R.788(E) , dt. 10.10.1985.

² Subs. by. G.S.R. 13(E) , dt. 7.1.1983.

___________________________________________________________________________________________________________________________ 3.

Added by S.O. 903, dt. 28.2.1976.

1[FORM 25D (See rule 154) Licence to manufacture for sale of Ayurvedic (including Siddha) or Unani drugs

No. of Licence.....................................................................

1. .... ..................................... is / are hereby licensed to manufacture the following

Ayurvedic (including Siddha) or Unani drugs on the premises situated at.................................................................................................. under the direction and supervision of the following technical staff: —

(a) Technical staff (Names)
(b) Names of drugs (each item to be separately specified). 2. The licence shall be in force from .............................................. to ................... 3. The licence is subject to the conditions stated below and to such other conditions as may be specified in the Rules for the time being in force under the Drugs and Cosmetics Act, 1940.

Date: ................ Signature ...............

Designation ............ Conditions of Licence 1. This licence and any certificate of renewal in force shall be kept on the approved premises and shall be produced at the request of an Inspector appointed under the Drugs and Cosmetics Act, 1940. 2. Any change in the expert staff named in the licence shall be forthwith reported to the Licensing Authority. 3. This licence shall be deemed to extend to such additional items as the licensee may intimate to the Licensing Authority from time to time, and as may be endorsed by the Licensing Authority. 4. The licensee shall inform the Licensing Authority in writing in the event of any change in the constitution of the firm operating under the licence. Where any change in the constitution of the firm takes place, the current licence shall be

Drugs and Cosmetics Rules, 1945 209

deemed to be valid for a maximum period of three months from the date on which the change takes place unless, in the meantime, a fresh licence has been taken from the Licensing Authority in the name of the firm with the changed constitution. ___________________________________________________________________________________________________________________________ 1. Added by Notfn. No. 1-23/67 -D, dt. 2-2-1970.

1[FORM 25E (See rule 154A) Loan Licence to manufacture for sale Ayurvedic (including Siddha) or Unani Drugs

loan licence to manufacture for sale Ayurvedic (including Siddha) or Unani drugs, on the premises situated at .................................................... C/o.....................................................under the direction and supervision of the following expert technical staff:

(a) Technical staff (Names).....................................
(b) Names of drugs (each item to be separately specified) 3. The licence shall be in force from .................................... to....................................... 4. The licence is subject to the conditions stated below and to such other conditions as may be specified in the Rules for the time being in force under the Drugs and Cosmetics Act, 1940. Date of Issue................................................. Signature .................... Designation ................. Conditions of Licence 1. This licence and any certificate of renewal in force shall be kept on the approved premises and shall be produced at the request of an Inspector appointed under the Drugs and Cosmetics Act, 1940. 2. Any change in the technical staff named in the licence shall be forthwith reported to the Licensing Authority. 3. This licence shall be deemed to extend to such additional items as the licensee may intimate to the Licensing Authority from time to time, and as may be endorsed by the Licensing Authority. 4. The licensee shall inform the Licensing Authority in writing in the event of any change in the constitution of the firm operating under the licence. Where any change in the constitution of the firm takes place, the current licence shall be deemed to be valid for a maximum period of three months from the date on which the change takes place unless, in the meantime, a fresh licence has been taken from the Licensing Authority in the name of the firm with the changed constitution. ______________________________________________________________________

1. Added by G.S.R. 376 (E), dt. 20.7.1978

1[FORM 25F (See rule 70)

2[Licence to manufacture for sale or for distribution of] drugs specified in Schedule X and not specified in Schedules C and C(I) 1. ...................................................of.......................is hereby licensed to manufacture at the premises situated at.................................the following drugs specified in Schedule X to the Drugs and Cosmetics Rules, 1945.

Drugs and Cosmetics Rules, 1945 210

2. Names of drugs. 3. Names of approved

3[competent technical staff] 4. The licence authorises the sale by way of wholesale dealing and storage for sale by the licensee of the drugs manufactured under the licence subject to the conditions applicable to licence for sale. 5. The licence shall be in force ................... to....................................

6. The licence is subject to conditions stated below and to other conditions as may

be specified in the rules for the time being in force under the Drugs and Cosmetics Act, 1940.

4[Date ........................... Signature.............................

Licence No ..................... Designation......................... ______________*Licensing Authority Central Licence Approving Authority.] *Delete whichever portion is not required. Conditions of Licence 1. The licence and any certificate of renewal in force shall be kept on the licensed premises and shall be produced at the request of an Inspector appointed under the Drugs and Cosmetics Act, 1940. 2. If the licensee wishes to undertake during the currency of the licence the manufacture of any drug specified in Schedule X not included above, he should apply to the Licensing Authority for the necessary endorsement of this licence. This licence shall be deemed to extend to only those items so endorsed. 3. Any change in the

3[competent technical staff] shall be forthwith reported to the Licensing Authority. 4. The licensee shall inform the Licensing Authority in writing in the event of any

change in the constitution of the firm operating under the licence. Where any change in the

¹ Subs. by G.S.R. 462(E) dt. 22.6.1982.

² Subs. by G.S.R.788(E) dt. 10.10.1985.

³ Subs. by G.S.R.231(E) dt. 4.6.1996.

⁴ Subs. by G.S.R. 923(E) dt. 14.2.1992.

constitution of the firm takes place, the current licence shall be deemed to be valid for a maximum period of three months from the date on which the change takes place unless, in the meantime, a fresh licence has been taken from the Licensing Authority in the name of the firm with the changed constitution. 5. The licensee shall furnish to the Licensing Authority copies of the invoices of sales made to dealers. 6. The licensee shall not manufacture drugs covered by this licence for use as 'Physician's Samples'.] ________________________________________________________________________________________

1[FORM 26 (See rules 73 and 83)

Certificate of renewal of licence to manufacture for sale of drugs other than those specified in Schedule X

1. Certified that licence No ........................................................................ granted on

the..................to ....................... for the manufacture of the following categories of drugs being

*drugs other than those specified in Schedules C, C (1) and X_________________

*drugs specified by Schedules C and C (1) excluding those specified in Schedule X to the Drugs and Cosmetics Rules, 1945, at the premises situated at .................... .................................... has been renewed from....................... to.....................

2. Name(s) of approved

2[competent technical staff] ...............

Drugs and Cosmetics Rules, 1945 211

3[3 Names of the drugs (each item to be separately specified) ....................... ]

Signature .............................

4[Date........ Designation ...................

¹ Subs. by G.S.R. 462(E) dt. 22.6.1982.

² Subs. by G.S.R.231(E) dt. 4.6.1996

³ Ins. By G.S.R. 370(E) dt. 7.4.1994.

⁴ Subs. by G.S.R. 923(E), dt. 14.12.1992.

______________*Licensing Authority *Central Licence Approving Authority.] *Delete whichever portion is not required. ______________________________________________________________________________________________ FORM 26A (See rules 73-A and 83-A) Certificate of renewal of loan licence to manufacture for sale of drugs other than those specified in Schedule X

1. Certified that a loan licence No ............................................................granted on

the.............................................. to........................................... for the manufacture of the

*drugs other than those specified in Schedules C, C (1) and X_____________________

the undermentioned drugs being drugs specified in Schedules C and C (1) excluding those to the Drugs and Cosmetics Rules, 1945, at the premises situated specified in Schedule X. at.............................. C/o .........................has been renewed from ......................... to...................

1[competent technical staff]

Signature........... Designation.........

2[Date ............................. ______________*Licensing Authority *Central Licence Approving Authority.]

• Delete whichever is not applicable. ________________________________________________________________________________________________________________________________ 1[FORM 26B (See rule 73B) Certificate of renewal of licence to repack for sale or distribution of drugs being drugs other than those specified in Schedules C and C (1)

¹ Subs. by G.S.R.231(E) dt. 4.6.1996.

² Subs. by G.S.R. 923(E), dt. 14.12.1992.

the....................... to......................................for the repacking of the following drugs at the

premises situated at .........................................has been renewed from .....................

to ............................................................... Names of drugs to be repacked ..........................................................................

2. Names of competent staff. .................................................

3[Date : ..... Signature.........

Designation..........

Drugs and Cosmetics Rules, 1945 212

*Licensing Authority.

*Central licence Approving Authority.]

• Delete whichever is not applicable.] _______________________________________________________________

³ Subs. by G.S.R. 923(E) dt. 14.12.1992

FORM 26C (See rule 85G) Certificate of renewal of licence to manufacture for sale of Homoeopathic medicines

1. Certified that licence No ........................ granted on the............................

to............ for the manufacture for sale of the Homoeopathic mother tinctures/potentised preparation at the premises situated at ............... has been renewed for a period from the ...................................................................... to ...................................... ......

2. Name of the technical staff .................................................................. ......

1[3. Names of the drugs (each item to be separately specified) ............................ ]

¹ Ins. by G.S.R. 370(E) dt. 7.4.1994.

Date.................... Signature .................. Designation.. ......... __________________________________________________________________________________________________________________________

1[FORM 26D (See rule 155) Certificate of renewal of licence to manufacture for sale of Ayurvedic / Siddha or Unani drugs

manufacture of Ayurvedic/Siddha/Unani drugs at the premises situated at......................has been renewed from...............................to ....................................

2. Names of technical staff ................................................................

¹ Ins. by F. No.1 -23/67-D, dt. 2-2-1970.

² Ins. by G.S.R 376 (E), dt. 20.7.1978

Designation........... ____________________________________________________________________________

FORM 26E (See rule 155A)

Certificate of renewal of loan licence to manufacture for sale of Ayurvedic / Siddha or Unani Drugs

1. Certified that loan Licence No ....................................granted on the..........................................to.................................................................. for the manufacture ofAyurvedic/ Siddha or Unani drugs at the premises situated

at.............................................................. C/o ...........................................has been renewed

from..............................................................to ..................................................... ................

Date: ............ Signature............

Designation...........

1[FORM 26E1 (See rule 155B)

Certificate of Good Manufacturing Practices (GMP) to manufacture of Ayurveda, Siddha or Unani drugs

Certified that manufacturing unit licensee, namely ...................... situated at ................

State .................. Licence No ........................... comply with the requirements of Good Manufacturing Practices of Ayurveda-Siddha-Unani drugs as laid down in Schedule T of the Drugs and Cosmetics Rules, 1945. This certificate is valid for a period of three years.

¹ Ins. by G.S.R. 561(E), dt. 23.6.2000 and subs. by G.S.R.198(E), dt. 7.3.2003.

Licensing Authority for Ayurveda/ Siddha/ Unani Drugs.] _________________________________________________________________________________________________________________

1[FORM 26F (See rules 73 and 83)

for the manufacture of drugs specified in Schedule X to the Drugs and Cosmetics

Rules, 1945, at the premises situated at................................ has been renewed

from........................................... to......................................................

2[competent technical staff].

3[Date: ............ Signature.............. Designation..........

______ *Licensing Authority

*Central Licence Approving Authority.]

• Delete whichever is not applicable. ___________________________________________________________________________ 1[FORM 26G (See rule 122-F) Certificate of renewal of licence to operate a Blood Bank for processing of whole human blood and/or* for preparation for sale or distribution of its component

¹ Ins. by. G.S.R. 462(E) ,dt. 22.6.1982.

² Subs. by G.S.R. 231(E), dt. 4.6.1996.

³ Subs. by G.S.R. 923(E), dt. 14.12.1992.

1. Certified that Licence No....................... . granted on ................. to

Drugs and Cosmetics Rules, 1945 214

M/s............................................................................ for the operation of a Blood Bank for processing of whole human blood and*/or for preparation of its components at the premises situated ........................................................... is hereby renewed with effect from........................................................................................ to ...................................

2. Name(s) of items :

1. 2. 3.

3. Name(s) of competent Technical Staff:

1. 2. 3. 4. 5. 6.

Dated............. Signature .............................. Name and Designation................ ______________Licensing Authority. Central Licence Approving Authority.]

• Delete whichever is not applicable.] __________________________________________________________________________ 1[FORM 26H (See rules 68A, 76, 77, 78) Certificate of renewal of licence to manufacture for sale of Large Volume Parenterals/Sera and Vaccines specified in Schedules C and C(I) excluding those specified in Schedule X

¹ Subs. by G.S.R 245(E) dt. 5.4.1999.

1. Certified that licence No............................... granted on the .................. to ............ for

the manufacture of following Large Volume Parenterals/Sera and Vaccines at the premises situated at...................................................................... has been renewed from........to.........

2. Name(s) of drug(s) ........................................ ..............................................

(each item to be separately specified).

3. Name(s) of competent technical staff:

(a) responsible for manufacturing (b) responsible for testing 1. 1.

Drugs and Cosmetics Rules, 1945 215

¹ Ins. by G.S.R. 119(E), dt. 11.3.1996.

Signature: .................... Designation: ................ ______________Licensing Authority Central Licence Approving Authority Date: ............] __________________________________________________________________________________________________________________________

1[FORM 26-I (See rules 122-I) Certificate of renewal of licence for manufacture of blood product.

renewed with effect from ............................................. .................. to..........................

2. Name(s) of item (s):

1. 2. 3.

3. Name(s) of competent technical staff:

(a) responsible for manufacturing (b) responsible for testing 1. 1.

¹ Ins. by G.S.R 245(E), dt. 5.4.1999.

Signature .... ......... Designation............. ______________Licensing Authority Central Licence Approving Authority Date ............................... _______________________________________________________________________

FORM 27

Application for grant or renewal of a

1[licence to manufacture for sale or for distribution] of drugs specified in Schedules C and C (1)

2[excluding those specified in Schedule XB and Schedule X]

1 . 1 / We ........................................................ hereby apply for the grant / renewal of a licence to manufacture on the premises situated at the undermentioned drugs, being drugs specified in Schedules C and C (1)

2[excluding those specified in Schedule XB and Schedule X] to the Drugs and Cosmetics Rules, 1945.

Names of drugs.................................................................................

(each item to be separately specified).

Drugs and Cosmetics Rules, 1945 216

2. The names, qualifications and experience of the expert staff responsible for the manufacture and testing of the above mentioned drugs.

(a) Name (s) of staff responsible for test ....................................
(b) Name (s) of staff responsible for manufacture..........................

3. The premises and plan are ready for inspection______

will be ready for inspection on

4. A fee of rupees .................................................... and an inspection fee of rupees

..............................has been credited to Government under the head of account................

Date......................................... Signature.........

¹ Ins. by. G.S.R. 788(E), dt. 10.10.1985.

² Subs. by G.S.R. 245(E), dt. 5.4.1999.

Designation..... Note-The application shall be accompanied by a plan of premises. _______________________________________________________________________

FORM 27A (See rule 75A) Application for grant or renewal of a loan

1[licence to manufacture for sale or for distribution

of] drugs specified in Schedules C and C (1)

2[excluding those specified in Schedule XB and Schedule X]

1. I / We* .....................................of# .................................................... .....hereby apply

for the grant/ renewal of Loan Licence to manufacture on the premises situated

at C/o$.............................................. the undermentioned drugs, being drugs

specified in Schedules C and C (1)

2[excluding those specified in Schedule XB and Schedule X] to the Drugs and Cosmetics Rules. Names of drugs (each substance to be separately specified).

2. T h e n a me s , q u a l i f i c at i o n s a nd experience of the expert staff actually connected with

the manufacture and testing of the specified products in the manufacturing premises.

(a) Name (s) of expert staff responsible for manufacture ..................................
(b) Name (s) of the expert staff responsible for testing ...........................................

3. I /We enclose:

(a) A true copy of a letter from me / us to manufacturing concern whose manufacturing capacity is intended to be utilized by me / us.
(b) A true copy of a letter from the manufacturing concern that they agree to lend the services of their competent technical staff, equipment and premises for the manufacture of each item required by me / us and that they shall will analyse every batch of finished product and maintain the registers of raw materials, finished products and reports of analysis separately on this behalf.
(c) Specimens of labels, cartons of the drugs proposed to be manufactured.

4. A fee of Rs ........................................................ has been credited to Government under

the head of account.......................................................... ...........................................

Date....................................... Signature .................. ......

Designation....................

Drugs and Cosmetics Rules, 1945 217

• Enter here name of the proprietor, partners or Managing Director, as the case may be. # Enter here name of the applicant firm and the address of the principal place of business. $ Enter here the name and address of the manufacturing concern where the manufacture will be actually carried out and also the licence number under which the latter operates. ___________________________________________________________________________________________________________________ 1[FORM 27B Application for grant or renewal of a 2[licence to manufacture for sale or for distribution of]

¹ Subs. by G.S.R. 788(E) ,dt. 10.10.1985.

drugs specified in Schedules C, C(I) and X

1. I/We................... of ........................... hereby apply for the grant/renewal of a licence to manufacture on the premises situated at................................. the undermentioned drugs, specified in Schedules C, C(I) and X to the Drugs and Cosmetics Rules, 1945. 2. Names of drugs. 3. The names, qualifications and experience of the expert staff responsible for the manufacture and testing of the above-mentioned drugs.

(a) Name(s) of staff responsible for testing:
(b) Name(s) of staff responsible for manufacture: 4. The premises and plant* are ready for inspection/will be ready for inspection on .....

5. A fee of rupees .......................................... and an inspection fee of rupees ......... has

been credited to the Government under the head of account......................................................

Date.................. Signature...............

Note: The application shall be accompanied by a plan of the premises.]

• Delete whichever is not applicable. ___________________________________________________________________________________________________________________________ 1[FORM 27C (See rule 122-F) Application for grant/renewal* of licence for the operation of a Blood Bank for processing of whole blood and/or* preparation of Blood Components

¹ Subs. by G.S.R. 462(E) dt. 22.6.1982.

² Subs. by G.S.R. 788(E) ,dt. 10.10.1985.

1. I/We ................................ of M/s ..................................................... hereby apply for the

grant of licence/renewal of licence number ................................................ dated.............to operate a Blood Bank, for processing of whole blood and/or* for preparation of its components

1. 2. 3.

3. The name(s), qualification and experience of competent Technical Staff are as under:

(a) Name(s) of Medical Officer.

Drugs and Cosmetics Rules, 1945 218

(b) Name(s) of Technical Supervisor
(c) Name(s) of Registered Nurse.
(d) Name(s) of Blood Bank Technician. 4. The premises and plant are ready for inspection/will be ready for inspection on..... .... 5. A licence fee of rupees .................... and an inspection fee of rupees .................. has been credited to the Government under the Head of Account ........................................................................ (receipt enclosed) Signature .... .....................

Dated. ........... Name and Designation.........

• Delete whichever is not applicable. Notes :

1. The application shall be accompanied by a plan of the premises, list of machinery and

¹ Subs. by G.S.R. 245(E), dt. 5.4.1999.

equipment for collection, processing, storage and testing of whole blood and its components, memorandum of association/constitution of the firm, copies of certificate relating to educational qualifications and experience of the competent technical staff and documents relating to ownership or tenancy of the premises. 2. A copy of the application together with the relevant enclosures shall also be sent to the Central Licence Approving Authority and to the Zonal/Sub-Zonal Officers concerned of the Central Drugs Standard Control Organization]. _______________________________________________________________________

1[FORM 27D (See rule 75)

Application for grant or renewal of a licence to manufacture for sale or for distribution of Large Volume Parenterals/Sera and Vaccines excluding those specified in Schedule X

1. I/We ............................ of ..................................hereby apply for grant/renewal of a licence to manufacture for sale or distribution on the premises situated at........................................................................................................the under-mentioned Large Volume Parenterals/Sera and Vaccines, specified in Schedules C and C(1) to the Drugs and Cosmetics Rules, 1945.

2. Name(s) of drug(s) ......................................... .............................................

(each item to be separately specified).

3. The name(s), qualifications and experience of the competent technical staff responsible

for the manufacture of the above mentioned drugs.

(a) Name(s) of staff responsible for testing ...................
(b) Name(s) of staff responsible for manufacturing ............. 4. The premises and plant are ready for inspection/will be ready for inspection on...........................

5. A fee of rupees .............................. and an inspection fee of rupees .............has been

credited to the Government under the Head of Account....................................................

¹ Ins. by. G.S.R.119(E), dt. 11-3-1996.

Designation......................... *Delete whichever is not applicable. Notes: 1. The application is to be accompanied by a plan of the premises, list of machinery and equipment to be employed for manufacture and testing, memorandum of association/constitution of the firm, copies of qualification and experience of competent technical staff and documents relating to ownership or tenancy of the premises. 2. A copy of the application together with the relevant enclosures shall also be sent each to the Central Licence Approving Authority and concerned Zonal/Sub-Zonal Officers of Central Drugs Standard Control Organization]. ________________________________________________________________________

1[FORM 27E (See rule 122F) Application for grant/renewal* of licence to manufacture blood products for sale or distribution

manufacture Blood products on the premises situated at.......................... ...................

2. Name(s) of the item(s)

1. 2. 3. 4. 3. The name(s), qualification and experience of competent Technical Staff are as under:

(a) responsible for manufacturing (b) responsible for testing 1. 1.

4. The premises and plant are ready for inspection/will be ready for inspection on....... 5. A licence fee of rupees ................. ...................and an inspection fee of rupees ............................................................................. has been credited to the Government under the Head of Account.................................................. (receipt enclosed) Signature .... .............

Dated. ........... Name and Designation............

• Delete whichever is not applicable. Notes:

1. The application shall be accompanied by a plan of the premises, list of machinery and

equipment for manufacture of blood products, memorandum of association/constitution of the firm, copies of certificate relating to educational qualifications and experience of the competent technical staff and documents relating to ownership or tenancy of the said premises. 2. A copy of the application together with the relevant enclosures shall also be sent to the Central Licence Approving Authority and to the Zonal/Sub-Zonal Officers

Drugs and Cosmetics Rules, 1945 220

¹ Ins. by G.S.R. 245(E), dt. 5-4-1994.

concerned of the Central Drugs Standard Control Organization]. ____________________________________________________________________________

FORM 28 (See rule 76)

1[Licence to manufacture for sale or for distribution of] drugs specified in Schedules C and C (1)

2[excluding those specified in Schedule X] Number of Licence and date of issue ................................................................. 1. ..................................... is hereby licensed to manufacture at the premises situated at the following drugs, being drugs specified in Schedules C and C (1)

2[excluding those specified in Schedule X] to the Drugs and Cosmetics Rules, 1945. Names of drugs .........................................................

2. Names of approved

3[competent technical staff].

3. The licence authorises the sale by way of wholesale dealing and storage for sale by

the licensee of the drugs manufactured under the licence subject to the conditions applicable to licences for sale.

may be specified in the Rules for the time being in force under the Drugs and Cosmetics Act,1940.

4[Date : .............

Signature................... Designation.............. _____________*Licensing Authority.

• Central Licence Approving Authority.] *Delete whichever is not applicable. Conditions of Licence

1 This licence and any certificate of renewal in force shall be kept on the approved

premises and shall be produced at the request of an Inspector appointed under the Drugs and Cosmetics Act, 1940. 2 If the licensee wants to undertake during the currency of the licence the manufacture any drug specified in Schedules C and C (1)

¹ Subs. by G.S.R. 788(E), dt. 10.10.1985.

² Ins. by G.S.R. 462(E), dt. 22.6.1982.

³ Subs. by G.S.R. 231(E), dt. 4.6.1996

⁴ Subs. by G.S.R. 923(E), dt. 14.12.1992.

2[excluding those specified in Schedule X] not included above, he should apply to the Licensing Authority for the necessary endorsement as provided in rule 75(3). This licence will be deemed to extend to the items so endorsed. 3 Any change in the expert staff shall be forthwith reported to the Licensing Authority. 4 The licensee shall inform the Licensing Authority in writing in the event of any change in the constitution of the firm operating under the licence. Where any change in the constitution of the firm takes place, the current licence shall be deemed to be valid for a maximum period of three months from the date on which the change takes place unless, in the meantime, a fresh licence has been taken from the Licensing Authority in the name of the firm with the changed constitution. __________________________________________________________________________

Drugs and Cosmetics Rules, 1945 221

FORM 28A (See rule 76-A) Loan

1[Licence to manufacture for sale or for distribution of] drugs specified in Schedules C and C (1)

2[excluding those specified in Schedule X]

1. Number of licence and date of issue ............................................................

............................................................................ the following drugs being drugs specified in Schedules C and C (1)

2[excluding those specified in Schedule X] to the Drugs and Cosmetics Rules, 1945. Names of Drugs ...................................................... 3. Names of

3[competent technical staff] ................................................

4[3A. The licence shall be in force from ............................................ to....................

4. The licence authorises the sale by way of wholesale dealing by the licensee and storage for sale by the licensee of the drugs manufactured under the licence subject to the conditions applicable to licence for sale. 5 The licence is subject to the conditions stated below and to such other conditions as may be specified in the Rules for the time being in force under the Drugs and Cosmetics Act, 1940.

Date of issue: .......... Signature............ Designation................ Conditions of Licence 1. This licence and any certificate of renewal in force shall be kept on the approved premises and shall be produced at the request of an Inspector appointed under the Drugs and Cosmetics Act, 1940. 2. If the licensee wishes to undertake during the currency of the licence to manufacture any drugs specified in Schedules C and C (1)

2[excluding those

specified in Schedule X] not included above, he should apply to the Licensing Authority for the necessary endorsement to the licence as provided in rule 75A. This licence will be deemed to extend to the items so endorsed. 3. Any change in the expert staff shall be forthwith reported to the Licensing Authority. The licensee shall inform the Licensing Authority in writing in the event of any change in the constitution of the firm operating under the licence. Where any change in the constitution of the firm takes place, the current licence shall be deemed to be valid for a maximum period of three months from the date on which the change takes place unless, in the meantime, a fresh licence has been taken from the Licensing Authority in the name of the firm with the changed constitution.

¹ Subs. by G.S.R 788(E), dt. 10-10-1985.

² Ins. by G.S.R. 462(E), dt. 22.6.1982.

_______________________________________________________________ 3.

Subs. by G.S.R.231(E) dt. 4.6.1996. 4. Added by Notfn. F. No. 1-10/62-D, dated 11.4.1964.

Drugs and Cosmetics Rules, 1945 222

1[FORM 28B (See rule 76)

2[Licence to manufacture for sale or for distribution of] drugs specified in Schedules C, CI and X No of Licence.................................................................................... 1. .............................................................. is hereby licensed to manufacture at the premises situated at .................................................. the following drugs specified in Schedules C, C(I) and X to the Drugs and Cosmetics Rules, 1945.

3[competent technical staff] 3. The licence authorises the sale by way of wholesale dealing and storage for sale by the licensee of the drugs manufactured under the licence subject to the conditions applicable to licence for sale. 4. The licence will be in force...................to ....................................

5. The licence is subject to conditions stated below and to other conditions as may be

specified in the rules for the time being in force under the Drugs and Cosmetics Act, 1940.

4[Date ............................ Signature .......................... Designation...................... ________________*Licensing Authority *Central Licence Approving Authority. *Delete whichever is not applicable. Conditions of Licence 1. The licence and any certificate of renewal in force shall be kept on the approved premises and shall be produced at the request of an Inspector appointed under the Drugs and Cosmetics Act, 1940. 2. If the licensee wishes to undertake during the currency of the licence the manufacture of any drug specified in Schedule X not included above, he should apply to the

Licensing Authority for the necessary endorsement as provided in Rule 75(4). This licence will

be deemed to be applicable to the items so endorsed. 3. Any change in the

1[competent technical staff] shall be forthwith reported to the Licensing Authority. 4. The licensee shall inform the Licensing Authority in writing in the event of any

change in the constitution of the firm operating under licence. Where any change in the

¹ Subs. by G.S.R. 462(E) dt. 22.6.1982.

² Subs. by G.S.R.788(E) dt. 10.10.1985.

³ Subs. by G.S.R.231(E) dt. 4.6.1996.

⁴ Subs. by G.S.R. 923(E) dt. 14.2.1992.

constitution of the firm takes place, the current licence shall be deemed to be valid for a maximum period of three months from the date on which the change takes place unless, in the meantime, a fresh licence has been taken from the Licensing Authority in the name of the firm with the changed constitution. 5. The licensee shall furnish to the Licensing Authority copies of the invoices of sales made to dealers. 6. The licensee shall not manufacture drugs specified in Schedule X covered by this licence for use as “Physicians Samples”.] ___________________________________________________________________________

Drugs and Cosmetics Rules, 1945 223

1[FORM 28C (See rule 122-G) Licence to operate a Blood Bank for collection, storage and processing of whole human blood and/or* its components for sale or distribution

l. Number of licence................ date of issue ........................... at the premises situated

at ................................................................................................. 2. M/s ..........................................is hereby licensed to collect, store, process and distribute whole blood and/or its components.

3. N a m e ( s ) o f t h e i t e m ( s ) :

1. 2. 3. 4. Name(s) of the Competent Technical Staff: 1. 2. 3. 5. The licence authorises licensee to collect, store, distribute and processing of whole blood and/or blood components subject to the conditions applicable to this licence. 6. The licence shall be in force from ................ ................to................ 7. The licence shall be subject to the conditions stated below and to such other conditions as may be specified from time to time in the Rules made under Drugs and Cosmetics Act, 1940.

Dated: ......

. Signature...........................

Name and Designation ............. Licensing Authority Central Licence Approving Authority

• Delete whichever is not applicable Conditions of Licence 1. The licensee shall neither collect blood from any professional donor or paid donor nor shall he prepare blood components from the blood collected from such a donor. 2. The licence and any certificate of renewal in force shall be displayed on the approved premises and the original shall be produced at the request of an Inspector appointed under the Drugs and Cosmetics Act, 1940. 3. Any change in the technical staff shall be forthwith reported to the Licensing Authority and/or Central Licence Approving Authority. 4. The licensee shall inform the Licensing Authority and/or Central Licence approving Authority in writing in the event of any change in the constitution of the firm operating under the licence. Where any change in the constitution of the firm takes places, the current licence shall be deemed to be valid for maximum

Drugs and Cosmetics Rules, 1945 224

¹ Ins. by G.S.R. 245(E), dt. 5.4.1999.

period of three months from the date on which the change has taken place unless, in the meantime, a fresh licence has been taken from the Licensing Authority and/or Central Licence Approving Authority in the name of the firm with the changed constitution.] ___________________________________________________________________________

1[FORM 28D (See Rules 76)

Licence to manufacture for saleor for distribution of Large Volume Parenterals/Sera and

Vaccines specified in Schedules C and C(I) excluding those specified in Schedule X Number of licence ...............................................and date of issue............................ 1. ................................. is hereby licensed to manufacture at the premises situated at................................................. the following Large Volume Parenterals/Sera and Vaccines specified in Schedules C and C(1) excluding those specified in Schedule X to the Drugs and Cosmetics Rules, 1945.

2. Name(s) of drug(s)......................................................................................

(each item to be separately specified).

3. Name(s) of competent technical staff:

(a) responsible for manufacturing (b) responsible for testing 1. 1.

4. The licence authorises the sale by way of wholesale dealing and storage for sale by the licensee of the drugs manufactured under the licence, subject to the conditions applicable to licence for sale. 5. The licence shall be in force from...................................................... to ...................... 6. The licence shall be subject to the conditions stated below and to such other conditions as shall be specified in the rules for the time being in force under the Drugs and Cosmetics Act, 1940.

Date: ........ Signature.........

Designation...... Licensing Authority Central Licence Approving Authority

Conditions of Licence 1. The licence and any certificate of renewal in force shall be kept on the approved premises and shall be produced at the request of an Inspector appointed under the Drugs and Cosmetics Act, 1940. 2. If the licensee wishes to undertake during the currency of the licence to manufacture of any drug specified in Schedule C and/or C(I) excluding those specified in Schedule X not included above, he should apply to the Licensing Authority and or Central Licence Approving Authority for the necessary endorsement as provided in the rules. This licence shall be deemed to extend to the items so endorsed. 3. Any change in the competent technical staff named in the licence shall be forthwith reported to the Licensing Authority.

4. The licensee shall inform the licensing authority and/or Central Licence Approving

Authority in writing in the event of any change in the constitution of the firm operating under the licence. Where any change in the constitution of the firm takes place, the current

Drugs and Cosmetics Rules, 1945 225

¹ Ins. by G.S.R. 245, dated 5.4.1999.

licnece shall be deemed to be valid for a maximum period of three months from the date on which the change takes place unless, in the meantime, a fresh licence has been applied along with prescribed fee and necessary documents to the Licensing Authority and/or Central Licence Approving Authority in the name of the firm with the changed constitution.] ______________________________________________________________________

1[FORM 28E (See rule 122 G) Licence to manufacture and store blood products for sale or distribution.

l. Number of licence ............ date of issue ................................ at the premises situated

at........................................................................................................... 2. M/s ........................................is hereby licensed to manufacture, store, sell or distribute the following blood products:-

3. N a m e ( s ) o f t h e i t e m ( s ) :

1. 2. 3. 4. Name(s) of the competent technical staff:

(a) responsible for manufacturing (b) responsible for testing 1. 1.

5. The licence authorises licensee to manufacture, store, sell or distribute the blood products, subject to the conditions applicable to this licence. 6. The licence shall be in force from ................ to........................ 7. The licence shall be subject to the conditions stated below and to such other conditions as may be specified from time to time in the rules made under Drugs and Cosmetics Act, 1940.

Dated.: ........ Signature.......... ....................

Name and Designation ............ ______________Licensing Authority Central Licence Approving Authority

• Delete whichever is not applicable. Conditions of Licence 1. The licensee shall not manufacture blood products from the blood drawn from any professional donor or paid donor. 2. The licence and any certificate of renewal in force shall be displayed on the approved premises and shall be produced at the request of an Inspector appointed under the Drugs and Cosmetics Act, 1940. 3. Any change in the technical staff shall be forthwith reported to the Licensing Authority and/or Central Licence Approving Authority. 4. The licensee shall inform the Licensing Authority and/or Central Licence Approving Authority in writing any change in the constitution of the firm operating under the licence. In the event of any change in the constitution of the firm, the licence shall be deemed to be valid for a period of three months from the date on which the change takes place unless, in the meantime, a fresh licence has been taken from the Licensing Authority and/or Central

Drugs and Cosmetics Rules, 1945 226

¹ Ins. by G.S.R. 245(E), dt. 5.4.1999.

Licence Approving Authority in the name of the firm with the changed constitution.] __________________________________________________________________________

FORM 29 (See rule 89) Licence to manufacture drugs for purposes of examination, test or analysis

1. ... .....................................of...........................................................

is hereby licensed to manufacture the drugs specified below for purposes of examination, test or analysis at ............................................................... 2. This licence is subject to the conditions prescribed in Part VIII of the Drugs and Cosmetics Rules, 1945.

3. This licence shall be in force for one year from date specified below.

Names of drugs

Date : ......... Licensing Authority..................

FORM 30 (See rule 90) Application for licence to manufacture drugs for purposes of examination, test or analysis

1. ...........................................of .............. .....................by occupation .....................

hereby apply for licence to manufacture the drugs specified below for purposes of examination,

test or analysis at and I undertake to comply with the conditions applicable to the licence.

Names of Drugs

Date......................................... Signature.......................

FORM 31 (See rule 139) Application for grant or renewal of a

1[licence to manufacture cosmetics for sale or for

Distribution]

1 . 1 / We......................................... of. ........................ hereby apply for grant /renewal of a

licence to manufacture on the premises situated at.......... the following cosmetics :- 2. Names of Cosmetics ......................................................................

3. Names, qualifications and experience of technical staff employed for manufacture

and testing.......................................................... ......... 4. A fee of rupees ...........................................has been credited to Government under the head of account........................................................

¹ Subs. by G..S.R .788 (E), dt. 10.10.1985.

_______________________________________________________________________________________________________________________________

Drugs and Cosmetics Rules, 1945 227

1[FORM 31A

(See rule138A) Application for grant or renewal of loan

2[ licence to manufacture cosmetics for sale or for distribution]

1. I / W e ...............................................of. .............................hereby apply for

grant/renewal of a loan licence to manufacture cosmetics for sale on the premises s i t u at e d at...............................C/o.................................the following cosmetics :— 2. Names of Cosmetics.............................................................. 3. The names, qualifications and experience of the expert shall actually connected with the manufacture and testing of the specified products in the manufacturing premises. 4. I /We enclose−

(a) A true copy of a letter from me / us to the manufacturing concern whose manufacturing capacity is intended to be utilized by me / us.
(b) A true copy of a letter from the *manufacturing concern that they agree to lend the services of their competent technical staff, equipment and premises for the manufacture of each item required by me / us and that they will analyse every batch of and maintain the registers of raw materials , finished products and reports of analysis separately in this behalf.
(c) specimen of labels, cartons of the products proposed to be manufactured. 5. A fee of rupees ......................................................... has been credited to Government under the head of account..........................................................

Date............. Signature............

¹ Ins. by G.S.R. 444, dt. 28-4-1973.

² Subs. by G.S.R. 788(E), dt. 10.10.1985.

*Enter here the name and address of the manufacturing concern where the manufacture will be actually carried out and also their licence number. _________________________________________________________________________________________________________________ FORM 32 (See rule 140)

1[Licence to manufacture cosmetics for sale or for distribution]

Number of Licence and date of issue 1 ........................is hereby licensed to manufacture on the premises situated at ........................................... the following cosmetics under the supervision of the following technical staff:-

(a) Names of cosmetics.
(b) Names of technical staff 2. The licence shall remain in force from..........................to..................... 3. The licence is subject to the conditions stated below and to such other conditions as may be specified in the Drugs and Cosmetics Rules, 1945.

Date.......................................... Signature ..............

Designation............ Conditions of Licence 1. This licence and any certificate of renewal in force shall be kept on the approved

Drugs and Cosmetics Rules, 1945 228

premises and shall be produced at the request of an Inspector appointed under the Drugs and Cosmetics Act, 1940. 2. Any change in the technical staff shall be forthwith reported to the Licensing Authority. 3. If the licensee wants to manufacture for sale of additional items he should apply to the Licensing Authority for the necessary endorsement to the licence as provided in rule 138 (3). This licence shall be deemed to extend to the cosmetics so endorsed.

¹ Subs. by G.S.R. 788 (E), dt. 10.10.1985.

2[4. The licensee shall inform the Licensing Authority in writing in the event of any change in the constitution of the firm operating under the licence. Where any change in the constitution of the firm takes place, the current licence shall be deemed to be valid for a maximum period of three months from the date on which the change takes place unless, in the meantime, a fresh licence has been taken from the Licensing Authority in the name of the firm with the changed constitution.] __________________________________________________________________________

2. Added by S.O. 903, dt. 28-2-1976.

1[FORM 32A (See rule 139B) Loan

2[licence to manufacture cosmetics for sale or for distribution]

licence to manufacture the following cosmetics on the premises situated at..............................................................C/o............................................ under the direction and personal supervision of the following technical staff:

(a) Names of technical staff.
(b) Names of cosmetics.

are specified in the rules for the time being in force under the Drugs and Cosmetics Act, 1940.

Date.................................... Signature ..................

Designation .............. Conditions of Licence 1. This licence and any certificate of renewal in force shall be kept on the approved premises and shall be produced at the request of an Inspector appointed under the Drugs and Cosmetics Act, 1940. 2. Any change in the technical staff shall be forthwith reported to the Licensing Authority. 3. If the licensee wants to manufacture for sale additional items he should apply to the Licensing Authority for the necessary endorsement to the licence as provided in rule 138A(5).This licence shall be deemed to extend to the cosmetics so endorsed. ____________________________________________________________________ 1.

² Ins. by G.S.R. 788 (E), dt. 10.10.1985.

Ins. by G.S.R. 444, dt. 28-4-1973.

FORM 33 (See rule 141)

Certificate of renewal of licence to manufacture cosmetics for sale

1. Certified that licence No......................granted on the............................

premises situated at........................has been renewed from...............and shall expire on.................................

¹ Ins. by G.S.R. 1183, dt. 17.8.1964.

Designation............... _____________________________________________________________________________________

1[FORM 33A (See rule 141-A) Certificate of renewal of loan licence to manufacture cosmetic for sale

1. Certified that loan licence No.............granted on the .................... . to........................for the manufacture for sale of the following cosmetics at the premises situated at C/o.............................................has been renewed from.......................................to .......................................................

Designation......... ___________________________________________________________________________________________

1. Added by G.S.R. 444, dt. 28-4-1973.

FORM 34 (See rules 131 and 150) Certificate of test or analysis of cosmetic by the Central Drugs Laboratory or the Government Analyst

1. Name of the officer or Inspector from whom received ........................................

2. Serial number and date of the Officer's / Inspector's memorandum...................................................................................

5. Name of the Cosmetic purporting to be contained in the sample

6. Condition of seals on the

1[packet or on portion of sample or container] 7. Results of test or analysis :— The sample of cosmetics—

(a) contains a prescribed colour only____________________________________________ does not contain a prescribed colour.
(b) does not contain harmful ingredients__________________________________________ contains harmful ingredients

Drugs and Cosmetics Rules, 1945 230

does not conform to claims made on the label as to the nature and quality of the cosmetic

2[d) contains not more than .....................................................................parts per

million of Arsenic.]

Date: ....................................

¹ Subs. by G.S.R. 59(E), dt. 7.2.1995.

² Subs. by G.S.R. 510(E), dt. 26.7.1982.

Director, Central Drugs Laboratory / Government Analyst. _____________________________________________________________________

1[FORM 35

2[See Rules 65, 67-G, 74, 74A, 74B, 78, 78A, 85H, 142, 142-A, 158 and 158A] Form in which the Inspection Book shall be maintained

(A) The cover of the Inspection Book shall contain the following particulars, namely :—

(B) (i) The pages of the Inspection Book shall be serially numbered and duly stamped by the Licensing Authority. The pages, other than the first and the last pages, shall have the following particulars:-- Name and designation of the Inspector who inspects the premises of the licensee:− Date of Inspection........................ Observations of the Inspector ........................ Signature of the Inspector
- (ii) The first and last pages of the Inspection Book shall be endorsed by the Licensing Authority with the following words, namely:— Inspection Book maintained by M/s...................................................... situated at.....................................for licence number.................................. . in Form....................................under the Drugs and Cosmetics Rules, 1945. Seal and Signature of the Licensing Authority. Notes:
- (i) Printed copy of the Inspection Book may be obtained by the licensee from the Licensing Authority on payment.
- (ii) The Inspection Book shall be maintained at the premises of the licensee.
- (iii) The observations made by the Drug Inspector shall be in triplicate. The original copy shall be retained in the Inspection Book to be maintained in the premises of the licensee. The duplicate copy shall be sent to the Licensing Authority. The triplicate copy shall be taken as record by the Inspector. ________________________________________________________________________

² Subs. by Notfn. No. G.S.R. 331(E). dt. 8.5.1984.

1. Added by Notfn. No.F.1-14/68-D, dt. 26.10.1968.

Drugs and Cosmetics Rules, 1945 231

FORM 36 (See rule 150B) Application for grant or renewal of approval for carrying out tests on drugs/ cosmetics or raw materials used in the manufacture thereof on behalf of licensees for manufacture for sale of drugs /cosmetics

(1) *I/We........................................of...............................hereby apply for the grant or renewal of approval for carrying out tests of identity, purity, quality and strength on the following categories of drugs / items of cosmetics or raw materials used in the manufacture thereof on behalf of licensees for manufacture for sale of drugs / cosmetics.
(2) *Categories of drugs, items of cosmetics:
- (a) Drugs other than those specified in Schedules C and C (1) and also excluding Homoeopathic Drugs:-

or Chromatography.

(b) Drugs specified in Schedules C and C (1):—

1. Sera, Vaccines, Antigens, Toxins, Antitoxins, Toxoids,

Bacteriophages and similar Immunological Products.

Chromatography.

9. Other drugs.

(c) Homoeopathic drugs.
(d) Cosmetics.

(3) Name, qualifications and experience of expert staff employed for testing and the person-in-charge of testing.
(4) List of testing equipments provided.
(5) *I/We enclose a plan of the testing premises showing the location and area of the different sections thereof.
(6) An inspection fee of rupees ........................................................has been credited to Government under the Head of Account........................................................

Date.......................... Signature.........

• Delete whichever is not applicable _______________________________________________________________________________________

¹ Ins. by Notfn. No .X. 11014/7/76-D&MS, dt. 23-8-1977.

Drugs and Cosmetics Rules, 1945 232

FORM 37 (See rule 150C) Approval for carrying out tests on drugs / cosmetics and raw materials used in their manufacture on behalf of licensees for manufacture for sale of drugs /cosmetics Number of approval and date of issue:

(1) Approval is hereby granted to ............................................................... .......for carrying out tests for identity, purity, quality and strength on the following categories of drugs/items of cosmetics and the raw materials used in the manufacture thereof on the premises situated ................................................................................................................... Categories of drugs / items of cosmetics ______________________________ ______________________________ ______________________________
(2) Names of 1[competent technical staff] employed for testing and the person-in- charge of testing.
(3) The approval shall be in force from......................................... to........................
(4) The approval is subject to the conditions stated below and such other conditions as may be specified in the rules for the time being in force under the Act.

Date..................................... Signature...................................

Designation ................................

Conditions of Approval

(1) This approval and any certificate of renewal in Form 38 shall be kept in the approved premises and shall be produced at the request of the Inspectors appointed under the Act.
(2) If the approved institution wishes to undertake during the currency of the approval the

testing of any other category of drugs or items of cosmetics it should apply to the approving

authority for necessary endorsement as provided in rule 150-B.This approval will be deemed to extend to the item so endorsed.

(3) Any change in the analytical staff or in the person-in-charge of the testing shall be forthwith reported to the approving authority. 2[(4) The approved institution shall inform the approving authority in writing in the event of any change of the constitution of the institution operating under this Form. Where any change in the constitution of the institution takes place, the current approval shall be deemed to be valid for a maximum period of three months from the date on which the change takes place unless in the meantime, a fresh approval has been taken from the approving authority in the name of the institution with the changed constitution.] ___________________________________________________________________________ FORM 38 (See rule 150J) Certificate of renewal of approval for carrying out tests on drugs / cosmetics and raw materials used in the manufacture thereof on behalf of licensees for manufacture for sale of drugs / cosmetics
(1) Certified that approval number .................................. granted on the

¹ Subs. by. G.S.R. 231(E), dt. 4.6.1996.

² Ins. by G.S.R. 681 (E), dt. 5-12-1980.

of identity, purity, quality and strength on the following categories of drugs/ items of cosmetics and the raw materials used in the manufacture thereof at the premises situated at...................................................has been renewed from....................................................to ......................................... Categories of drugs/items of cosmetics ______________________________ _____________________________ . ________________________________

(2) Names of 1[competent technical staff] and person-in-charge of testing.

Date ............................... Signature.................

¹ Subs. by. G.S.R.231(E) ,dt. 4.6.1996.

Designation.............. _____________________________________________________________________________

FORM 39 [See rule150E(f)] Report of test or analysis by approved institution

(1) Name of manufacturer from whom sample received together with his manufacturing licence number under the Act and under the rules made thereunder.
(2) Reference number and date of the letter from the manufacturer under which the sample was forwarded.
(3) Date of receipt of the sample.
(4) Name of drug / cosmetics / raw material purporting to be contained in the sample.
(5) Details of raw material/final product in bulk/final product (in finished pack)* as obtained from the manufacturer:
- (a) Original manufacturer's name in the case of raw materials and drugs repacked.
- (b) Batch number. 1[(c) Batch size as represented by sample.]
- (d) Date of manufacture, if any.
- (e) Date of expiry, if any.
(6) Results of test or analysis with protocols of test or analysis applied. In the opinion of the undersigned, the sample referred to above is *of standard quality/is not of standard quality as defined in the Act and the rules made thereunder for the reasons given below.

Date.................................. ......................................................

¹ Subs. by. G.S.R. 681(E), dt. 6.6.1988.

Signature of Person-in-charge of testing Note:- Final product includes repacked material. *Delete whichever is not applicable ______________________________________________________________________

Drugs and Cosmetics Rules, 1945 234

Forms 40 to 43 (Pertaining to Ayurveda, Siddha and Unani drugs replaced by Forms Nos .47 to 50.)

[1. Ins. by G.S.R. 701(E), dt. 27.9.2001 ]

1[FORM 40

(See rule 24-A)

Application for issue of Registration Certificate for import of drugs into India under the Drugs

and Cosmetics Rules 1945 I/We* _________________________________________________________ ___________________________ (Name and full address) hereby apply for the grant of Registration Certificate for the manufacturer, M/s. ___________________(full address with telephone, fax and E-mail address of the foreign manufacturer) for his premises, and manufactured drugs meant for import into India.

1. N a m e s o f d r u g s f o r r e g i s t r a t i o n .

• * *
• * *
• * *

`2. I/We enclose herewith the information and undertakings specified in Schedule D (1)

and Schedule D(II) duly signed by the manufacturer for grant of Registration Certificate for the premises stated below.

3. A fee of_______________for registration of premises, the particulars of which

are given below, of the manufacturer has been credited to the Government under the Head of Account "0210-Medical and Public Health, 04-Public Health, 104-Fees and Fines” under the Drugs and Cosmetics Rules, 1945-Central vide Challan No.________ dated__________________(attached in original). 4. A fee of__________________for registration of the drugs for import as specified at Serial No. 2 above has been credited to the Government under the Head of Account "0210-Medical and Public Health, 04-Public Health, 104-Fees and Fines" under the Drugs and Cosmetics Rules, 1945-Central vide Challan No._______, dated___________. (attached in original).

5. Particulars of premises to be registered where manufacture is carried on:

Address (es) ___________ Telephone No.___________ Fax__________________ _ E-mail_______________ I/We* undertake to comply with all terms and conditions required to obtain Registration Certificate and to keep it valid during its validity period. Place: __________ Date: ___________ Signature__________ Name____________ Designation_______ Seal/Stamp of manufacturer or his authorised Agent in India.

(Note: In case the applicant is an authorised agent of the manufacturer in India, the Power of Attorney is

to be enclosed).

¹ Ins. by G.S.R. 604(E) dt. 24-8-2001 (w.e.f. 1-1-2003).

*Delete whichever is not applicable. __________________________________________________________________ 2. Figures 1,2,3 omitted by G.S.R. 32, dt. 20.1.2005.

Drugs and Cosmetics Rules, 1945 235

1[FORM 41 (See rule 27 A) Registration Certificate Registration Certificate to be issued for import of drugs into India under Drugs and Cosmetics Rules, 1945 Registration Certificate No._____________ Date________________ M/s ___________________________________ (Name and full address of registered office) having factory premises at full address) has been registered under rule 27-A as a manufacturer and is hereby issued this Registration Certificate. 2. Name (s) of drugs which may be imported under this Registration Certificate:

• * *
• * *
• * * 3. This Registration Certificate shall be in force from __________ to__________unless it is sooner suspended or cancelled under the rules.

4. This Registration Certificate is issued through the office of the manufacturer

or his authorised agent in India M/s (name and full address)________ who will be responsible for the business activities of the manufacturer, in India in all respects. 5. This Registration Certificate is subject to the conditions, stated below and to such other conditions as may be specified in the Act and the rules, from time to time. Place:__________ Date: _________ Licensing Authority Seal / Stamp

Conditions of the Registration Certificate.

1. The Registration Certificate shall be displayed at a prominent place by the authorised

agent. 2. No drug shall be registered unless it has a free sale approval in the country of origin, and/or in other major countries.

3. The manufacturer or his authorised agent in India shall comply with the conditions

of the import licence issued under the Drugs and Cosmetics Rules, 1945.

4. The manufacturer or his authorised agent in India shall inform the licensing authority

forthwith in the event of any administrative action taken due to adverse reaction, viz. market withdrawal, regulatory restrictions, or cancellation of authorization, and/or not of standard quality report of any drug pertaining to this Registration Certificate declared by the Regulatory Authority of the country of origin or by any Regulatory Authority of any other country, where the drug is marketed/sold or distributed. The dispatch and marketing of the drug in such cases shall be stopped immediately, and the licensing authority shall be informed immediately. Further action in respect of such stopped marketing of drug shall be followed as per the direction of the licensing authority. In such cases, action equivalent to that taken with reference to the concerned drug in the country of

Drugs and Cosmetics Rules, 1945 236

origin or in the country of marketing shall be followed in India also, in consultation with the

licensing authority. The licensing authority may, however, direct any further modification

to this course of action, including the withdrawal of the drug from Indian market within 48 hours time period. 5. The manufacturer or his authorised agent in India shall inform the licensing authority within 30 days in writing in the event of any change in manufacturing process, or in packaging, or in labelling or in testing, or in documentation of any of the drugs pertaining to this Registration Certificate. In such cases, where there shall be any major change/modification in manufacturing, or in processing or in testing, or in documentation as the case may be, at the discretion of the licensing authority, the manufacturer or his authorised agent in India shall obtain necessary approval within 30 days by submitting a separate application along with the registration fee, as specified in clause (ii) of sub-rule (3) of rule 24-A. 6. The manufacturer or his authorised agent in India shall inform the licensing authority immediately in writing in the event of any change in the constitution of the firm and / or address of the registered office / factory premises operating under this Registration Certificate. Where any such change in the constitution of the firm and/or address takes place, the current Registration Certificate shall be deemed to be valid for a maximum period of three months from the date on which the change has taken place unless, in the meantime, a fresh Registration Certificate has been taken from the licensing authority in the name of the firm with the changed constitution of the firm and/or changed address of the registered office or factory premises.]

¹ Ins. by G.S.R. No.604(E), dt. 24-8-2001 (w.e.f. 1-1-2003)

_______________________________________________________________________ 2. Figures 1,2,3 omitted by G.S.R. 32, dt. 20.1.2005.

1[FORM 44 (See rules 122A, 122B, 122D and 122 DA) Application for grant of permission to import or manufacture a New Drug or to undertake clinical trial.

I/We*................................................ of M/s. ........................ ..............

(address) hereby apply for grant of permission for import of and/or clinical trial or for approval to manufacture a new drug or fixed dose combination or subsequent permission for

already approved new drug. The necessary information / data is given below :

1. Particulars of new drug :

(1) Name of the drug.
(2) Dosage form.
(3) Composition of the formulation :
(4) Test specification.
- (i) active ingredients.
- (ii) inactive ingredients.
(5) Pharmacological classification of the drug.

Drugs and Cosmetics Rules, 1945 237

(6) Indications for which proposed to be used.
(7) Manufacturer of the raw material (bulk drug substances).
(8) Patent status of the drug. 2. Data submitted along with the application (as per Schedule Y with indexing and page numbers:) A. Permission to market a new drug :
(1) Chemical and Pharmaceutical information.
(2) Animal Pharmacology.
(3) Animal Toxicology.
(4) Human / Clinical Pharmacology (Phase I).
(5) Exploratory Clinical Trials (Phase II).
(6) Confirmatory Clinical Trials (Phase III) (including published review articles)
(7) Bio-availability, dissolution and stability study data.
(8) Regulatory status in other countries.
(9) Marketing information :
- (a) Proposed product monograph.
- (b) Drafts of labels and cartons.
(10) Application for test licence. B. Subsequent approval / permission for manufacture of already approved new drug :
- (a) Formulation:
(1) Bio-availability / bio-equivalence protocol.
(2) Name of the investigator/center.
(3) Source of raw material (bulk drug substances) and stability study data.
- (b) Raw material (bulk drug substances):
(1) Manufacturing method.
(2) Quality control parameters and/or analytical specification, stability report.
(3) Animal toxicity data.
- (C) Approval / Permission for fixed dose combination:
(1) Therapeutic Justification. (authentic literature in pre-reviewed journals/text books)
(2) Data on pharmacokinetics/pharmacodynamics combination.
(3) Any other data generated by the applicant on the safety and efficacy of the combination.
- (D) Subsequent Approval or approval for new indication - new dosage form:
(1) Number and date of Approval / permission already granted.
(2) Therapeutic justification for new claim / modified dosage form
(3) Data generated on safety, efficacy and quality parameters.

is enclosed).

Dated : ..... Signature ....................

Designation................ Note: *Delete whichever is not applicable. ___________________________________________________________________ 1. Forms 44 to 46 A ins. by No.G.S.R. 900 (E), dt. 12.12.2001.

FORM 45 (See rules 122 A, 122 D and 122 DA) Permission to import Finished Formulation of the New Drug.. Number of the permission and date of issue..................................................... M/s ..................................................................... of.............................................. (address) is hereby permitted to import the following new drug formulation under rule 122 A /122 D/122 DA of the Drugs and Cosmetics Rules, 1945.

(1) Name of the New Drug :
(2) Dosage form :
(3) Composition :
(4) Indications :

Dated: ................ Signature............................

Name and designation of Licensing Authority Conditions for Grant of Approval / Permission.

(1) The formulation shall conform to the specifications approved by the Licensing Authority.
(2) The proper name of the drug shall be printed or written in indelible ink and shall appear in a more conspicuous manner than the trade name, if any, which shall be shown immediately after or under the proper name on the label of the innermost container of the drug or every other covering in which the container is packed.
(3) The label of the innermost container of the drug and every other covering in which the container is packed shall bear a conspicuous red vertical line on the left side running throughout the body of the label which shall not be less than 1 mm in width and without disturbing the other conditions printed on the label to depict it as prescription drug.
(4) The label on the immediate container of the drug as well as the packing in which the container is enclosed should contain the following warning:

"WARNING : To be sold by retail on the prescription of a .............................. Only."

(5) Post marketing surveillance study shall be conducted during initial period of two

Drugs and Cosmetics Rules, 1945 239

years of marketing of the new drug formulation, after getting the protocol and the names of the investigator duly approved by the Licensing Authority.

(6) All reported adverse reactions related to the drug shall be intimated to the Drugs Controller, India and Licensing Authority and regulatory action resulting from their review should be complied with.
(7) No claims except those mentioned above shall be made for the drug without the prior approval of the Licensing Authority.
(8) Specimen of the carton, labels, package insert that will be adopted for marketing the drug in the country shall be got approved from the Licensing Authority before the drugs is marketed.
(9) Each consignment of imported drug shall be accompanied by a test/analysis report. FORM 45A (See rules 122 A and 122 DA) Permission to import raw material (new bulk drug substance)

Number of the permission and date of issue....................................................

M/s ...................................................................................of........................(address) is hereby permitted to import the following raw material (new bulk drug substances) under rule 122 A / 122DA of the Drugs and Cosmetics Rules, 1945, namely :- Name of the raw material (new bulk drug substances):

(1) ............................................
(2) .............................................
(3) ............................................

Dated .................. Signature ..............

Name and Designation of the Licensing Authority...............

Conditions for Grant of Approval / Permission

(1) The raw material (new bulk drug substance) shall conform to the test specifications as approved by the Licensing Authority.
(2) For manufacture of raw material (new bulk drug substance) or its formulation in the country, separate approval under rule 122-B shall be obtained from the Licensing Authority.
(3) The permission to import shall not be used to convey or imply that the raw material (new bulk drug) is categorized as "life saving or essential drug."

Drugs and Cosmetics Rules, 1945 240

FORM 46 (See rules 122 B, 122 D and 122 DA) Permission / Approval for manufacture of new drug formulation Number of permission and date of issue ....................... .....................................

M/s of ............................................ (address) is hereby granted Permission/Approval to

manufacture following new drug formulation under rule 122B/122D/122DA of the Drugs and Cosmetics Rules, 1945, namely :-

(1) Name of the formulation:
(2) Dosage form:
(3) Composition:
(4) Indications:

Dated ................ Signature ...... .....................

Name and designation of Licensing Athority.......... Conditions for Grant of Approval / Permission.

(1) The formulation shall conform to the specifications approved by the Licensing Authority.
(2) The proper name of the drug shall be printed or written in indelible ink and shall appear in a more conspicuous manner than the trade name, if any, which shall be shown immediately after or under the proper name on the label of he innermost container of the drug or every other covering in which the container is packed.
(3) The label of the innermost container of the drug and every other covering in which the container is packed shall bear a conspicuous red vertical line on the left side running throughout the body of the label which shall not be less than 1 mm in width and without disturbing the other conditions printed on the label to depict it as prescription drug.
(4) The label on the immediate container of the drug as well as the packing in which the container is enclosed should contain the following warning: "WARNING : To be sold by retail on the prescription of a ...........................only."
(5) Post marketing surveillance study shall be conducted during initial period of two years of marketing of the new drug formulation, after getting the protocol and the names of the investigator duly approved by the Licensing Authority.
(6) All reported adverse reactions related to the drug shall be intimated to the Drugs Controller, India and Licensing Authority and regulatory action resulting from their review should be complied with.
(7) No claims except those mentioned above shall be made for the drug without the prior approval of the Licensing Authority.
(8) Specimen of the carton, labels, package insert that will be adopted for marketing the drug in the country shall be got approved from the Licensing Authority before the drug is marketed.

Drugs and Cosmetics Rules, 1945 241

FORM 46A (See rules 122 B and 122 DA) Permission/ Approval for manufacture of raw material (new bulk drug substance)

Name of the permission/ approval and date of issue.................................................

M/s ............................................of........................................... (address) is hereby granted

Permission/Approval to manufacture the following raw material (new bulk drug substance) under rule 122 B / 122 DA of the Drugs and Cosmetics Rules, 1945. Name of the raw material (new bulk drug substance)

(1) ..................................................................
(2) ................................................................
(3) ..............................................................

Dated .................................. Signature ..........................

Name and designation of Licensing Authority.

Conditions for Grant of Permission /Approval

(1) The raw material (new bulk drug substance) shall conform to the specifications approved by the Licensing Authority.
(2) The raw material (new bulk drug substance) can be sold to only those manufacturers who have permission, in writing, from Licensing Authority, either to use the drug for development purpose/clinical trial-bio-equivalence study or to manufacture the formulation.
(3) For manufacture of the formulation in the country, separate approval under rule 122-B shall be obtained from the Licensing Authority. 1[FORM 47 (See rule 160 A) Application for grant or renewal of approval for carrying out tests on Ayurvedic, Siddha and Unani drugs or raw materials used in the manufacture thereof on behalf of licensees for manufacture for sale of Ayurvedic, Siddha and Unani drugs

Drugs and Cosmetics Rules, 1945 242

1. *I/We................................................ of .................................... hereby apply for the grant/renewal of approval for carrying out tests of identity, purity, quality and strength on the following categories of Ayurvedic, Siddha and Unani drugs or raw materials used in the manufacture thereof on behalf of licensee for manufacture for sale of Ayurvedic, Siddha and Unani drugs. 2. *Categories of Ayurvedic, Siddha and Unani drugs other than those specified in the First Schedule to this Act for which testing will be carried out:

AYURVEDA AND SIDDHA UNANI

______________________________________________________________________ 1. Asava and Arista 1. Nabeez, Khal (Sirka) 2. Arka-Tinir 2. Majoon and its sub-categories Itrifal, Jawarish, Khameera, Laooq, Halwar 3. Avaleha and Paka-Ilakam3.Sufoof, Zuroor, Sunoon. 4. Kavatha Curna-Kutinir Curanam 4. Namak, Khar 5. Guggulu 5. Raughan 6. Ghrita-Ney 6.Zimad 7 Churna-Curanam 7.Habb (Pill) 8. Taila-Tailam 8. Shiyaf 9. Dravaka-Tiravakam 9. Qutoor (drops) 10. Lavana-Uppu 10. Kohal (Surma), Kajal 11. Kshara-Saram 11. Satt, Usara 12. Lepa-Pacai 12. Kushta 13. Vati, Gutika-Kulikai 13. Joshanda (Single drugs) 14. Vartti 14. Sharbat Sikanjabeen 15. Netrabindu (Aschyotan) 15. Sayyal, Arq (Distillates) 16. Anjana-Kanmai 16. Qurs (Tablet) 17. Sattva-Sattu 17. Marham, Qairooti 18. Kupipakva Rasayana-Kuppi Centuram 18. Humool, Furzaja 19. Parpati 19. Bakhoor 20. Pishti 20. Nabati Advia 21. Bhasma-Parpam 21. Maadni Advia 22. Mandura-Atai kutinir 22. Asjad Advia

Drugs and Cosmetics Rules, 1945 243

23. Rasay oga-C entur am 23. Haiwani Advia 24.Lauha24.Jauhar 25. Ghana Sattva 25. Natool 26. Kvath Pravahi- Kutinir 26. Nashooq, Naswar 27. Panak (Syrup)-Manappaku 27. Shamoom 28. Tablet-Mattirai 28. Saoot (Nasal drops) 29. Capsule 29. Mazoogh 30. Ointment- Kalimapu 30. Tila 31. Phalavarti 31. Lashooq 32. Dhoomravarti/Doopan 32. Gulqand 33. Kshar Sutra/Kshar Varti 33.Fateela 34. Single drugs: 34. Ghaza, Utban, Sasbhh

(a) Plant based
(b) Mineral based
(c) Metal based
(d) Animal based
(e) Synthetic
(f) Any other Ayurvedic, Siddha, Unani formulation 35. Pushp (Phool) 35. Capsule 36. Nasya 36. Huqna 37. Swarasa (Fresh juice) 37. Naurah 38. Karna Bindu (Ear drops) 38. Latookh

39. Any other dosage of Patent and 39. Vajoor (Throat paint)

Proprietary and Ayurvedic, Siddha, Unani Drug

40. Mazmazah (Mouth washer)

(3) Names, qualifications and experience of experts employed for testing and the person in-charge of testing.
(4) List of testing equipment provided.
(5) *I/We enclose a plan of the testing premises showing the location and area of the different sections thereof.
(6) An inspection fee of rupees ..........................has been credited to Government under the head of account .......................................................................

¹ Ins. by G.S.R. 701(E), dt. 27.9.2001 and subs. by G.S.R. 73(E), dt. 31.1.2003.

Full address of the Applicant *Delete whichever is not applicable. ______________________________________________________________________________________

Drugs and Cosmetics Rules, 1945 244

1[FORM 48 (See Rule 160 B) Approval for carrying out tests or analysis on Ayurvedic, Siddha and Unani drugs or raw materials used in the manufacture thereof on behalf of licensees for manufacture for sale of Ayurvedic, Siddha and Unani drugs

Number of approval and date of issue..............................................................

1. Approval is hereby granted to .........................................................for carrying

out tests in identity, purity, quality and strength on the following categories of Ayurvedic, Siddha or Unani drugs and the raw materials used in the manufacture thereof on the premises situated at .............................................................. Categories of Ayurvedic, Siddha and Unani drugs. ______________________________________ _____________________________________ ______________________________________

2. Name of experts employed for testing and the person-in-charge of testing

....................................(experts) and........................... (person in-charge).

3. The approval shall be in force from ......................... to.....................................

4. The approval is subject to the conditions stated below and such other conditions as may be specified in the rules for the time being in force under the Act.

Seal of State Licensing Authority

Conditions of approval

(1) This approval and any certificate of renewal in Form 49 shall be displayed in the approved premises and shall be produced at the request of the Inspectors appointed under the Act.
(2) If the applicant wishes to undertake during the currency of the approval the testing of any other category of Ayurvedic, Siddha or Unani drugs it should apply to the approving authority for necessary endorsement as provided in Rule 160A. This approval will be deemed to extend to the items so endorsed.
(3) Any change in the experts or in the person in-charge of the testing shall be forthwith reported to the approving authority.
(4) The applicant shall inform the approving authority in writing in the event of any change of the constitution of the laboratory operating under this Form. Where any change in the constitution of the laboratory takes place, the current approval shall be deemed to be valid for a maximum period of three months from the date on which the change takes place unless in the meantime, a fresh approval has been taken from the approving authority in the name of the laboratory with the changed constitution.] ____________________________________________________________________

¹ Ins. by G.S.R. No.702(E) dt. 27-9-2001 and subs.by.G.S.R.73(E), dt.31.01.2003.

Drugs and Cosmetics Rules, 1945 245

1[Form 49 (See rule 160- I)

Certificate of renewal for carrying out tests or analysis on Ayurvedic, Siddha or

Unani drugs or raw materials used in the manufacture thereof on behalf of licensees for manufacture for sale of Ayurvedic, Siddha or Unani drugs

1. Certified that approval number ........................... granted on the ...........

day o f ...................................................................................... 19.... for carrying out tests of identity, purity, quality and strength on the following categories of Ayurvedic, Siddha or Unani, drugs and the raw materials used in the manufacture

thereof at the premises situated at ............................... has beenrenewed from . to

................................................................................................. (date). Catagories of Ayurvedic, Siddha or Unani drugs: ....................................................... ....................................................... 2. Name of experts and the person-in-charge of

¹ Ins. by G.S.R. No.701(E) dt. 27-9-2001 and subs. by G.S.R.73(E) dt. 31.01.2003.

Place : ................. Designation ......... Seal of State Licensing Authority ] _____________________________________________________________________

1[FORM 50 [See rule 160 D(f)] Report of test analysis by approved Laboratory

(1) Name of manufacturer from whom sample received together with his manufacturing licence number under the Act or the rules made thereunder. ......................................................................................................
(2) Reference number and date of the letter from the manufacturer under which the same was forwarded. ......................................................................................................
(3) Date of receipt of the sample .........................................................................................................
(4) Name of Ayurvedic, Siddha and Unani drug of raw material purporting to be contained in the sample. .........................................................................................................
(5) Details of raw material of final product (in bulk finished pack)* as obtained from the manufacturer:
- (a) Original manufacturer's name in the case of raw materials and drugs repacked...... ..................................

Drugs and Cosmetics Rules, 1945 246

(b) Batch number.......................................
(c) Batch size as represented by sample.................
(d) Date of manufacture, if any ............................
(e) Date of expiry, if any........................................

(6) Results of test or analysis with protocols of test or analysis applied or as per Ayurvedic, Siddha or Unani Pharmacopoeial standards.
(7) Other specific tests for identity, purity, quality and strength of Patent and Proprietary drugs. In the opinion of the undersigned, the sample referred to above is of standard *quality/is not of standard quality as defined in the Act or the rules made thereunder for the reasons given below ......................................................................................................... ......................................................................................................... ...

Date: ......

(Signature of the Person in-charge of testing)

Place :....... (F. No. .......................................)

Name and Designation and Seal

Name and Address of the Laboratory Licence No....................................... Note : Final product includes repacked material.

• Delete whichever is not applicable.] _____________________________________________________________________ Drugs and Cosmetics Rules, 1945 247

¹ Ins. by G.S.R. 701(E) dt. 27-9-2001 and subs. by G.S.R.73(E) dt. 31.1.2003

B

(See rules 7 and 48)

Fees for test or analysis by the Central Drugs Laboratories or State Drugs Laboratories :

I. Fees for test and assay of Drugs requiring use of animals

Rupees Adrenocorticotrophic hormone assay 1000 Gonadotrophic hormone for LH activity

FSH Activity 1000 Posterior pituitary extract or its synthetic substitute for oxytocin activity Vasopressor activity

Insulin and insulin in combination for hypoglycaemic activity

Pyrogen test

Determination of Lethal doses, LD or LD in mice 800

2. Microbiological tests and assays -

Bioassay of Antibiotic 400

Microbiological assay of vitamins

Phenol coefficient 300

Preservatives – Microbial challenge test 2000

Transfusion and infusion sets or assemblies Other sterile devices

¹ Subs. by G.S.R. No.478(E), dt. 7-8-1998.

___________________________________________________________________________

Drugs and Cosmetics Rules, 1945 248

3. Identification tests -

(a)

Chemical Methods

(b) Microscopical 50
(c) IR Spectroscopy 150
(d) UV Spectroscopy
(e) Chromotography
- (i) Paper
- (ii) Thin layer
- (iii) Column
- (iv) GLC
- (v) HPLC
- (vi) Gel Filtration
(f) Electrophoresis
- (i) Paper and Cellulose acetate 200
- (ii) Polyacrylamide Gel, starch gel, agar gel 300 each 4. Physical tests –
(a) Optical rotation, specific gravity, refractive index, weight per ml, fluorescence. 75 each
(b) Viscocity 100
(c) pH, Solubility, loss on drying, net content, ash, sulphated ash etc. 20 each
(d) Absorbancy, wt/unit area (surgical), foreign matter, extractive value, thread count etc. 30 each
(e) Uniformity of weight
- (i) Tablets 15
- (i) Capsules 20
(f) Acid value, iodine value, peroxide value,

Soponification value, acetyl value.

100 each

(g) Disintegration tests –
- (i) Ordinary tablets
- (ii) Capsule
- (iii) Sugar Coated tablets
- (iv) Enteric coated tablets
(h) Dissolution test 250
- (i) Uniformity of content. 500
(j) Wt. per unit area (powder), particle size, count, methoxy value. 200 each
(k) Limit test for impurities 100 each
(l) Related substances
- (i) T LC method
(A) Without reference standard
(B) With reference standard Drugs and Cosmetics Rules, 1945 249
- (ii) Gas Liquid Chromatography
(A) Without reference standard
(B) With reference standard (iii)High pressure Liquid Chromatography (A)Without reference standards (B)With reference standards
(m) Water (Karl Fisher) 200

(5) Assays -
- (a) General chemical methods 100 for each ingredient
- (b) Non-aqueous/instrumental 200 for each ingredient
- (c) Chromatography
  - (i) TLC
  - (ii) Column
  - (iii) GLC
  - (iv) HPLC
  - (v) Gel filtration
- (d) Nitrogen determination 200
- (e) Medicinal gases 400
(6) Polymorph test -

(Content of polymorph A in chloramphenicol palmitate)

II Fees for Sera and Vaccine – Sterility test

Potency testing of rabies vaccine 2025 Potency testing of pertussis fraction of DPT vaccine 2025 Potency testing of tetanus fraction of DPT/DT/TT vaccine

Potency testing of diphtheria Fraction of DPT/DTE vaccine. 2700

Testing of Oral Polio Vaccine (OPV) – Potency Identity Stability Potency testing of Japanese Encephalitis Vaccine 3900 Potency testing of Snake Venom serum for each venom Identity testing for vaccines/sera Cell culture (Other than OPV)

Other than cell culture 100

Drugs and Cosmetics Rules, 1945 250 Estimation of volume/pH/total solids/No. of organisms/Physical checking. 50 each Estimation of total proteins/aluminium content/phenol/formaldehyde/thiomersal/moisture.

200 each Pyrogen testing 500 Stability test for vaccines other than Oral Polio Vaccine 4550

III

Cosmetics

400 – 1500 (The exact amount of the fee shall be determined by the Director of Laboratory or the Government Analyst, as the case may be).

IV Rubber Condoms

IV Homoeopathic medicines :

1. Identification test for raw material of botanical origin (other than assay of constituents). 2. Identification test for raw material of chemical origin (other than assay)

5. Identification test for drugs of animal origins or microbiological. 6. Fees for testing of Mother tincture, lower potencies upto 3x

or equivalent.

7. U.V. or I.R. or H.P.C.L. defect determination

Determination of Biochemic drug through atomic absorbance spectrophotometer.

Note :-

1. For tests not listed in the Schedule, charges will be determined by the Director or the Government Analyst of the laboratory / institute as the case may be.

2. For the tests relating to Ayurvedic, Unani and Siddha medicines, charges will be determined by the Adviser (Indigenous System of Medicine), Director or Government Analyst of the Laboratory / Institute, as the cased may be.]

Drugs and Cosmetics Rules, 1945 251

Schedule C

(See rules 23, 61 and 76 and Part X)

Biological and Special Products

1. Sera.

2. Solution of serum proteins intended for injection.

3. Vaccines for parenteral injections.

4. Toxins.

5. Antigen. 6. Antitoxins. 7. Neo-arsphenamine and analogous substances used for the specific treatment of infective diseases. 8. Insulin. 9. Pituitary (Posterior Lobe) Extract. 10. Adrenaline and Solutions of Salts of Adrenaline.

3[11. Antibiotics and preparations thereof in a form to be administered parenterally.]

4[12 Any other preparation which is meant for parenteral administration as such or after being made up with a solvent or medium or any other sterile product and which-

(a) requires to be stored in a refrigerator; or
(b) does not require to be stored in a refrigerator.] 13. Sterilized surgical ligature and sterilized surgical suture. 14. Bacteriophages.

5[15 Ophthalmic preparations.]

6[16 Sterile Disposable Devices for single use only.]

___________________________________________________________________ 1. Amended by Notfn. No. F. 1-30/47-A, dt. 5-1-1950

³ Subs. by No. G.S.R. 487(E) ,dt. 2.7.1984.

2. Amended by Notfn. No. F. 1-8/60-D, dt. 31-8-1960

⁵ Ins. by Notfn. No. G.S.R. 1242(E) ,dt. 17.9.1979

⁶ Ins. by Notfn. No. G.S.R. 109(E) ,dt. 22.2.1994.

4. Amended by Notfn. No. F. 1-14/68-D, dt. 26-10-1968

(1)

Drugs and Cosmetics Rules, 1945 252

(See Rule 23, 61 and 76)

Other Special Products

1 Drugs belonging to the Digitalis group and preparations containing drugs belonging to the

Digitals group not in a form to be administered parenterally. 2 Ergot and preparations containing Ergot not in a form to be administered parenterally. 3 Adrenaline and preparations containing Adrenaline not in a form to be administered parenterally. 4 Fish Liver Oil and preparations containing Fish Liver Oil. 5 Vitamins and preparations containing any vitamins not in a form to be administered parenterally. 6 Liver extract and preparations containing liver extract not in a form to be administered parenterally. 7 Hormones and preparations containing Hormones not in a form to be administered parenterally. 8 Vaccine not in a form to be administered parenterally.

2[9. Antibiotics and preparations thereof not in a form to be administered parenterally.]

² Subs. by.G.S.R.487(E) ,dt. 2-7-1984.

³ Ins. By G.S.R. 601(E), dt. 27.8.2002.

___________________________________________________________________ 1. Amended by. Notfn. No. F. 1-22/59-D, dt. 9-4-1960

Drugs and Cosmetics Rules, 1945 253

Schedule D

Class of drugs Extent and conditions of exemption

1. Substances not intended for medicinal use All provisions of Chapter III of the Act and rules thereunder subject to the condition that if the substance is imported in bulk, the importer shall certify that the substance is imported for non- medicinal uses, and if imported otherwise than in bulk, each container shall bear a label indicating that the substance is not intended for medicinal

use or or is of commercial quality.

• * *
• * * *
• * * * * * * *
• * * * * * * * 5. The following substances, which are used both as articles of food as well as drugs:- All provisions of Chapter III of the Act and rules thereunder. (i) (ii) (iii) (iv) All condensed or powdered milk whether pure, skimmed or malted, fortified with vitamins and minerals. Farex, Oats, Lactose and all other similar cereal preparations whether fortified with vitamins or otherwise

excepting those for parenteral

use.

Virol, Bovril, Chicken essence and

all other similar predigested foods.

Ginger, Pepper, Cumin, Cinnamon and all other similar spices and condiments unless they are specifically labelled as conforming to the standards in the Indian Pharmacopoeia or the

official pharmacopoeias and the

official compendia of the drug standards prescribed under the Act and rules made thereunder.

____________________________________________________________________________________________

1. Entry 2 and 3 omitted by Notfn. No. F.1-6/62-D ,dt. 2-7-1969 2. Entry 4 omitted by Notfn. No.604 (E) ,dt. 24-8-2001

3. Amended by Notfn. F. 1-53/55-D, dt. 7.1.1957.

4. Amended by Notfn. No. X11013/1/77-D&MS, dt. 15.12.1977.

Drugs and Cosmetics Rules, 1945 254 __________________________________________________________________________

Class of drugs Extent and conditions of exemption

______________________________________________________________________________________________________________ _______

1[6.

Zones” as notified by the Government of India

from time to time.

The provisions of Chapter III of the Act and rules thereunder which required them to be covered by an import licence, import registration and import through notified port of entry, subject to the conditions that these

drugs and cosmetics shall not be diverted for sale in the

country: Provided that such imported drugs and cosmetics may be permitted to the domestic area if they meet the requirements of standard procedure for import and registration as required under Chapter III of the Act and rules thereuder.]

______________________________________________________________________________________________________________________

¹ Ins. by G.S.R. 528(E), dt. 8.7.2003.

______________________________________________________________________________________________________________________

Drugs and Cosmetics Rules, 1945 255

(I)

(See rule 21 (d) and rule 24 A)

Information and undertaking required to be submitted by the manufacturer or his authorized

agent with the Application Form for a Registration Certificate. The format shall be properly

filled in for each application in Form 40. The detailed information, secret in nature, may be furnished on a Computer Floppy.

1. Particulars of the manufacturer and manufacturing premises 1.1 Name and address of the manufacturing premises (Telephone No.,

1.5 A copy of Plant Master File (duly notarised)

notarised)

1.7 A brief profile of the manufacturer’s research activity.

2. Particulars of the manufactured drugs to be registered under Registration

Certificate.

2.1 Names of drugs (Bulk/Formulation/Special product) to be registered meant for import into and use in India.

in the country of origin (duly notarized).

2.3 A copy of Good Manufacturing Practice (GMP) certificate, as per WHO-GMP

guidelines, or Certificate of Pharmaceutical Products (CPP), issued by the National Regulatory Authority of the foreign country concerned, in relation to the bulk drugs or formulations or special products, meant for import into India.

2.4 The domestic prices of the drugs to be registered in India, in the currency of the

country of origin.

2.5 The name(s) of the drug(s) which are original research products of the

manufacturer.

¹ Ins. by G.S.R. No.604(E) , dt. 24-8-2001 (w.e.f. 1-1-2003).

___________________________________________________________________

Drugs and Cosmetics Rules, 1945 256

3. Undertaking to declare that: -

3.1. We shall comply with all the conditions imposed on the Registration Certificate,

read with rules 74 and 78 of the Drugs and Cosmetics rules, 1945.

3.2 We declare that we are carrying on the manufacture of the drugs mentioned in

this Schedule, at the premises specified above, and we shall from time to time report any change of premises on which manufacture will be carried on and in cases where manufacture is carried on in more than one factory any change in the distribution of functions between the factories.

3.3 We shall comply with the provisions of Part IX of the Drugs and Cosmetics Rules, 1945.

3.4 Every drug manufactured by us for import under the Registration Certificate into India shall be as regard strength, quality and purity conforms with the provisions of Chapter III of Drugs and Cosmetics Act, 1940 and Part IV of the Drugs and Cosmetics Rules 1945, and their amendments from time to time.

3.5 We shall from time to time report for any change or manufacturing process, or

in packaging, or in labelling, or in testing, or in documentation of any of the drugs, pertaining to the Registration Certificate, to be granted to us. Where any change in respect of any of the drugs under the Registration Certificate has taken place, in respect of any of the above matters, we shall inform the same to the licensing authority in writing within 30 days from the date of such changes. In such cases, where there will be any major change/modification in manufacturing or in processing or in testing, or in documentation, as the case may be, at the discretion of the licensing authority, we shall obtain necessary approval within 30 days by submitting a separate application, alongwith the registration fee as specified in clause (ii) of sub rule (3) of rule 24-A.

3.6 We shall from time to time report for any administrative action taken due to adverse reaction, viz. market withdrawal regulatory restriction, or cancellation of authorization and/or “not of standard quality report” of any drug pertaining to the Registration Certificate declared by any Regulatory Authority of any country where the drug is marketed/sold or distributed. The despatch and marketing of the drug in such cases, shall be stopped immediately and the licensing authority shall be informed immediately. Further action in respect of stop marketing of drug shall be taken as per the directions of the licensing authority. In such cases, action equivalent to that taken with reference to the concerned drug(s) in the country of origin or in the country of marketing will be followed in India also, in consultation with the licensing authority. The licensing authority may direct any further modification to this course of action, including the withdrawal of the drug from Indian market within 48 hours time period.

3.7 We shall comply with such further requirements, if any, as may be specified, by

the Government of India, under the Act and the rules made there under.

3.8 We shall allow the licensing authority and/or any person authorized by him in that behalf to enter and inspect the manufacturing premises and to examine the process/procedure and documents in respect of any drug manufactured by us for which the application for Registration Certificate has been made.

Drugs and Cosmetics Rules, 1945 257

3.9 We shall allow the licensing authority or any person authorized by him in that

behalf to take samples of the drugs concerned for test, analysis or examination, if considered necessary by the licensing authority.

Place: Date:

Signature of the manufacturer

¹ Ins. by G.S.R. 35(E), dt. 20.1.2005.

1[or his authorized agent] Seal / Stamp ___________________________________________________________________________

Drugs and Cosmetics Rules, 1945 258

(II)

[See rule 21 (d) and rule 24 A]

Information required to be submitted by the manufacturer or his authorized agent with the Application Form for the registration of a bulk drug/formulation/special product for its import into India. The format shall be properly filled in and the detailed information, secret in nature, may be furnished on a Computer Floppy

1. GENERAL

1.1. Name of the drug/formulation/special product, a brief description and the

therapeutic class to which it belongs.

1.2 Regulatory status of the drug. Free Sale Certificate and/or Certificate of

Pharmaceutical Products (CPP) issued by the Regulatory Authority of the country of origin. Free sale approval issued by the Regulatory Authorities of other major countries.

issued by National Regulatory Authority of the country of origin (duly notarised).

1.5 List of countries where marketing authorization or import permission for the said

drug is granted with date (respective authorisation shall be enclosed).

1.6 List of countries where marketing authorisation or import permission for the said

drug is cancelled/withdrawn with date.

1.7 List of countries where marketing authorisation or import permission for the said

drug is pending since (date).

2. CHEMICAL AND PHARMACEUTICAL INFORMATION OF DRUGS.

2.1 Chemical name.

Code name or number, if any. Non-proprietary or generic name, if any. Structure. Physico-chemical properties.

2.2 Dosage form and its composition.

Qualitative and Quantitative composition in terms of the active substances(s) and excipient(s) List of active substance(s) separately from the constituent(s) of excipients.

2.3 Specifications of active and inactive ingredient (s) including pharmacopoeial references.

2.4 Source of active ingredient(s), name and address.

¹ Ins. by G.S.R. No.604(E) , dt. 24-8-2001( w.e.f. 1-1-2003).

___________________________________________________________________________

Drugs and Cosmetics Rules, 1945 259

2.5 Tests for identification of the active ingredient(s),

Method of its assays and tests for impurity profile with reference standards for the impurities (Protocol to be submitted alongwith reference standards for the impurities / relative substances).

2.6 Outline method and flow chart of manufacture of the bulk drug or finished formulation or special product.

2.7 Detailed test protocol for the drug with pharmacopoeial reference or in- house specification as approved by the registration authority, in the country of origin.

2.8 Stability data including accelerated stability and real time stability analysis.

2.9 Documentation on pack size.

2.10 Numerical expression on EAN bar code on the labels and cartons,

2.11 Safety documents on containers and closures.

2.12 Documentation on storage conditions.

2.13 Three samples of medicinal product/drug and outlet packing are to be submitted with batch certificates. Additional samples as well as reference substances with batch certificates including date of manufacture, shelf life, and storage conditions of reference substance may be required both during registration procedure and during validity of registration decision.

2.14 Batch test reports/certificate of five consecutive production batches in details of the medicinal product are to be submitted for every site of manufacturing premises.

2.15 Manner of labelling as per rule 96 of the Drugs and Cosmetics Rules 1945.

2.16 Package insert.

2.17 Details of safety handling procedure of the drug.

2.18 Details of PMS study report for marketing period not exceeding five years. .

3. BIOLOGICAL AND BIOPHARMACEUTICAL INFORMATION OF DRUGS

3.1 Biological control tests applied on the starting material, if applicable.

3.2 Biological control tests applied on the intermediate products, if applicable.

3.3

Biological control tests applied on the finished medical products, if applicable.

3.4 Stability of the finished products in terms of biological potency of the drug, if applicable.

3.5 Sterility tests, if applicable, specification and protocol therein.

3.6 Pyrogen tests, if applicable, specification and protocol therein.

Drugs and Cosmetics Rules, 1945 260

3.7 Acute and sub-acute toxicity tests, if applicable specification and protocol therein.

3.8 Bio-availability studies and bio-equivalence data, if applicable.

3.9 Data relating to the environmental risk assessment for r-DNA products.

3.10 Other information relevant under the section.

4. PHARMACOLOGICAL AND TOXICOLOGICAL INFORMATION OF DRUGS.

Executive summary of the product is to be submitted mentioning the specific and general pharmacological actions of the drug and pharmacokinetic studies on absorption, metabolism, distribution and excretion. A separate note is to be given on acute and sub-acute toxicity studies and long term toxicity studies. Specific studies on reproductive toxicity, local toxicity and carcinogenic activity of the drug is to be elaborated, as far as possible.

5 CLINICAL DOCUMENTATION

A new drug as defined under rule 122-E of the Drugs and Cosmetics Rules, 1945 is required to be permitted separately by the licensing authority under rule 122-A of the said rules prior to its registration. Such a new drug requires a brief summary and clinical documentation, alongwith permission under 122-A of the said rules for its Registration Certificate.

6. LABELLING AND PACKAGING INFORMATION OF DRUGS.

6.1 Labels should conform as per the specifications under the Drugs and Cosmetics Rules 1945.

6.2 Package insert should be in English and shall indicate the following therapeutic indications: - Posology and method of administration. . Contra-indications. Special warnings and special precautions for use, if any. Interaction with other medicaments and other forms of interaction. Pregnancy and lactation, if contra-indicated. Effects on ability to drive and use machines, if contra-indicated.

6.3 Package insert should indicate the following pharmaceutical information: -

List of excipients. Incompatibilities. Shelf life in the medical product as packaged for sale. Shelf life after dilution or reconstitution according to direction. Shelf life after first opening the container. Special precautions for storage. Nature and specification of the container. Instructions for use/handling.

7 SPECIFIC INFORMATION REQUIRED FOR THE SPECIAL PRODUCTS (to be supplied, separately in Annexures, as ‘A’, ‘B’ and ‘C’)

Drugs and Cosmetics Rules, 1945 261

The information submitted above is true to the best of my knowledge and belief.

Place: Date :

Signature of the manufacturer

1[or his authorized agent] Seal/Stamp

NB:

Any change in the process of manufacture, method of testing, labelling, packaging, designing of the sale pack, medical literature and documentation is to be intimated to the licensing authority forthwith and permission to be obtained from him within 30 days time period.

2. Information relating to Serial No.4 and Serial No.5 are not applicable for drugs

figuring in Indian Pharmacopoeia and also for the drugs figuring in United States of

Pharmacopoeia, European Pharmacopoeia, and British Pharmacopoeia provided such drugs have already been approved for marketing in India for the applicant under rules 122A, 122B, 122C or 122D of the Drugs and Cosmetics Rules 1945.

___________________________________________________________________________

¹ Ins. by G.S.R. 35(E), dt. 201.2005.

ANNEXURE A

(See Schedule D-II, item No.7)

INFORMATION TO BE SUBMITTED IN SCHEDULE D-II

SPECIFIC INFORMATION REQUIRED FOR THE BLOOD PRODUCTS

A product dossier showing the:

1. Details of source Plasma, its viral screening, storage and transport from Collection Centres to Fractionation Centre. Regulatory status of Collection Centres. 2. Details of Fractionation Centre, Regulatory Status, Method of Fractionation and Control Processes. 3. Details of viral inactivation process for enveloped and non-enveloped virus(es) and viral validation studies to assess the viral load of the product. Testing of viral screening at any stage is to be highlighted with the details of the kits used with their respective sensitivity and specificity.

4. Bulk filtration prior to pharmaceutical packing giving the full details of Micro-filtration or nanofiltration followed.

5. Complete details of pharmaceutical processing and utilization.

6. Test protocol of the product showing the specifications and pharmacopoeial method followed for various testing parameters. Specific batch test report for at least 3 batches showing the specifications of each testing parameter.

Drugs and Cosmetics Rules, 1945 262 7. Pack size and labelling.

8. Product insert.

. Specimen Batch Release Certificate issued by the National Regulatory Authority of the country of origin. Specific processings like safe handling, material control, area control, pasteurization, stability studies, storage at quarantine stage and finished stage and packaging should be highlighted in the product dossier.

The information submitted above is true to the best of my knowledge and belief.

Place: Date:

Signature of the manufacturer Seal / Stamp

NB: 1. Any change in the process of manufacture, method of testing, labelling, packaging, designing of the sale pack, medical literature and documentation is to be intimated to the licensing authority forthwith and permission to be obtained from him within 30 days time period.

ANNEXURE-B

(See Schedule D-II, item No.7)

INFORMATION TO BE SUBMITTED IN SCHEDULE D-II SPECIFIC INFORMATION REQUIRED FOR THE DIAGNOSTIC KITS

A Product dossier showing the :

1. The details of source antigen or antibody as the case may be and characterization of

the same. Process control of coating of antigen or antibody on the base material like Nitrocellulose paper, strips or cards or ELISA wells etc.

Detailed composition of the kit and manufacturing flow chart process of the kit showing the specific flow diagram of individual components or source of the individual components.

2. Test protocol of the kit showing the specifications and method of testing.

In house evaluation report of sensitivity, specificity and stability studies carried out by the manufacturer.

3. The report of evaluation in details conducted by the National Control Authority of country of origin.

Specimen batch test report for at least consecutive 3 batches showing specification of each testing parameter.

Drugs and Cosmetics Rules, 1945 263

4. The detailed test report of all the components used/packed in the finished kit.

5. Pack size and labelling.

6. Product insert.

Specific evaluation report, if done by any laboratory in India, showing the sensitivity and specificity of the kit.

Specific processing like safe handling, material control, area control, process control, stability studies, storage at quarantine stage and finished stage, packaging should be highlighted in the product dossier.

The information submitted above is true to the best of my knowledge and belief.

Place: Date:

Signature of the manufacturer Seal / Stamp

NB: 1.Any change in the process of manufacture, method of testing, labelling, packaging,

designing of the sale pack, medical literature and documentation is to be intimated to the licensing authority forthwith and permission to be obtained from him within 30 days time period. ANNEXURE-C

(See Schedule D-II, item No.7)

INFORMATION TO BE SUBMITTED IN SCHEDULE D-II SPECIFIC INFORMATION REQUIRED FOR VACCINES.

strain.

2. Detailed flow chart of manufacturing process showing all the details of in-process

control on toxicity, potency study and stability data of the final bulk and the final finished product including the storage temperature.

3. Complete details of chemical and pharmaceutical data for the product.

Composition and dosage form – method of manufacture with detailed flow chart – control of starting material – control tests on intermediate and finished products – certificate of analysis of finished products – validation of critical manufacturing steps.

4. Test protocol of the vaccines showing the specification and method of testing

including pharmacopoeial specification.

5. Specimen batch test report for at least consecutive three batches showing the

specification of each testing parameter.

6. The detailed test reports of all the components used / packed in the finished vaccine.

Drugs and Cosmetics Rules, 1945 264

9. Specimen batch release certificates issued by the National Regulatory Authority of the country of origin.

10. Summary of pre-clinical and clinical data including :

(a) Prescribing information.
(b) Pharmacological and toxicological data pertaining to tests on animals Characterisation of immuno response and safety study in human use, in specific conditions. Specific information on source of seed strain, its characterization, inactivation, etc. and processings like safe handling, material control, area control, process control, stability studies, storage at quarantine stage and finished state, packaging should be highlighted in the product dossier. Specimen production and quality control protocols for at least three consecutive lots showing the specifications for each quality control parameter including pharmacopoeial requirement shall be submitted for study. The information submitted above is true to the best of my knowledge and belief. Place: Date: Signature of the manufacturer Seal / Stamp NB: 1. Any change in the process of manufacture, method of testing, labelling, packaging, designing of the sale pack, medical literature and documentation is to be intimated to the licensing authority forthwith and permission to be obtained from him within 30 days time period. 2. All vaccines shall be new drugs unless certified otherwise by the liencesing authority approved under rule 21 of the Drugs and Cosmetic Rules, 1945. A copy of approval of the vaccine issued by the said licensing authority is to be enclosed, prior to issue of Registration Certificate of the said vaccines. Drugs and Cosmetics Rules, 1945 265

-E (Omitted)

___________

-E(1)

[See rule 161 (2)]

List of poisonous substances under the Ayurvedic (including Siddha) and Unani Systems of Medicine

A. AYURVEDIC SYSTEM

Drugs of vegetable origin

Ahipena

Papaver somniferum Linn.

Vatsanabha Acontium chasmanthum Stapfex Holm.

Vishamushti Strychnox nuxvomica Linn.

Shringivisha Acontium chasmanthum Stapfex Holm.

II Drugs of Animal Origin.

Sarpa Visha

Snake poison.

III

Drugs of Mineral Origin

Gauripashana Arsenic.

Hartala Arseno sulphide.

Sindura Red oxide of lead. Girisindura Red oxide of mercury.

________________________________________________________________ 1 “Schedule E” omitted No.G.S.R. 462(E),dt 22-6-1982] 2. Added by Notfn. No. 1-23/67-D dt. 2-2-1970

Drugs and Cosmetics Rules, 1945 266 B. SIDDHA SYSTEM

Aloe sp.

C. UNANI SYSTEM

I Drugs of vegetable origin

Afiyun Papaver somniferum Linn.

Shokran Conium maculatum Linn. . II

Drugs of Animal origin

Sanp (head)

Snake (head).

Telni makkhi Mylabris cichori Linn.

Mylabaris pustulata Thund. Mylabris macilenta .

Drugs and Cosmetics Rules, 1945 267 III Drugs of Mineral origin

Darchikna Hydrargryi perchloridum.

Hira Diamond.

Ras Kapoor Hydrargryi Subchloridum (calomel).

Shingruf Hydrargryi bisulphuratum.

Zangar Cupri subacetas.

Sammul-Far(Abyaz, Asfar, Aswad and Ahmar) Arsenic (white, yellow, black and red).

Tootiya Copper Sulphate.

Para Hydrargyrum.

Hartal Arsenic trisulphide (yellow).]

Drugs and Cosmetics Rules, 1945 268

F

(See rule 78)

1[Part I to Part XII-A]– Omitted

_______

2[PART XII B

REQUIREMENTS FOR THE FUNCTIONING AND OPERATION OF A BLOOD BANK AND / OR FOR PREPARATION OF BLOOD COMPONENTS. I. BLOOD BANKS / BLOOD COMPONENTS

A. GENERAL

1. Location and Surroundings : The blood bank shall be located at a place which

shall be away from open sewage, drain, public lavatory or similar unhygienic surroundings.

2. Building : The building (s) used for operation of a blood bank and/or

preparation of blood components shall be constructed in such a manner so as to

permit the operation of the blood bank and preparation of blood components under hygienic conditions and shall avoid the entry of insects, rodents and flies. It shall be well lighted, ventilated and screened (mesh), wherever necessary. The walls and floors of the rooms, where collection of blood or preparation of blood components or blood products is carried out shall be smooth, washable and capable of being kept clean. Drains shall be of adequate size and where connected directly to a sewer, shall be equipped with traps to prevent back siphonage.

3. Health, clothing and sanitation of staff: The employees shall be free from contagious or infectious diseases. They shall be provided with clean overalls, head-gears, foot-wears and gloves, wherever required. There shall be adequate, clean and convenient hand washing and toilet facilities.

B. ACCOMMODATION FOR A BLOOD BANK.

A blood bank shall have an area of 100 square meters for its operations and an additional area of 50 square meters for preparation of blood components. It shall be consisting of a room each for –

(1) registration and medical examination with adequate furniture and facilities for registration and selection of donors;
(2) blood collection (air-conditioned); _________________________________________________ 1. Schedule ‘F’ subs. by G.S.R. 245(E), dt. 5.4.1999 and corrected vide corrigendum G.S.R. 27(E), dated 22.1.1993. 2. Parts XII-A XIIC subs. by G.S.R. 245(E), dt. 5.4.1999. Drugs and Cosmetics Rules, 1945 269
(3) blood component preparation. (This shall be air-conditioned to maintain temperature between 20 degree centigrade to 25 degree centigrade);
(4) laboratory for blood group serology (air-conditioned);
(5) laboratory for blood transmissible diseases like Hepatitis, Syphilis, Malaria, HIV-antibodies (air-conditioned);
(6) sterilization-cum-washing;
(7) refreshment-cum-rest room (air-conditioned);
(8) store-cum-records. NOTES :
(1) The above requirements as to accommodation and area may be relaxed, in respect of testing laboratories and sterilization-cum-washing room, for reasons to be recorded in writing by the Licensing Authority and/or the Central Licence Approving Authority, in respect of blood banks operating in hospitals, provided the hospital concerned has a pathological laboratory and a sterilization-cum-washing room common with other departments in the said hospital.
(2) Refreshments to the donor after phlebotomy shall be served so that he is kept under observation in the blood bank.

C PERSONNEL

Every blood bank shall have following categories of whole time competent technical staff:-

(a) Medical Officer, possessing the qualifications specified in condition (i) of rule 122-G.
(b) Blood Bank Technician(s) possessing –
- (i) Degree in Medical Laboratory Technology (M.L.T) with six months’ experience in the testing of blood and/or its components; or
- (ii) Diploma in Medical Laboratory Technology (M.L.T) with one year’s experience in the testing of blood and / or its components, the degree or diploma being from a University / Institution recognized by the Central Government or State Government.
(c) Registered Nurse(s);
(d) Technical supervisor (where blood components are manufactured), possessing-
- (i) Degree in Medical Laboratory Technology (M.L.T) with six months’ experience in the preparation of blood components; or
- (ii) Diploma in Medical Laboratory Technology (M.L.T) with one year’s experience in the preparation of blood components, the degree or diploma being from a University / Institution recognized by the Central Government or State Government. Drugs and Cosmetics Rules, 1945 270 NOTES : (1) The requirements of qualification and experience in respect of Technical Supervisor and Blood Bank Technician shall apply in the cases of persons who are approved by the Licensing Authority and/or Central Licence Approving Authority after the commencement of the Drugs and Cosmetics (Amendment) Rules, 1999.

(2) As regards, the number of whole time competent technical personnel, the blood bank shall comply with the requirements laid down in the Directorate General of Health Services Manual.
(3) It shall be the responsibility of the licensee to ensure through maintenance of records and other latest techniques used in blood banking system that the personnel involved in blood banking activities for collection, storage, testing and distribution are adequately trained in the current Good Manufacturing Practices/Standard Operating Procedures for the tasks undertaken by each personnel. The personnel shall be made aware of the principles of Good Manufacturing Practices / Standard Operating Procedures that affect them and receive initial and continuing training relevant to their needs.

D. MAINTENANCE

The premises shall be maintained in a clean and proper manner to ensure adequate cleaning

and maintenance of proper operations. The facilities shall include:-

(1) Privacy and thorough examination of individuals to determine their suitability as donors.
(2) Collection of blood from donors with minimal risk of contamination of exposure to activities and equipment unrelated to blood collection.
(3) Storage of blood or blood components pending completion of tests.
(4) Provision for quarantine, storage of blood and blood components in a designated location, pending repetition of those tests that initially give questionable serological results.
(5) Provision for quarantine, storage, handling and disposal of products and reagents not suitable for use.
(6) Storage of finished products prior to distribution or issue.
(7) Proper collection, processing, compatibility testing, storage and distribution of blood and blood components to prevent contamination.
(8) Adequate and proper performance of all procedures relating to plasmapheresis, plateletpheresis and leucapheresis.
(9) Proper conduct of all packaging, labelling and other finishing operations.
(10) Provision for safe and sanitary disposal of –
- (i) Blood and/or blood components not suitable for use, distribution or sale.
- (ii) Trash and items used during the collection, processing and compatibility testing of blood and / or blood components. Drugs and Cosmetics Rules, 1945 271 E. EQUIPMENT Equipment used in the collection, processing, testing, storage and sale/distribution of blood and its components shall be maintained in a clean and proper manner and so placed as to facilitate cleaning and maintenance. The equipment shall be observed, standardized and calibrated on a regularly scheduled basis as described in the Standard Operating Procedures Manual and shall operate in the manner for which it was designed so as to ensure compliance with the official requirements (the equipments) as stated below for blood and its components. Equipment that shall be observed, standardized and calibrated with at least the following frequencies: 1. Temperature Recorder Compare against thermometer Daily As often as necessary 2 Refrigerated centrifuge Observe speed and temperature Each day of use As often as necessary Hematocrit centrifuge – – Standardise before initial use, after repair or adjustments and annually.

4, General lab.

Centrifuge – – Tachometer, every 6 months.

5. Automated Blood

typing

Observe controls for correct results Each day of use –

6. Haemoglobinometer Standardize against

cyanamethemoglob ulin standard

−ditto−

–

7. Refractiometer or

Urinometer Standardize against distilled water

− ditto − –

8. Blood container

weighing device Standardize against container of known weight.

− ditto –

As often as

necessary 9 Water Bath Observe temperature − ditto −

−ditto−

Rh view box

(wherever necessary)

–ditto–

− ditto −

− ditto−

_______________________________________________________________ EQUIPMENT PERFORMANCE FREQUENCY FREQUENCY OF CALIBRATION _______________________________________________________________________________________________

Drugs and Cosmetics Rules, 1945 272

Autoclave

Observe temperature

Each day of use

As often as

necessary

Serologic rotators

Observe controls for correct results

-- ditto--

Speed as often as necessary.

13 Laboratory

thermometers – – Before initial use

14 Electronic thermometers – Monthly – 15 Blood agitator Observe weight of the first container of blood filled for correct results

adjustments.

F. SUPPLIES AND REAGENTS:

All supplies and reagents used in the collection, processing, compatibility, testing, storage and distribution of blood and blood components shall be stored at proper temperature in a safe and hygienic place, in a proper manner and in particular:–

(a) all supplies coming in contact with blood and blood components intended for transfusion shall be sterile, pyrogen-free, and shall not interact with the product in such a manner as to have an adverse effect upon the safety, purity, potency or effectiveness of the product.
(b) supplies and reagents that do not bear an expiry date shall be stored in a manner that the oldest is used first.
(c) supplies and reagents shall be used in a manner consistent with instructions provided by the manufacturer.
(d) all final containers and closures for blood and blood components not intended for transfusion shall be clean and free of surface solids and other contaminants.
(e) each blood collecting container and its satellite container(s), if any, shall be examined visually for damage or evidence of contamination prior to its use and immediately after filling. Such examination shall include inspection for breakage of seals, when indicated, and abnormal discoloration. Where any defect is observed, the container shall not be used or, if detected after filling, shall be properly discarded.
(f) representative samples of each lot of the following reagents and/or solutions shall be tested regularly on a scheduled basis by methods described in the Standard Operating Procedures Manual to determine their capacity to perform as required, Drugs and Cosmetics Rules, 1945 273 Anti-human serum Blood grouping serums Each day of use Each day of use Lectin Each day of use Antibody screening and reverse grouping cells Each day of use

Hepatitis test reagents Each run

Syphilis serology reagents Each run Enzymes Each day of use HIV I and II reagents Each run Normal saline (LISS and PBS) Each day of use Bovine Albumin Each day of use.

Reagents and solutions Frequency of testing alongwith controls

G. GOOD MANUFACTURING PRACTICES (GMPs) /STANDARD OPERATING PROCEDURES (SOPs):

Written Standard Operating Procedures shall be maintained and shall include all steps to be followed in the collection, processing, compatibility testing, storage and sale or distribution of blood and/or preparation of blood components for homologous transfusion, autologous transfusion and further manufacturing purposes. Such procedures shall be available to the personnel for use in the concerned areas. The Standard Operating Procedures shall inter alia include:

1. (a) criteria used to determine donor suitability.

(d) method of accurately relating the product (s) to the donor;
(e) blood collection procedure, including in-process precautions taken to measure accurately the quality of blood drawn from the donor;
(f) methods of component preparation, including any time restrictions for specific steps in processing;
(g) all tests and repeat tests performed on blood and blood components during processing;
(h) pre-transfusion testing, wherever applicable, including precautions to be taken to identify accurately the recipient blood components during processing; (b) (c) methods of performing donor qualifying tests and measurements including minimum and maximum values for a test or procedure, when a factor in determining acceptability; solutions and methods used to prepare the site of phlebotomy so as to give maximum assurance of a sterile container of blood; Drugs and Cosmetics Rules, 1945 274
(n) quality control procedures for supplies and reagents employed in blood collection, processing and re-transfusion testing;
(o) schedules and procedures for equipment maintenance and calibration;
(p) labelling procedures to safeguard its mix-ups, receipt, issue, rejected and in-hand;
(q) procedures of plasmapheresis, plateletphersis and leucapheresis if performed, including precautions to be taken to ensure re-infusion of donor’s own cells;
(r) procedures for preparing recovered (salvaged) plasma if performed, including details of separation, pooling, labelling, storage and distribution;
(s) all records pertinent to the lot or unit maintained pursuant to these regulations shall be reviewed before the release or distribution of a lot or unit of final product. The review or portions of the review may be performed at appropriate periods during or after blood collection, processing, testing and storage. A thorough investigation, including the conclusions and follow-up, of any unexplained discrepancy or the failure of a lot or unit to meet any of its specification shall be made and recorded.

(2) A licensee may utilise current Standard Operating Procedures, such as the Manuals of the following organizations, so long as such specific procedures are consistent with, and at least as stringent as, the requirements contained in this Part, namely :-
- (i) Directorate General of Health Services Manual.
- (ii) Other Organisations or individual blood bank’s manuals, subject to the approval of State Licensing Authority and Central Licence Approving Authority.

H. CRITERIA FOR BLOOD DONATION:

Conditions for donation of blood:

(1) General – No person shall donate blood and no blood bank shall draw blood from a person, more than once in three months. The donor shall be in good health, mentally alert and physically fit and shall not be inmates of jail, persons having multiple sex partners and drug-addicts. The donors shall fulfil the following requirements, namely: -
- (i) procedures of managing adverse reactions in donor and recipient reactions:
- (j) storage temperatures and methods of controlling storage temperatures for blood and its components and reagents;
- (k) length of expiry dates, if any assigned for all final products;
- (l) criteria for determining whether returned blood is suitable for re-issue;
- (m) procedures used for relating a unit of blood or blood component from the donor to its final disposal; Drugs and Cosmetics Rules, 1945 275
- (a) the donor shall be in the age group of 18 to 60 years;
- (b) the donor shall not be less than 45 kilograms;

medication;

(e) haemoglobin which shall not be less than 12.5 grams;
(f) the donor shall be free from acute respiratory diseases;
(g) the donor shall be free from any skin diseases at the site of phlebotomy;
(h) the donor shall be free from any disease transmissible by blood transfusion, insofar as can be determined by history and examination indicated above;
- (i) the arms and forearms of the donor shall be free from skin punctures or scars indicative of professional blood donors or addiction of self injected narcotics.

(2) Additional qualifications of donor – No person shall donate blood, and no blood bank shall draw blood from a donor, in the conditions mentioned in column (1) of the Table given below before the expiry of the period of deferment mentioned in the column (2) of the said Table. Table: Deferment of blood donation ___________________________________________________________________________

CONDITIONS PERIOD OF DEFERMENT

___________________________________________________________________________ _____________________(1)___________________________(2)______________________

(a) Abortions 6 months
(b) History of Blood transfusion 6 months
(c) Surgery 12 months
(d) Typhoid 12 months after recovery
(e) History of Malaria and duly treated 2 months (endemic) 3 years (non endemic area)
(f) Tattoo 6 months
(h) Breast feeding 12 months after delivery
- (i) Immunization (Cholera, Typhoid, Diphtheria, Tetanus, Plague, Gammaglobulin) 15 days
(j) Rabies vaccination 1 year after vaccination
(k) History of Hepatitis in family or close contact 12 months
(l) Immunoglobulin 12 months

(3) No person shall donate blood and no blood bank shall draw blood from a person, suffering from any of the diseases mentioned below, namely:–
- (a) Cancer
- (b) Heart disease Drugs and Cosmetics Rules, 1945 276
- (c) Unexplained weight loss
- (d) Diabetes-controlled on insulin 1[(f) Hepatitis infection]
- (g) Chronic nephritis
- (h) Signs and symptoms, suggestive of AIDS (i ) Liver diseases
- (j) Tuberculosis
- (k) Polycythemia Vera.
- (l) Asthma
- (m) Epilepsy
- (n) Leprosy
- (o) Schizophrenia
- (p) Endocrine disorders

I. GENERAL EQUIPMENTS AND INSTRUMENTS.

¹ For blood collection room:

(i) Donor beds, chairs and tables: These shall be suitably and comfortably cushioned and shall be of appropriate size.
(ii) Bedside table
(iii) Sphygmomanometer and stethoscope
(iv) Recovery beds for donors.
(v) Refrigerators, for storing separately tested and untested blood, maintaining temperature between 2 to 6 degree centigrade with digital dial thermometer, recording thermograph and alarm device, with provision for continuous power supply.
(vi) Weighing devices for donor and blood containers.
(i) Copper sulphate solution (specific gravity 1.053)
(ii) Sterile lancet and impregnated alcohol swabs.
(iii) Capillary tube (1.3 x 1.4 x 96 mm for Pasteur pipettes)
(iv) Rubber bulbs for capillary tubings.
(v) Sahli’s haemoglobinometer / Colorimetric method.
(i) Clinical thermometers
(ii) Watch (fitted with a second-hand) and a stop-watch. (i) Citrate Phosphate Dextrose Adenine solution (CPDA) or Citrate Phosphate Dextrose Adenine – 1 (CPDA-1) – 14 ml solution shall be required for

² For haemoglobin determination:

³ For temperature and pulse determination.

⁴ For blood containers:

(a) Only disposable PVC blood bags shall be used (closed system) as per specifications of IP/USP/BP.
(b) Anti-coagulants: The anti-coagulant solution shall be sterile, pyrogen-free

1 . Subs. by G.S.R. No. 40(E), dt. 29.1.2001.

Drugs and Cosmetics Rules, 1945 277 100 ml of blood.

Note 1.- (i) In case of single/double/triple/quadruple blood collection bags used for

blood component preparations, CPDA blood collection bags may be used.

(ii) Acid Citrate Dextrose solution (A.C.D. with Formula-A) I.P. – 15 ml solution

shall be required for 100 ml of blood,

(iii) Additive solutions such as SAGM, ADSOL, NUTRICEL may be used for storing and retaining Red Blood Corpuscles up to 42 days. Note 2.- The licensee shall ensure that the anti-coagulant solutions are of a licensed manufacturer and the blood bags in which the said solutions are contained have

a certificate of analysis of the said manufacturer.

5. Emergency equipments/items:

(i) Oxygen cylinder with mask, gauge and pressure regulator.
(ii) 5 per cent Glucose or Normal Saline.
(iii) Disposable sterile syringes and needles of various sizes.
(iv) Disposable sterile I.V. infusion sets.
(v) Ampoules of Adrenaline, Noradrenaline, Mephentin, Betamethasone

or Dexamethasone, Metoclorpropamide injections.

(vi) Aspirin.

6. Accessories:

(i) Such as blankets, emesis basins, haemostats, set clamps, sponge forceps, gauze, dressing jars, solution jars, waste cans.
(ii) Medium cotton balls, 1.25 cm adhesive tapes.
(iii) Denatured spirit, Tincture Iodine, green soap or liquid soap.
(iv) Paper napkins or towels.
(v) Autoclave with temperature and pressure indicator.
(vi) Incinerator
(vii) Stand-by generator 7. Laboratory equipment:
(i) Refrigerators, for storing diagnostic kits and reagents, maintaining a temperature between 4 to 6 degree centigrade (plus/minus 2 degrees centigrade) with digital dial thermometer having provision for continuous power supply.
(ii) Compound Microscope with low and high power objectives.
(iii) Centrifuge Table Model.
(iv) Water bath: having range between 37 degree centigrade to 56 degree centigrade.
(v) Rh viewing box in case of slide technique.
(vi) Incubator with thermostatic control.
(vii) Mechanical shakers for serological tests for Syphilis.
(viii) Hand-lens for observing tests conducted in tubes.
(ix) Serological graduated pipettes of various sizes.
(x) Pipettes (Pasteur).
(xi) Glass slides. Drugs and Cosmetics Rules, 1945 278
(xii) Test tubes of various sizes / micrometer plates (U or V type).
(xiii) Precipitating tubes 6mm x 50mm of different sizes and glass beakers of different sizes.
(xiv) Test tube racks of different specifications.
(xv) Interval timer electric or spring wound.
(xvi) Equipment and materials for cleaning glass wares adequately.
(xvii) Insulated containers for transporting blood, between 2 degree centigrade to 10 degree centigrade temperatures, to wards and hospitals.

(xviii) Wash bottles.

(xix) Filter papers.
(xx) Dielectric tube sealer.

(xxi) Plain and EDTA vials.
(xxii) Chemical balance (wherever necessary). (xxiii) ELISA reader with printer, washer and micropipettes. J. SPECIAL REAGENTS :

(1) Standard blood grouping sera Anti A, Anti B and Anti C with known controls. Rh typing sera shall be in double quantity and each of different brand or if from the same supplier each supply shall be of different lot numbers.
(2) Reagents for serological tests for syphilis and positive sera for controls.
(3) Anti Human Globulin Serum (Coomb’s serum).
(4) Bovine Albumin 22 percent Enzyme reagents for incomplete antibodies.
(5) ELISA or RPHA test kits for Hepatitis and HIV I & II.
(6) Detergent and other agents for cleaning laboratory glass wares. K. TESTING OF WHOLE BLOOD :
(1) It shall be responsibility of the licensee to ensure that the whole blood collected, processed and supplied conforms to the standards laid down in the Indian Pharmacopoeia and other tests published, if any, by the Government.
(2) Freedom from HIV antibodies (AIDS) Tests. – Every licensee shall get samples of every blood unit tested, before use, for freedom from HIV 1 and HIV II antibodies either from laboratories specified for the purpose by the Central Government or in his own laboratory. The results of such testing shall be recorded on the label of the container.
(3) Each blood unit shall also be tested for freedom from 1[(Hepatitis B surface antigen and Hepatitis C Virus antibody)] VDRL and malarial parasite and results of such testing shall be recorded on the label of the container. NOTES
- (a) Blood samples of donors in pilot tube and the blood samples of the Recipient shall be preserved for 7 days after issue.
- (b) The blood intended for transfusion shall not be frozen at any stage.
- (c) Blood containers shall not come directly in contact with ice at any stage. L RECORDS : Drugs and Cosmetics Rules, 1945 279 The records which the licensee is required to maintain shall include inter alia the following particulars, namely:
(2) Master records for blood and its components: It shall indicate bag serial number, date of collection, date of expiry, quantity in ml. ABO/Rh Group, results for testing of HIV I and HIV II antibodies, Malaria, V.D.R.L. 1[(Hepatitis B surface antigen and Hepatitis C Virus antibody)] and irregular antibodies (if any), name and address of the donor with particulars, utilization issue number, components prepared or discarded and signature of the Medical Officer in charge.
(3) Issue Register: It shall indicate serial number, date and time of issue bag serial number, ABO/RH Group, total quantity in ml, name and address of the recipient, group of recipient, unit/institution, details of cros-matching report, indication for transfusion. (4 ) Records of components supplied: Quantity supplied; compatibility report, details of recipient and signature of issuing person.
(5) Records of ACD/CPD/CPD-A/SAGM bags giving details of manufacturer, batch number, date of supply, and results of testing.
(6) Register for diagnostic kits and reagents used: name of the kits/reagents, details of batch number, date of expiry and date of use.
(7) Blood bank must issue the cross matching report of the blood to the patient together with the blood unit.
(8) Transfusion adverse reaction records.
(9) Records of purchase, use and stock in hand of disposable needles, syringes, blood bags, shall be maintained. NOTE : The above records shall be kept by the licensee for a period of five years. M. LABELS : The labels on every bag containing blood and/or component shall contain the following particulars, namely;
(1) The proper name of the product in a prominent place and in bold letters on the bag.
(2) Name and address of the blood bank
(3) Licence number 1 Subs. by G.S.R. 40(E), dt. 29.1.2001 (w.e.f. 1.6.2001).
(1) Blood donor record: It shall indicate serial number, date of bleeding, name, address and signature of donor with other particulars of age, weight, haemoglobin, blood grouping, blood pressure, medical examination, bag number and patient’s detail for whom donated in case of replacement donation, category of donation (voluntary / replacement) and deferral records and signature of Medical Officer In-charge. Drugs and Cosmetics Rules, 1945 280
(4) Serial number
(5) The date on which the blood is drawn and the date of expiry as prescribed under Schedule P to these rules.
(6) A colored label shall be put on every bag containing blood. The following color scheme for the said labels shall be used for different groups of blood: _______________________________________________

Blood Group Colour of the label

(7) The results of the tests for 1[(Hepatitis B surface antigen and Hepatitis C Virus antibody)] syphilis, freedom from HIV I and HIV II antibodies and malarial parasite.
(8) The Rh. Group.
(9) Total volume of blood, the preparation of blood, nature and percentage of anti- coagulant.
(10) Keep continuously temperature at 2 degree centigrade to 6 degree centigrade for whole human blood and/or components as contained under III of Part XII B.
(11) Disposable transfusion sets with filter shall be used in administration equipment.
(12) Appropriate compatible cross-matched blood without atypical antibody in recipient shall be used.
(13) The contents of the bag shall not be used if there is any visible evidence of deterioration like haemolysis, clotting or discoloration.
(14) The label shall indicate the appropriate donor classification like “Voluntary Donor” or “Replacement Donor” in no less prominence than the proper name. NOTES : 1. In the case of blood components, particulars of the blood from which such components have been prepared shall be given against item numbers (5), (7), (8),
(9) and (14). 2. The blood and/or its components shall be distributed on the prescription of a Registered Medical Practitioner.

II. BLOOD DONATION CAMPS.

A blood donation camp may be organized by –

¹ Subs. by G.S.R 40(E), dt. 29.1.2001.

Drugs and Cosmetics Rules, 1945 281

(a) a licensed designated Regional Blood Transfusion Centre ; or
(b) a licensed Government blood bank; or 1[(c) the Indian Red Cross society; or
(d) a licensed blood bank run by registered voluntary or charitable organizations recognized by State or Union Territory Blood Transfusion Council.)] NOTES:
- (i) “ Designated Regional Blood Transfusion Centre” shall be a center approved and designated by a Blood Transfusion Council constituted by a State Government to collect, process and distribute blood and its components to cater to the needs of the region and that center has also been licensed and approved by the Licensing Authority and Central Licence Approving Authority for the purpose.
- (ii) The designated Regional Blood Transfusion Centre, Government blood bank and Indian Red Cross Society shall intimate within a period of seven days, the venue where the blood camp was held and details of group wise blood units collected in the said camp to the Licensing Authority and Central Licence Approving Authority. For holding a blood donation camp, the following requirements shall be fulfilled/complied with, namely: -
(A) Premises, personnel etc.
(a) Premises under the blood donation camp shall have sufficient area and the location shall be hygienic so as to allow proper operation, maintenance and cleaning.
(b) All information regarding the personnel working, equipment used and facilities available at such a Camp shall be well documented and made available for inspection, if required, and ensuring -
- (i) Continuous and uninterrupted electrical supply for equipment used in the Camp;
- (ii) Adequate lighting for all the required activities;
- (iii) Hand-washing facilities for staff;
- (iv) Reliable communication system to the central office of the Controller/ Organizer of the Camp;
- (v) Furniture and equipment arranged within the available space;
- (vi) Refreshment facilities for donors and staff;
- (vii) Facilities for medical examination of the donors;
- (viii) Proper disposal of waste.
(B) Personnel for Out-door Blood Donation Camp: To collect blood from 50 to 70 donors in about 3 hours or from 100 to 200 donors in 5 hours, the following requirements shall be fulfilled / complied with:

1 Subs. by G.S.R. No.218(E), dt. 28-03-2001

Drugs and Cosmetics Rules, 1945 282

(i) one Medical Officer and two nurses or phlebotomists for managing 6-8 donor tables;
(ii) two medico social workers;
(iii) three blood bank technicians;
(iv) two attendants;
(v) vehicle having a capacity to seat 8-10 persons, with provision for carriage of donation goods including facilities to conduct a blood donation camp;

3. Blood bags (single, double, triple, quadruple).

4. Donor questionnaire.

5. Weighing device for donors. 6. Weighing device for blood bags. 7. Artery forceps, scissors. 8. Stripper for blood tubing. 9. Bed sheets, blankets/mattress. 10. Lancets, swab stick/tooth picks.

11. Glass slides.

12. Portable Hb meter/copper sulphate. 13. Test tube (big) and 12x100mm (small). 14. Test tube stand. 15. Anti-A, Anti-B and Anti-AB, Antisera and Anti-D. 16. Test tube sealer film. 17. Medicated adhesive tape.

18. Plastic waste basket.

19. Donor cards and refreshment for donors. 20 Emergency medical kit. 21 Insulated blood bag containers with provisions for storing between 2 degree centigrade to 10 degree centigrade. 22. Dielectric sealer or portable tube sealer. 23. Needle destroyer (wherever necessary).

III. PROCESSING OF BLOOD COMPONENTS FROM WHOLE

BLOOD BY A BLOOD BANK

The Blood components shall be prepared by blood banks as a part of the Blood Bank services. The conditions for grant or renewal of licence to prepare blood components shall be as follows: -

A. ACCOMMODATION:

(1) Rooms with adequate area and other specification, for preparing blood components depending on quantum of workload shall be as specified in item B under the heading “1. BLOOD BANKS/BLOOD COMPONENTS’ of this Part. Drugs and Cosmetics Rules, 1945 283
(2) Preparation of Blood components shall be carried out only under closed system using single double, triple or quadruple plastic bags except for preparation of Red Blood Cells Concentrates, where single bags may be used with transfer bags. B. EQUIPMENT :
- (i) Air Conditioner;
- (ii) Laminar air flow bench;
- (iii) Suitable refrigerated centrifuge;
- (iv) Plasma expresser;
- (v) Clipper and clips and/or dielectric sealer;
- (vi) Weighing device;
- (vii) Dry rubber balancing material;
- (viii) Artery forceps, scissors;
- (ix) Refrigerator maintaining a temperature between 2 degree centigrade to 6 degree centigrade, a digital dial thermometer with recording thermograph and alarm device, with provision for continuous power supply;
- (x) Platelet agitator with incubator (wherever necessary);
- (xi) Deep freezers maintaining a temperature between minus 30 degree centigrade to minus 40 degree centigrade and minus 75 degree centigrade to minus 80 degree centigrade;
- (xii) Refrigerated Water bath for Plasma Thawing;
- (xiii) Insulated blood bag containers with provisions for storing at appropriate temperature for transport purposes;

C. PERSONNEL:

The whole time competent technical staff meant for processing of Blood Components (that is Medical Officer, Technical Supervisor, Blood Bank Technicians and Registered Nurse) shall be as specified in item C, under the heading “ 1. BLOOD BANKS/BLOOD COMPONENTS” of this Part.

D. TESTING FACILITIES:

General: Facilities for A, B, AB and O groups and Rh(D) grouping.

1[(Hepatitis B surface antigen and Hepatitis C Virus antibody)], VDRL, HIV I and HIV II antibodies and malarial parasites shall be mandatory for every blood unit before it is used for the preparation of blood components. The results of such testing shall be indicated on the label.

E. CATEGORIES OF BLOOD COMPONENTS:

(1) CONCENTRATED HUMAN RED BLOOD CORPUSCLES: The product shall be known as “Packed Red Blood Cells” that is Packed Red Blood Cells remaining after separating plasma from human blood. General Requirements:
- (a) Storage: Immediately after processing, the Packed Red Blood Cells shall be kept at a temperature maintained between 2 degree centigrade to 6 degree centigrade.
- (b) Inspection: The component shall be inspected immediately after separation of the Drugs and Cosmetics Rules, 1945 284 plasma, during storage and again at the time of issue. The product shall not be issued if there is any abnormality in color or physical appearance or any indication of microbial contamination. (c) Suitability of Donor: The source of blood for Packed Red Blood Cells shall be obtained from a donor who meets the criteria for Blood Donation as specified in item H under the heading “I. BLOOD BANKS/BLOOD COMPONENTS” of this Part.
- (d) Testing of Whole Blood: Blood from which Packed Red Blood Cells are prepared shall be tested as specified in item K relating to Testing Of Whole Blood under the heading “I. BLOOD BANKS/BLOOD COMPONENTS” of this Part.
- (e) Pilot samples: Pilot samples collected in integral tubing or in separate pilot tubes shall meet the following specifications: ___________________________________________________________
  - (i) One or more pilot samples of either the original blood or the Packed Red Blood Cells being processed shall be preserved with each unit of Packed Red Blood Cells which is issued.
  - (ii) Before they are filled, all pilot sample tubes shall be marked or identified so as to relate them to the donor of that unit or Packed Red Blood Cells.
  - (iii) Before the final container is filled or at the time the final product is prepared, the pilot samples tubes accompanying a unit of Packed Red Blood Cells, shall be attached in a tamper-proof manner that shall conspicuously identify removal and re-attachment.
  - (iv) All pilot sample tubes, accompanying a unit of packed red blood cells, shall be filled immediately after the blood is collected or at the time the final product is prepared, in each case, by the person who performs the collection of preparation.

¹ Subs. by G.S.R. 40(E), dt. 29.1.2001.

F. Processing:

(i) Separation: Packed Red Blood Cells shall be separated from the whole blood, --

(a) if the whole blood is stored in ACD solution within 21 days, and
(b) if the whole blood is stored in CPDA-1 solution, within 35 days, from the date of collection. Packed Red Blood Cells may be prepared either by centrifugation done in a manner that shall not tend to increase the temperature of the blood or by normal undisturbed sedimentation method. A portion of the plasma, sufficient to ensure optimal cell preservation, shall be left with the packed Red Blood Cells. Drugs and Cosmetics Rules, 1945 285
- (ii) Packed Red Blood Cells Frozen: Cryophylactic substance may be added to the Packed Red Blood Cells for extended manufacturer’s storage not warmer than minus 65 degree centigrade provided the manufacturer submits data to the satisfaction of the Licensing Authority and Central Licence Approving Authority, as adequately demonstrating through in-vivo cells survival and other appropriate tests that the addition of the substance, the material used and the processing methods results in a final product meets the required standards of safety, purity and potency for Packed Red Blood Cells, and that the frozen product shall maintain those properties for the specified expiry period.
- (iii) Testing: Packed Red Blood Cells shall conform to the standards as laid down in the Indian Pharmacopoeia.

(2) PLATELETS CONCENTRATES: The product shall be known as “Platelets Concentrates” that is platelets collected from one unit of blood and re-suspended in an appropriate volume of original plasma. General Requirements:
- (i) Source: The source material for platelets shall be platelet rich plasma or buffy coat which may be obtained from the whole blood or by plateletpheresis.
- (ii) Processing :
- (a) Separation of buffy-coat or platelet-rich plasma and platelets and re- suspension of the platelets shall be in a closed system by centrifugal method with appropriate speed, force and time.
- (b) Immediately after collection, the whole blood or plasma shall be held in storage between 20 degree centigrade to 24 degree centigrade. When it is to be transported from the venue of blood collection to the processing laboratory, during such transport action, the temperature as close as possible to a range between 20 degree centigrade to 24 degree centigrade shall be ensured. The platelet concentrates shall be separated within 6 hours after the time of collection of the unit of whole blood or plasma.
- (c) The time and speed of centrifugation shall be demonstrated to produce an unclamped product, without visible haemolysis, that yields a count of not less than 3.5 x 10 (3.5 x 10 raised to the power of 10) and 4.5 x 10 (4.5 x 10 raised to the power ten) i.e. platelets per unit from a unit of 350 ml and 450 ml blood respectively. One percent of total platelets prepared shall be tested of which 75 per cent of the units shall conform to the above said platelet count.
- (d) The volume of original plasma used for re-suspension of the platelets shall be determined by the maintenance of the pH of not less than 6 during the storage period. The pH shall be measured on a sample of Drugs and Cosmetics Rules, 1945 286 platelets which has been stored for the permissible maximum expiry period at 20 degree centigrade to 24 degree centigrade.
- (e) Final containers used for platelets shall be colorless and transparent to permit visual inspection of the contents. The caps selected shall maintain a hermetic seal to prevent contamination of the contents. The container material shall not interact with the contents, under the normal conditions of the storage and use, in such a manner as to have an adverse effect upon the safety, purity, potency, or efficacy of the product. At the time of filling, the final container shall be marked or identified by number so as to relate it to the donor.
  - (iii) Storage: Immediately after re-suspension, platelets shall be placed in storage not exceeding for a period of 5 days, between 20 degree centigrade to 24 degree centigrade, with continuous gentle agitation of the platelet concentrates maintained throughout such storage
  - (iv) Testing: The units prepared from different donors shall be tested at the end of the storage period for –
- (a) Platelet count;
- (b) pH of not less than 6 measured at the storage temperature of the unit;
- (c) measurement of actual plasma volume;
- (d) one percent of the total platelets prepared shall be tested for sterility;
- (e) the tests of functional viability of the platelets shall be done by swirling movement before issue.
- (f) if the results of the testing indicate that the product does not meet the specified requirements, immediate corrective action shall be taken and records maintained;
  - (v) Compatibility Test: Compatible transfusion for the purpose of variable number of Red Blood Cells, A, B, AB and O grouping shall be done if the platelets concentrate is contaminated with red blood cells.
(3) GRANULOCYTE CONCENTRATES:
- (i) Storage: It shall be kept between 20 degree centigrade to 24 degree centigrade for a maximum period of 24 hours;
- (ii) Unit of granulocytes shall not be less than 1 x 10 (i.e. 1 x 10 raised to the power of 10) when prepared on cell separator;
- (iii) Group specific tests/HLA test wherever required shall be carried out.
(4) FRESH FROZEN PLASMA: Plasma frozen within 6 hours after blood collection and stored at a temperature not warmer than minus 30 degree centigrade, shall be preserved for a period of not more than one year.
(5) CRYOPRECIPITATE: Concentrate of anti-hemophiliac factor shall be prepared by thawing of the fresh plasma frozen stored at minus 30 degree centigrade. Drugs and Cosmetics Rules, 1945 287
- (a) Storage:

Cryoprecipitate shall be preserved at a temperature not higher than minus 30

degree centigrade and may be preserved for a period of not more than one year from the date of collection.

(b) Activity: Anti-hemophiliac factor activity in the final product shall be not less than 80 units per bag. One percent of the total cryoprecipitate prepared shall be tested of which seventy five percent of the unit shall conform to the said specification. F PLASMAPHERESIS, PLATELETPHERESIS, LEUCAPHERESIS, USING A CELL SEPARATOR. An area of 10 square meters shall be provided for apheresis in the blood bank. The blood banks specifically permitted to undertake the said apheresis on the donor

shall observe the criteria as specified in item H relating to Criteria for blood donation “1

Blood Banks/Blood Components” of this Part. The written consent of the donor shall be taken and the donor must be explained, the hazards of apheresis. The Medical Officer shall certify that the donor is fit for apheresis and it shall be carried out by a trained person under supervision of the Medical Officer.

(A) PLASMAPHERESIS, PLATELETPHERESIS AND LEUCAPHERESIS: The donors subjected to plasmapheresis, plateletpheresis and leucapheresis shall, in addition to the criteria specified in item H relating to the CRITERIA FOR BLOOD

DONATION, under the heading “I. BLOOD BANKS/BLOOD COMPONENTS” of this Part

being observed, be also subjected to protein estimation on post-pheresis/first sitting whose results shall be taken as reference for subsequent/sitting. It shall also be necessary that the total plasma obtained from such donor and periodicity of Plasmapheresis shall be according to the standards described under validt. Standard Operating Procedures.

NOTE :

(i) At least 48 hours must elapse between successive apheresis and not more than twice in a week.
(ii) Extracoporeal blood volume shall not exceed 15% of donor’s estimated blood volume.
(iii) Platelet pheresis shall not be carried out on donors who have taken medication containing Asprin within 3 days prior to donation.
(iv) If during plateletpheresis or leucapheresis, RBCs cannot be re-transfused then at least 12 weeks shall elapse before a second cytapheresis procedure is conducted.

(B) MONITORING FOR APHERESIS: Before starting apheresis procedure, hemoglobin or haematocrit shall be done. Platelet count, WBC counts, differential count may be carried out. In repeated plasmapheresis, the serum protein shall be 6 gm./ml. Drugs and Cosmetics Rules, 1945 288
(C) COLLECTION OF PLASMA: The quantity of plasma separated from the blood of donor shall not exceed 500 ml. per sitting and once in a fortnight or shall not exceed 1000 ml per month. PART XII C I. REQUIREMENTS FOR MANUFACTURE OF BLOOD PRODUCTS The blood products shall be manufactured in a separate premises other than that meant for blood bank. The requirements that are essential for grant or renewal of licence to manufacture blood products such as Albumin, Plasma Protein Fraction, Immunoglobins and Coagulation Factor Concentrates, shall be as follows, namely: - A. GENERAL REQUIREMENTS:

1. Location and surroundings, buildings and water supply:

The requirements as regards location and surrounding, buildings and water supply as contained in paragraphs 1.1.1, 1.1.2, 1.1.3 of Part 1 of Schedule M shall

(i) The requirements as regards disposal of waste and infectious materials as contained in paragraph 1.1.4 of Part 1 of Schedule M shall apply mutatis

mutandis to the manufacture of blood products.

(ii) Proper facility shall also be provided for potentially infectious materials, particularly HIV I & HIV II 1[(Hepatitis B surface antigen and Hepatitis C Virus antibody)] through autoclaving, incineration or any other suitable validt. methods.

3. Health, clothing and sanitation personnel:

(i) The requirement as contained in paragraph 3 of Part of Schedule M shall be complied with.
(ii) The personnel working in the manufacturing areas shall be vaccinated against Hepatitis B virus and other infectious transmitting diseases.

4. Requirements for manufacturing area for Blood Products:

(i) For the manufacture of blood products, separate enclosed areas specifically designated for the purpose shall be provided. These areas be provided with air locks for entry and shall be essentially dust free and ventilated with an air supply. Air supply for manufacturing area shall be filtered through bacteria retaining filters (HEPA Filters) and shall be at a pressure higher than in the adjacent areas. The filters shall be checked for performance on installation and periodically thereafter, and records thereof shall be maintained.
(ii) Interior surfaces (walls, floors and ceilings) shall be smooth and free from

cracks, they shall not shed matter and shall permit easy cleaning and disinfection. Drains

shall be excluded from aseptic areas.

Drugs and Cosmetics Rules, 1945 289 Routine microbial counts of the manufacturing area shall be carried out during manufacturing operations. The results of such counts shall be checked against well documented in-house standards and records maintained. Access to the manufacturing areas shall be restricted to a minimum number of authorized personnel. Special procedures for entering and leaving the manufacturing areas shall be prominently displayed.

(iii) Sinks shall be excluded from aseptic areas. Any sink installed in other clean areas shall be of suitable material such as stainless steel, without an overflow, and be supplied with water of potable quality. Adequate precautions shall be taken to avoid contamination of the drainage system with dangerous effluents and airborne dissemination of pathogenic micro-organisms. ________________________________________________________________________
(iv) Lighting, air-conditioning, ventilation shall be designed to maintain a satisfactory temperature and relative humidity to minimize contamination and to take account of the comfort of personnel working with protective clothing.
(v) Premises used for the manufacture of blood products shall be suitably designed and constructed to facilitate good sanitation.
(vi) Premises shall be carefully maintained and it shall be ensured that repair and maintenance operations do not present any hazard to the quality of products. Premises shall be cleaned and, where applicable, disinfected according to detailed written validt. procedures.
(vii) Adequate facilities and equipments shall be used for the manufacture of blood products derived from blood plasma.
(viii) All containers of blood products, regardless of the stage of manufacture, shall be identified by securely attached labels. Cross contamination shall be prevented by adoption of the following measures, namely: –

¹ Subs. by G.S.R. 40(E), dt. 29.1.2001.

(a) processing and filling shall be in segregated areas;
(b) manufacture of different products at the same time shall be avoided;
(c) simultaneous filling of the different products shall be avoided;
(d) ensure transfer, containers/materials by means of airlocks, air extraction, clothing change and careful washing and decontamination of equipment;
(e) protecting containers/materials against the risk of contamination caused by re-circulation of untreated air or by accidental re-entry of extracted air;
(f) using containers that are sterilized or are of documented low “bioburden”,
- (ix) Positive pressure area shall be dedicated to the processing area concerned;
- (x) Air-handling units shall be dedicated to the processing area concerned;
- (xi) Pipe work, valves and vent filters shall be properly designed to facilitate cleaning and sterilization. Valves on fractionation/reacting vessels shall be completely steam sterilisable. Air vent filters shall be hydrophobic and shall be validated for their designated use. Drugs and Cosmetics Rules, 1945 290

5. Ancillary Areas :

(i) Rest and refreshment rooms shall be separated from other areas.
(ii) Facilities for changing and storing clothes and for washing and toilet purposes shall be easily accessible and appropriate for the number of users. Toilets shall not be connected directly with production or storage areas.
(iii) Maintenance workshops shall be separated from production areas. Wherever parts and tools are stored in the production area, they shall be kept in rooms or lockers reserved for that use.
(iv) Animal houses shall be well isolated from other areas with separate entrance.

B. COLLECTION AND STORAGE OF PLASMA FOR FRACTIONATION

(a) Collection:

(1) Plasma shall be collected from the licensed Blood Banks through a cold chain process and stored in frozen condition not warmer than minus twenty degree centigrade.
(2) Individual plasma shall remain in quarantine till it is tested for 1[( Hepatitis B and Hepatitis C Virus antibody)], HIV I and HIV II.
(3) A sample from pooled – lot plasma of about 10-12 units of different donors shall be tested for

1[(Hepatitis B and Heptitis C Virus antibody)] HIV I

and HIV II and if the same sample found negative, only then it shall be taken up for fractionation.

(b) Storage Area :

(1) Storage areas shall be of sufficient space and capacity to allow orderly storage of the various categories of materials, intermediates, bulk and finished products, products in quarantine, released, rejected, returned, or recalled products.
(2) Storage areas shall be designed or adopted to ensure good storage conditioning. In particular, they shall be clean, dry and maintained within temperature required for such storage and where special storage conditions are required (e.g. temperature, humidity), these shall be provided, checked and monitored.
(3) Receiving and dispatch bays shall protect materials and products from the weather and shall be designed and equipped to allow containers of incoming materials to be cleaned, if necessary, before storage.
(4) Where quarantine status is ensured by storage in separate areas, these areas shall be clearly marked and their access restricted only to authorized personnel.
(5) There shall be separate sampling area for raw materials. If sampling is performed in the storage area, it shall be conducted in such a way so as to prevent contamination or cross-contamination.
(6) Segregation shall be provided for the storage of rejected, recalled, or returned materials or products.
(7) Adequate facility shall be provided for supply of ancillary material, such as ethanol, water, salts and polyethylene glycol. Separate facilities shall be provided for the recovery of organic solvents used in fractionation. Drugs and Cosmetics Rules, 1945 291 C. PERSONNEL :
(1) Manufacture : The manufacture of blood products shall be conducted under the active

¹ Subs. by G.S.R 40(E), dt. 29.1.2001 (w.e.f. 1.6.2001)

direction and personal supervision of competent technical staff, consisting of at

least one person who shall be a whole time employee, with one year practical experience in the manufacture of blood products / plasma fractionation and possesses –-

(a) Post-graduate degree in Medicine–M.D. (Microbiology/Pathology/ Bacteriology/Immunology/Biochemistry); or
(b) Post-graduate degree in Science (Microbiology); or
(c) Post-graduate degree ib Pharmacy (Microbiology), from a recognized University or Institution.

2. Testing :

(a) Post-graduate degree in Pharmacy or Science–(Chemistry/ Microbiology/ Bio-chemistry); or
(b) Post-graduate degree in Medicine–M.D(Microbiology/Pathology/ Biochemistry), from a recognized University or Institution.

D. PRODUCTION CONTROL :

(1) The production area and the viral inactivation room shall be centrally air- conditioned and fitted with HEPA filters having Grade C (Class 10,000) environment as given in the Table below.
(2) The filling and sealing shall be carried out under aseptic conditions in centrally air-conditioned areas fitted with HEPA Filters Grade A or, as the case may be, Grade B (Class 100) environment given in the said Table. TABLE AIR CLASSIFICATION SYSTEM FOR MANUFACTURE OF STERILE PRODUCTS. Maximum number of particles permitted per m Drugs and Cosmetics Rules, 1945 292 Grade Maximum number of particles permitted per m ______________________________

0.5 – 5 micron Less than 5 micron

Maximum number of Viable Micro-organism permitted per m A (Class 100) (Laminar - Airflow workstation)

3500 None Less than 1 B (Class 100) 3500 None Less than 5

C (Class 10,000) 3,50,000 2000 Less than 100

(3) The physical and chemical operations used for the manufacture of plasma fractionation shall maintain high yield of safe and effective protein.
(4) The fractionation procedure used shall give a good yield of products meeting the in-house quality requirements as approved by the Licensing Authority and Central Licence Approving Authority reducing the risk of microbiological contamination and protein denaturation to the minimum.
(5) The procedure adopted shall not affect the antibody activity and biological half- life or biological characteristics of the products. E. VIRAL INACTIVATION PROCESS : The procedure used by the licensee to inactivate the pathogenic organisms such as enveloped and non-enveloped virus, especially infectivity from HIV I & HIV II, 1[(Hepatitis B surface antigens and Hepatitis C Virus antibody)], the viral inactivation and validation methods adopted by the licensee, shall be submitted for approval to the Licensing Authority and Central Licence Approving Authority. NOTES:
(1) No preservative (except stabilizer to prevent – protein denaturation such as glycine, sodium chloride or sodium caprylate) shall be added to Albumin, Plasma Protein Fraction, Intravenous Immunoglobulins or Coagulation Factor Concentrates without the prior approval of Licensing Authority and Central Licence Approving Authority.
(2) The licensee shall ensure that the said stabilizers do not have deleterial effect on the final product in the quantity present so as not to cause any untoward or adverse reaction in human beings.

F. QUALITY CONTROL:

Separate facilities shall be provided for Quality Control such as Hematological, Bio- chemical, Physico-chemical, Microbiological, Pyrogens, Instrumental and Safety testing. The Quality Control Department shall have inter alia the following principal duties, namely :-

(1) To prepare detailed instructions for carrying out test and analysis.
(2) To approve or reject raw material, components, containers, closures, in-process materials, packaging material, labelling and finished products.
(3) To release or reject batch of finished products which are ready for distribution.
(4) To evaluate the adequacy of the conditions under which raw materials, semi- Drugs and Cosmetics Rules, 1945 293 finished products and finished products are stored.
(5) To evaluate the quality and stability of finished products and when necessary of raw materials and semi-finished products.
(6) To review production records to ensure that no errors have occurred or if errors have occurred that they have been fully investigated.
(7) To approve or reject all procedures, or specifications impacting on the identity, strength, quality and purity of the product.
(8) To establish shelf-life and storage requirements on the basis of stability tests related to storage conditions. ___________________________________________________________________
(9) To establish and when necessary revise, control procedures and specifications.
(10) To review complaints, recalls, returned or salvaged products and investigations conducted there under for each product.
(11) To review Master Formula Records/Cards periodically.

¹ Subs. by G.S.R 40(E), dt. 29.1.2001 (w.e.f. 1.6.2001)

G. TESTING OF BLOOD PRODUCTS:

The products manufactured shall conform to the standards specified in the Indian Pharmacopoeia and where standards of any product is not specified in the Pharmacopoeia, the standard for such product shall conform to the standard specified in the United States Pharmacopoeia or the British Pharmacopoeia. The final products shall be tested for freedom from HIV I and HIV II antibodies

1[(Hepatitis B surface antigen and Hepatitis C Virus antibody)]

H. STORAGE OF FINISHED PRODUCT :

(i) The final products shall be stored between two degree centigrade to eight degree centigrade, unless otherwise specified by the Central Licence Approving Authority.
(ii) The shelf-life assigned to the products by the licensee shall be submitted for approval to the Licensing Authority and Central Licence Approving Authority.

I. LABELLING :

1[(Hepatitis B surface antigen and Hepatitis C Virus

The licensee shall maintain records as per Schedule U and also comply with Batch manufacturing records as specified in Paragraph 9 of Part -I of Schedule M and any other requirement as may be directed by Licensing Authority and Central Licence Approving Authority.

K. MASTER FORMULA RECORDS:

The licensee shall maintain Master Formula Records relating to all manufacturing and quality control procedures for each product, which shall be prepared and endorsed by the

Drugs and Cosmetics Rules, 1945 294 Competent Technical Staff, i.e. Head of the manufacturing unit. The Master Formula Records shall contain: –

(i) the patent or proprietary name of the product along with the generic name, if any, strength and the dosage form;
(ii) a description or identification of the final containers, packaging materials, labels and closures to be used;
(iii) the identity, quantity and quality of each raw material to be used irrespective of whether or not it appears in the finished product. The permissible overage that may be included in a formulated batch shall be indicated;
(iv) a description of all vessels and equipments and the sizes used in the process; _____________________________________________________________________________________
(v) manufacturing and control instructions along with parameters for critical steps such as mixing, drying, blending, sieving and sterilizing the product;
(vi) the theoretical yield to be expected from the formulation at different stages of manufacture and permissible yield limits;
(vii) detailed instructions on precautions to be taken in the manufacture and storage of drugs and of semi finished products; and
(viii) the requirements in-process quality control tests and analysis to be carried out during each stage of manufacture including the designation of persons or departments responsible for the execution of such tests and analysis. II. REQUIREMENTS FOR MANUFACTURE OF BLOOD PRODUCTS FROM BULK FINISHED PRODUCTS Where the blood products, such as Albumin, Plasma Protein Fraction, Immunoglobulins and Coagulation Factor Concentrates are manufactured through the manufacturing activities of filling and sealing the blood products from bulk powder or solution or both, the requirements as they apply to the manufacture of blood products from whole blood shall apply mutatis mutandis to such manufacture of blood products, unless other requirements have been approved by the Central Licence Approving Authority. 1[PART XIII GENERAL Indian Pharmacopoeia shall be deemed to be a method approved by the Licensing Authority. 2. The Licensing Authority shall publish in the Official Gazette from time to time particulars of any test or method of testing approved by him.] Drugs and Cosmetics Rules, 1945 295 ______________________________________________________________ Drugs and Cosmetics Rules, 1945 295

¹ Subs. by G.S.R 40(E), dt. 29.1.2001(w.e.f. 1.6.2001)

¹ For the purposes of this Schedule, any test or method of testing described in the

¹ Renumbered by Notification No. F-18-1/46, dt. 18-6-48

F(I)

P ART 1–VACCINES

(A) PROVISIONS APPLICABLE TO THE PRODUCION OF BACTERIAL VACCINES: 1. Definition. –(1) This part of the Schedule applies to bacterial vaccines made from any micro-organism pathogenic to man or other animal and to vaccines made from other micro-organisms which have any antigenic value.

(2) For the purposes of this part of the Schedule, a bacterial vaccine means a sterile suspension of a killed culture of the micro-organism from which the vaccine derives its name or a sterile extract or derivative of a micro-organism, or a pure suspension of living micro- organisms which have been previously made avirulent. 2. Staff of Establishment.–A competent expert in bacteriology with sufficient experience in the manufacture and standardisation of biological products shall be in charge of the establishment responsible for the production of bacterial vaccine and he shall be assisted by a staff adequate for carrying out the tests required during the preparation and standardisation of the vaccines. 3. Proper Name.–The proper name of any vaccine shall be the name of the micro- organism from which it is made followed by the word “Vaccine” unless this Schedule otherwise provides or if there is no other special provision in this Schedule, some other name as approved by the Licensing Authority. Provided that in the case of the undermentioned preparations the proper name of the vaccine may be as follows: –

2[7. Multi Component Clostridial Vaccine.

8. Hemorrhagic Septicaemia Vaccine – Alum Treated.]

4. Records.–Cultures used in the preparation of vaccine before being manipulated into a vaccine, should be thoroughly tested for identity by the generally accepted tests applicable to the particular micro-organisms. The permanent records which the licensee is required to keep shall include amongst others, a record of the origin, properties and characteristics of the cultures. 5. Combined Vaccines.–Vaccines may be issued either singly or combined in any proportion in the same container. In the case of combination of vaccines, a name for the combined vaccine may be submitted by the licensee to the Licensing Authority, and if approved, may be used as the proper name of the vaccine.

____________________________________________________________________

² Ins. by G.S.R. 659(E) ,dt. 31.8.1994.

1. Added by Ministry of Health F.P., W.H and U.D. Notfn. No. F.1-6/62-D, dt. 2-7-1969

Drugs and Cosmetics Rules, 1945 296 6. Preparation– Bacterial vaccines, simple or polyvalent, are prepared from selected cultures after careful examination for their identity, specificity, purity and antigencity. They may be prepared in the following manner:.–

(a) Formal Cultures or Bacterins.– The selected pure culture strain or strain are grown in a suitable fluid medium, at an optimum temperature, for an appropriate period. The pure growth is then exposed to the action of solution of Formaldehyde I.P. in suitable concentration and temperature. The product is finally filled in suitable sterilised containers which are subsequently sealed.
(b) Vaccine of Bacterial Products or Bacterial Derivatives.–These vaccines are prepared by growing the organisms on suitable media and then deriving specific antigenic constituents of the bacteria by various special methods.
(c) Living Bacterial Vaccines.– They are prepared from non-pathogenic but fully immunogenic strains of micro-organism. Strict aseptic precautions are taken throughout the preparation against the introduction of microbial contaminants.

7. General Standards:.

(a )Description.– Bacterial vaccines are colourless to yellowish brown liquids containing dead or viable bacteria in homogenous suspension.

(b) Identification.–All types of vaccines confer active immunity in the susceptible animals which can be demonstrated by injecting suitable experimental animals with the calculated doses of the product and subsequently determining the presence of the protective antibodies in their serum and/or by challenging the vaccinated animals by injecting virulent strain of the homologous organisms. The protected animals should survive the challenge.
(c) Test for Sterility.–All bacterial vaccines shall be tested for sterility in accordance with the provision of Rules 115 to 119 (both inclusive). If the vaccine contains added bactericide or bacteriostatic, a quantity of medium sufficient to render the growth inhibitor ineffective is added to the sample, or a suitable substance is added to the sample, or a suitable substance is added in concentration sufficient to render the growth inhibitor ineffective but not itself to inhibit the growth of micro-organism.
(d) Purity Tests for Living Bacterial Vaccine.–Petri dishes containing suitable media are streaked with the final product and incubated at 37 ̊ C for 72 hours. The vaccine passes the test if no growth of micro-organisms other than those from which the

vaccine was prepared is observed. Other tests include examination for motility of the

organisms, fermentation reactions and thermoagglutination test and dye-inhibitor tests in case of bruceliza vaccine.

(e) Safety Test.– The safety of the vaccine shall be assessed by injecting it in appropriate doses in suitable susceptible animals. No animal should show any untoward, general or local reaction within seven days after inoculation. (f). Potency Test.–Wherever applicable, susceptible experimental animals are inoculated with the calculated doses of the final product. The animals are challenged after the period of immunisation, with virulent infective dose of the homologous culture along with the controls. The potency of the vaccine is assessed by the survival of the vaccinated animals and the death of the controls.

8. Labelling:

(a) The label on the ampoule or the bottle shall indicate:.–
- (i) Proper name.
- (ii) Contents in millilitres or doses.
- (iii) Potency, if any. Drugs and Cosmetics Rules, 1945 297
- (iv) Batch number.
- (v) Expiry date.
(b) The label on the outside container shall indicate:
- (i) Proper name.
- (ii) Contents in Millilitres or doses.
- (iii) Batch number.
- (iv) Date of manufacture.
- (v) Manufacturing licence No.
- (vi) Manufacturer’s name and address.
- (vii) “For animal treatment only”.
- (viii) Storage conditions. 9. Storage.–-Bacterial vaccines shall be stored, protected from light at temperature between 2 ̊C to 4 ̊C and shall not be frozen.

10. Date of manufacture.– The date of manufacture shall be, unless otherwise specified

in the individual monograph in this part, as defined in clause (b) of sub-rule (3) of rule 109.

Anthrax Spore Vaccine (Living) 1. Synonyms.–-Avirulent Anthrax Spore Vaccine or Bacillus Anthracis Vaccine (Living). 2. Definition.–-The vaccine is a suspension of living spores of an uncapsulated

avirulent strain of B anthracis in 50 per cent glycerine saline.

3. Preparation.–-Avirulent B, anthracis of known antigenicity is grown on suitable medium at pH 7.4 in Roux flasks. After 72 hours incubation at 37 ̊ C, the pure sporulated culture growth which shows 70 to 80 per cent sporulation is washed with normal saline and glycerinated to the extent of 50 per cent by weight of the culture washing and the whole suspension is kept at room temperature for twenty-one days to allow for the stabilization of the spores. 4. Standard:.

(a) Description.–- It is slightly opalescent or pale brown semi-viscous liquid.
(b) Identification.–-Uncapsulated B anthracis which is avirulent can be isolated from the vaccine.
(c) Sterility test.–- Should comply with the test for sterility described in the general monograph on “Bacterial Vaccine”.
(d) Purity Test.–- Complies with the “Purity Tests for Living Bacterial Vaccine”

described under the general monograph on “Bacterial Vaccines”.

(e) Safety Test.–-Four healthy adult guinea-pigs each weighing 300-450 g. not previously treated with any material which will interfere with the test are inoculated subcutaneously, two with 0.2 ml. each and two with 0.5 ml. each of the unglycerinated suspension respectively. Four more guinea-pigs are injected with 1:5 dilution of the glycerinated product in the same manner. No untoward reaction should be observed and none of the animals should die of anthrax during the period of observation for seven days. Drugs and Cosmetics Rules, 1945 298
(f) Safety and Potency Test in sheep and goat–Spore count of the glycerinated suspension is made after twenty-one days from the date of glycerination. Three plates for each of the three dilution 10 , 10 and 10 are made. Eight sheep and eight goats each weighing not less than 18 kg. are injected subcutaneously in the following manner:– two sheep : Each subcutaneously with 10 ml. of the stock suspension (for safety).

two goats : Each subcutaneously with 5 ml. of the stock

suspension (for safety).

six sheep : Each subcutaneously with one million spores

suspended in 50 per cent glycerine saline solution.

six goats : Each subcutaneously with one million spores suspended in

50 per cent glycerine saline solution.

None of these animals should die of anthrax. Twenty one days after vaccination, the animals are challenged with 100 lethal doses of virulent B. anthracis spores along with two healthy sheep and two goats as controls. All the controls should die of anthrax within 72 hours after challenge and at least 66 per cent of the vaccinated animals should survive. The animals shall be observed for a minimum of ten days from the date of challenge.

1[(g) Viable Count.– The vaccine when plated on suitable media should show 10

million viable spores per cattle dose and 5 million spores per sheep dose.]

5. Labelling and Storage.– Should comply with the requirements for “Labelling” and “Storage” as laid down in the general monograph on “Bacterial Vaccines”.

1[6. Expiry Date.– The date of expiry of the potency of the vaccine shall be not more than two years from the date of manufacture if stored in 4 o C and six months, if stored at room temperature.] Blackquarter Vaccine 1. Synonym.–Blackleg vaccine or Quarter Evil Vaccine.

2. Definition.– Blackquarter Vaccine is a culture of Clostridium chauvoei grown in a

suitable anaerobic fluid medium and rendered sterile and toxic by the addition of Solution of Formaldehyde I.P. in such a manner that it retains its immunising properties. 3. Preparation.–Cultures of Cl. Chauvoei are grown in a suitable anaerobic fluid medium and killed by the addition of a suitable concentration of Solution of Formaldehyde I.P. The final product shall be adjusted to pH.7.0. 4. Standards:.

(a) Description.–It is a yellowish brown liquid containing dead bacteria in suspension.
(b) Identification.–It protects susceptible animals against infection with Cl. Chauvoei.
(c) Sterility Test.–Should comply with the test for sterility described in the general monograph on “Bacterial Vaccine”. ____________________________________________________________________ Drugs and Cosmetics Rules, 1945 299
(d) Safety and Potency Tests.–At least six adult healthy guinea-pigs each weighing 300 g to 450 g are injected subcutaneously each with 3 ml. of the product followed a week later by a second injection with the same dose. They should not show any systemic reaction but may show only a minimum of local reaction. Fourteen days after the second injection six of the vaccinated guinea-pigs are challenged intramuscularly with 25 viable spores of Cl. Chauvoei equivalent to 5 c.h.d. along with 0.2 ml. of a 5 per cent solution of calcium chloride. Two controls are used. The controls should die of the specific injection and at least 4 of the six vaccinated animals should survive before the product is passed for issue. 5. Labelling and Storage.– Should comply with the requirements of “Labelling” and “Storage” as laid down in the general monograph on “Bacterial Vaccines”. 6. Expiry Date.–- The date of expiry of the potency of the vaccine shall not be more than twenty-four months from the date of manufacture. Brucella Abortus ( Strain 19 Vaccine) (Living) 1. Synonym.–Contagious Abortion Vaccine, (Strain 19) (Living). 2. Definition.–Brucella Abortus (Strain 19) Vaccine (Living) is a suspension of a pure smooth living culture of Br. Abortus of low virulence in normal saline solution. 3. Preparation.–Forty eight to seventy-two hour old growth of Br. Abortus (Strain 19) on potato agar medium in Roux flasks washed with buffered normal saline solution pH 6.4 and the pure growth from the flasks are pooled together, 0.5 ml. of the pooled product is mixed with 4.5 ml. of normal saline solution at pH 6.4 in graduated centrifuge tube and centrifuge at 3000 r.p.m for one hour. The percentage of cell deposit is assessed by reading the amount of cell deposit obtained. The concentrated suspension is then diluted with buffer normal saline solution so that the

¹ Subs. by. G.S.R 659 (E) ,dt.. 31-8-1994.

(a) Description.–It is an almost white turbid liquid containing live bacteria in suspension.
(b) Identification.–It consists of Gram-negative bacilli capable of protecting susceptible animals against Brucellosis.
(c) Sterility Test.–Should comply with the test for sterility described in the general monograph on “Bacterial Vaccine”.
(d) Purity Test.–A smear of the finished products is examined microscopically after staining by Gram’s method for evidence of any contamination. When grown on suitable media, Br. Abortus should be obtained in a pure state.
(e) Safety Test.–Two healthy guinea-pigs each weighing 300 g. to 450g. are inoculated subcutaneously each with 1.0 ml. of the final product. The guinea-pigs should not show excessive reaction of a toxic nature during the period of observation of ten days.
(f) Potency Test.–Each of a group of four healthy guinea-pigs, drawn from a uniform stock and each weighing 300 g. to 450 g. is injected intra-muscularly with 1 ml. of the vaccine, and is challenged nine weeks after vaccination by the intramuscular injection of 1 ml. of a suspension containing 5,000 fully virulent Br. Abortus organisms. Each of a group of two unvaccinated guinea-pigs is similarly injected. After a further six weeks, the guinea-pigs are killed and cultures are made from their spleens. More than half of the vaccinated guinea-pigs contain no demonstrable Br. Abortus in the spleen; all the controls are infected. Drugs and Cosmetics Rules, 1945 300
(g) Viable Count.–The vaccine when plated on suitable media should show between 14, 000 million and 18,000 million Br. Abortus organisms per ml. At least 80 per cent brucella organisms should be in the smooth phase. 4. Labelling and storage.– Should comply with the requirements of “Labelling” and “Storage” as laid down in the general monograph on “Bacterial Vaccines”. The liquid vaccine shall be issued fresh as far as possible without allowing any period of storage after manufacture. 5. Expiry Date–The date of expiry of the vaccine shall be not more than five weeks from the date of manufacture. Enterotoxaemia Vaccine 1. Synonyms.–Clostridium Welchii, Type D, Formal Culture: Pulpy Kidney Vaccine. 2. Definition.–Enterotoxaemia Vaccine is a culture of a highly toxigenic strain of Clostridium type D, group is an anaerobic medium rendered sterile and toxic by the addition of Solution of Formaldehyde I.P in such a manner that it retains its immunising properties. 3. Preparation.– Selected toxigenic strain of Cl. Welchii type D, is grown in a liquid medium under conditions which ensure maximum epsilon toxin production. The culture is checked for purity and toxicity as tested in mice. Solution of Formaldehyde I.P. is added in

suitable concentration and the formolised culture is kept at 37 ̊ C till the production is sterile

and non-toxic. 4. Standard:

(a) Description- It is a yellowish brown liquid containing dead bacteria in suspension.
(b) Identification- When injected into susceptible animals it stimulates the production of epsilon antitoxin of Cl. Welchii, type D.
(c) Sterility Test- Complies with the test for sterility described in the general monograph on ‘Bacterial Vaccines’.
(d) Safety and Potency Tests- At least eight sheep each weighing not less than 18

kg. or twelve rabbits each weighing 1 kg. to 1.5 kg. are used for testing the safety and

potency of each brew of the vaccine. Two sheep receive subcutaneously 10 ml. each and the other six sheep receive each 2.5 ml. of the product subcutaneously. The rabbits are given subcutaneously a dose of 5 ml. each. The sheep and rabbits are observed for five days. They should show only a minimum local reaction and no systemic reaction. The sheep receiving 10 ml. are withdrawn from experiments after five days. Each of the other six sheep is inoculated with a second dose of 2.5 ml. fourteen days after the first injection. The rabbits are inoculated with 5 ml. as a second dose, after one month of the first inoculation. Ten days after the second inoculation the sera of sheep or rabbits are pooled separately. The pooled serum of each group of animal shall contain in each ml. not less than two international units of Cl. Welchii epsilon antitoxin which is determined by testing on mice as follows:

One ml. of the pooled serum is mixed with one ml. of the epsilon toxin of Cl.

Welchii type D, containing 300 mouse-minimum-lethal-doses (mouse m.l.d.) and kept at room temperature for half an hour. At least two mice each weighing not less than 18 g. are each given intravenously 0.2 ml. of the mixture. As control two mice each weighing not less than 18 g. should each receive 0.2 ml. of the toxin containing 300 mouse m.l.d per ml. diluted with equal volume of normal saline. The control mice should die within 1 to 2 hours while the mice receiving the mixture of serum and toxin should survive for at

Drugs and Cosmetics Rules, 1945 301 least two days. Sera containing one International Unit of epsilon antitoxin per ml. will be able to neutralise 150 mouse m.l.d. of epsilon toxin of Cl. Welchii, type D. 5. Labelling and Storage.–Should comply with the requirements regarding

“Labelling” and “Storage” as laid down in the general monograph on “Bacterial Vaccines”.

6. Expiry Date.–The expiry date of potency of the vaccine shall be not more than twelve months from the date of manufacture. Fowl Cholera Vaccine (Polyvalent) 1. Synonym.–Pasteurella Septica Vaccine (Avian). 2. Definition.–Fowl Cholera Vaccine is a formolised pure broth culture of virulent strains of Pasteurella Septica (Avian). 3. Preparation.–The strains are grown separately in nutrient broth for 48 hours at 37 ̊ C. The pure growth is killed by the addition of a Solution of Formaldehyde I.P in a suitable concentration. The cultures are then mixed in equal proportions and the final vaccine is bottled in suitable containers. 4. Standard-

(a) Description.–It is a light yellow liquid containing dead bacteria in suspension.
(b) Identification.–It protects susceptible birds against P. aviseptica infection.
(c) Sterility test.–Complies with the test for “Sterility” described under the general monograph on “Bacterial Vaccines”..
(d) Safety Test.–Two healthy young fowls each weighing not less than 400 g. or twelve healthy mice are inoculated subcutaneously each with 1 ml. of the final product. The birds should not show any untoward reaction during the period of observation for seven days. 5. Labelling and Storage.–Should comply with the requirements of “Labelling” and “Storage” as laid down in the general monograph on “Bacterial Vaccines”.

Hemorrhagic Septicaemia Adjuvant Vaccine

1. Synonym.– Pasteurella Septica Adjuvant Vaccine.

2. Definition.–The vaccine is a homogenous suspension of formolised agar-washed Pasteurella septica with liquid paraffin and lanolin.

3. Preparation.–Pure growth of a highly antigenic strain of P. Septica in phase 1 grown

on nutrient agar medium containing 0.5 per cent yeast extract is washed with 0.5 per cent formol saline. The pooled suspension is diluted with normal saline to contain approximately 2100 million P. Septica organisms per ml. The safety test of this adjusted suspension is conducted on four white mice each weighing not less than 18 g. and observed for three days before it is mixed with liquid paraffin and lanolin in suitable proportion. The mixture is blended until a homogenous emulsion is obtained which is filled in suitable containers.

4. Standard:

(a) Description − It is a white thick oily liquid containing dead bacteria in suspension.
(b) Identification.–It protects susceptible animals against infection with P. Septica. Drugs and Cosmetics Rules, 1945 302
(c) Sterility Test.–It complies with the test for “Sterility” described in the general Monograph on “Bacterial Vaccines”.
(d) Safety Test.– Six white mice each weighing not less than 18 g. are inoculated intraperitoneally each with 0.5 ml. of the vaccine. None of the mice should die of pasteurellosis during the observation period for seven days.
(e) Potency Test.–Three susceptible calves in good condition between the ages of nine months to three years are injected intramuscularly, each with 2 ml. of the vaccine, in

the case of animals weighing upto 140 kg. and 3 ml. for heavier ones.

Three weeks later these animals along with two healthy animals of the same type and species are challenged subcutaneously with 18 hours old broth culture of P. Septica

equivalent to at least 50 million mouse minimum infective dose. Both the controls should die

of pasteurellosis and at least two out of the three protected animals should survive the challenge dose for a period of seven days. 5. Labelling and storage- Should comply with the requirements for “Labelling” and “Storage” as laid down in the general monograph on “Bacterial Vaccines”. 6. Expiry Date- The date of expiry of potency of the vaccine shall be not more than

twelve months from the date of manufacture.

Haemorrhagic Septicaemia Vaccine (Broth) 1. Synonym.–Pasteurella Septica Vaccine (Broth). 2. Definition.–Haemorrhagic Septicaemia Vaccine is formolised culture of a virulent strain of Pasteurella septica in nutrient broth. 3. Preparation.–.Septica culture is grown in nutrient broth at 37 ̊C. The pure growth is killed by the addition of a solution of Formaldehyde I.P. in a suitable concentration. 4. Standard:

(a) Description.–It is a pale yellow liquid containing dead bacteria in suspension.
(b) Identification.–It protects susceptible animals against infection with P.Septica.
(c) Sterility Test.–Complies with the test for “Sterility” described under the general monograph on “Bacterial Vaccines”.
(d) Safety Test.–Four healthy rabbits each weighing 1 kg. to 1.5 kg. are inoculated subcutaneously each with 5 ml. of the product. There should be no untoward reaction during the period of observation for seven days. Alternately two rabbits and six mice may be employed. The dose for mice will be 0.5 ml. 5. Labelling and Storage.–Should comply with the requirements of “Labelling” and “Storage” as laid down in the general monograph on “Bacterial Vaccines”.

Salmonella Abortus Equi Vaccine 1. Synonym.–Equine Abortion Vaccine. 2. Definition.– Equine Abortion Vaccine is a mixture of equal parts of pure formolised cultures of smooth laboratory strains of Salmonella abortus equi. 3. Preparation.–The strains are grown separately on plain agar in Roux flasks, for 24- 28 hours at 37 ̊ C. The pure growth is washed with normal saline solution and the washings are pooled together. The suspension is standardised to contain approximately 600 million Sal.Abortus equi organisms per ml. using normal saline solution as diluent. The culture is killed by the addition of sufficient quantity of solution of Formaldehyde I.P in a suitable

Drugs and Cosmetics Rules, 1945 303 concentration and the product is kept at 37 ̊ C for seven days. Potassium alum is added to give a final concentration of 1 per cent 4. Standard:

(a) Description.–It is an opalescent liquid containing dead bacteria in suspension.
(b) Identification.–It protects susceptible animals against infection with Sal. Abortus equi.
(c) Sterility Test.–Complies with the test for sterility described in the general monograph on “Bacterial Vaccines”.
(d) Safety Test- Six white mice each weighing not less than 18 g. are inoculated intraperitoneally each with 0.5 ml. of the product. None of the mice should die of salmonellosis. The mice are observed for ninety-six hours. 5. Labelling and Storage- Should comply with the requirements for “Labelling” and “Storage” as laid down in the general monograph on “Bacterial Vaccines”. 6. Expiry Date- The date of expiry of potency of the vaccine shall be not more than six months from the date of manufacture. Streptococcus Equi vaccine 1. Synonym.– Strangles Vaccine 2. Definition.– Streptococcus equi Vaccine is a phenolised culture of a number of different isolates of Streptococcus equi in glucose serum broth. 3. Preparation.– Equal proportions of forty-eight hours old pure cultures of different

isolates of Str. Equi in serum glucose both are mixed together. The suspension is centrifuged

and the deposit is washed with normal saline solution after removing the supernatant. The washed cells are suspended in normal saline and heated in a water bath 65 ̊C for two hours. Phenol and normal saline are added to give a final concentration of 1200 million Str. Equi organisms per ml. and 0.5 per cent of phenol in the vaccine.

4. Standard-

(a) Description.– It is a slightly opalescent liquid containing dead bacteria in suspension.
(b) Identification.–It protects susceptible animals against infection with Str. Equi.
(c) Sterility Test.–Complies with the test for “Sterility” described in the general monograph on “Bacterial Vaccines”, the nutrient broth being replaced by glucose broth.
(e) Safety Test.–Two ponies and two rabbits (each weighing not less than 1 kg.) are inoculated each with 10 ml. and 2 ml. respectively of the final product. The animals should not show any untoward reaction during the period of observation of seven days. 5. Labelling and Storage.–Should comply with the requirements for “Labelling” and “Storage” as laid down in the general monograph on “Bacterial Vaccines” 6. Expiry Date.– The date of expiry of potency of the vaccine shall be not more than six months from the date of manufacture. Old Adjuvant Vaccine against Pasteurellosis in Sheep and Goats. 1. Synonym- Pasteurella Septica Adjuvant Vaccine for ovines and Caprines. 2. Definition- The vaccine is a homogenous suspension of formolised agarwashed Pasteurella septica of ovine origin with liquid paraffin and lanolin. Drugs and Cosmetics Rules, 1945 304 3. Preparation − Pure growth of highly antigenic strains (R1, R2, R4) in phase I grown separately on nutrient agar medium containing 0.5 per cent yeast extract is washed with 0.5 per cent Normal saline. Equal quantities of the suspension of three strains diluted with Normal saline to contain approximately 2100 million organisms per ml. is pooled together. The safety test of this adjusted pooled suspension is conducted in for white mice each weighing not less than 18 g. and observed for three days before it is mixed with liquid paraffin and lanolin in suitable proportion. The mixture is blended until a homogenous emulsion is obtained which is filled in suitable containers. 4. Standards:
(a) Description- It is a white thick oily liquid containing dead bacteria in suspension.
(b) Identification- It protects susceptible animals against infection with P. Septica.
(c) Sterility Test- Complies with the test for sterility described in the general monograph on “Bacterial Vaccines”.
(d) Safety Test- Six white mice each weighing not less than 18 g. are inoculated intra-peritoneally each with 0.5 ml. of the vaccine. None of the mice should die of Pasteurellosis druing the observation period of seven days. The vaccine is also inoculated into six sheep and six goats in a dose of 3 ml. each intramuscularly and are observed for a period of seven days. During this period none should die of Pasteurellosis.
(e) Potency Test- Not being done at present. 5. Labelling and Storage- Should comply with the requirements for “Labelling” and “Storage” as laid down in the general monograph on “Bacterial Vaccines. 6. Expiry Date- The expiry date of Potency of the Vaccine shall be not more than twelve months from the date of manufacture. 1[Multicomponent of Clostridial Vaccine 1. Synonyms. – Combined anaculture of Clostridium perfringens type C and D, C1. septicum and CI., oedematies. 2. Definition – It consists of four highly antigenic components containing the toxoids of C. perfringens type D, CI. Perfringens type C, Cl. oedematiens and CI. septicum which are prepared in double strength and then combined in such a proportion that would invoke adequate anti-toxin response in the vaccinated sheep against each antigen incorporated in the vaccine

3. Preparation – The above strains are grown separately in suitable liquid media under

conditions which ensure maximum toxin production. The cultures are checked for purity and

o C till the product is sterilized and atoxic. The formalized anacultures are pooled, precipitated by the addition of Aluminium Chloride, 20 per cent solution in distilled water to have a final concentration of the chemical to 10 per cent and pH adjusted to 6.0.the sedimented toxoid is reconstituted to have its original volume in normal saline.

Drugs and Cosmetics Rules, 1945 305 4 Standards :

(a) Description – It is whitish liquid when shaken thoroughly to contain killed bacteria and toxoid in suspension.
(b) Identification – When injected to susceptible animals it stimulates the production of epsilon and beta antitoxins against CI. perfrigens type D and C and also

antitoxins against CI. septicum and toxin of CI. Oedematiens.

(c) Sterility Test – Complies with the test of sterility described in general monograph on “Bacterial Vaccines.”
(d) Safety Test – Four sheeps each are inoculated with 10 ml. S/C of the product and these are observed for 7 days during which period animals shall not show any local or systemic reaction.
(e) Potency Test – Eight sheep each are inoculated with 2 doses of vaccines S/C at an interval of 21 days and bled on 10th day after 2nd inoculation for collection of serum for assessing the antitoxin titre against each antigen incorporated in the vaccine. The

antitoxin. 5. Labelling and storage - Shall comply with the requirements regarding labelling and storage as laid down in the general monograph on “Bacterial Vaccine”.

6. Expirty date – The expiry date of potency of vaccine shall not be more than 6 months

from the date of manufacture.

Haemorrhagic Septicaemia Vaccine – Alum Treated 1. Synonyms – Pasterulla multocida/(Yersinia Multocida) vaccine – Alum treated. 2. Definition -- The vaccine is a formalized culture of a virulent strain of Pasteurella multocida in nutrient broth treated with potash alum. 3. Preparation -- A highly potent strain of Pasteurella multocida type I in Phase I is grown on nutrient broth at 37 o C. The pure growth is killed by the addition of a solution of Formalin I.P in suitable concentration (0.5 per cent). This is treated with Potassium Alum I.P to give a final concentration of 1 per cent. 4. Standard :

(a) Description – It is a white suspension containing dead bacteria and alum.
(b) Identification – It protects susceptible animals against infection with P. multocida.
(c) Sterility Test -- It complies with the test for sterility described under general monograph on “Bacterial Vaccines”.
(d) Safety Test -- Four healthy rabbits each weighting 1 to 1.5 kg. are inoculated subcutaneously each with 5 ml. of the product. There shall be no untoward reaction during the period of observation for 7 days except slight local swelling. Alternatively two rabbits and six mice may be employed. The dose for mice will be 0.5 ml. 5. Labelling and Storage :-- Shall comply with the requirements of labelling and storage as laid down in the general monograph on “Bacterial Vaccines”. _______________________________________________________________________ Drugs and Cosmetics Rules, 1945 306 6. Expiry date – The date of expiry of potency of the vaccine shall be not more than six months from the date of manufacture.]
(B) PROVISIONS APPLICABLE TO THE PRODUCTION OF VIRAL VACCINES 1. Definition- (i) This part of the Schedule applies to viral vaccines live or inactivated made from any virus pathogenic to domestic animals and poultry and made from other modified viruses which have any antigenic value.
- (ii) For the purpose of this Part of the Schedule, a virus vaccine means a sterile suspension or a freeze dried powder containing the modified living or inactivated virus particles, which in its original unaltered stage, causes disease from which the vaccine derives its name and which has been prepared from the blood or tissues of a suitable host in which it has been grown in vivo or from tissue culture. 2. Staff of Establishment- The establishment in which viral vaccines are prepared must be under the direction and control of an expert in bacteriology with specialized training in virology and sufficient experience in the production of viral vaccines, and he shall be assisted by a staff adequate for carrying out the tests required during the preparation and standardisation of the vaccines. 3. Proper Name- The proper name of any viral vaccine shall be the name of the disease which is caused by the particular virus from which the vaccine is produced followed by the word “vaccine” unless the Schedule otherwise provides, if there is no special provision

¹ Ins. by G.S.R. No. 659(E) ,dt. 31-8-1994.

in the Schedule such other name as is approved by the Licensing Authority. Provided that in

the case of the undermentioned preparations the proper name of the vaccine shall be as follows:

(i) Fowl Pox Vaccines, Chick Embryo Virus (Living).
(ii) Fowl Pox Vaccine, Pigeon Pox Virus (Living).
(iii) Horse Sickness Vaccine (Living)
(iv) Ranikhet Disease Vaccine (Living)
(v) Ranikhet Disease Vaccine F Strain (Living)
(vi) Rinderpest Goat Adapted Tissue Vaccine (Living)
(vii) Rinderpest Lapinised Vaccine (Living)
(viii) Rinderpest Lapinised Avianised Vaccine (Living)
(ix) Sheep and Goat Pox Vaccine (Living)
(x) Swine fever vaccine (crystal violet)
(xi) Swine fever vaccine lapinised (Living).

1[(xii) Foot and Mouth Dieseas Vaccine (Inactivated).

(xiii) Canine Hepatitis Vaccine (Living).] 2[4. Records- The seed virus used in the preparation of vaccine shall, before being used for preparing a batch, be thoroughly tested for purity, safety, sterility and antigenicity by the generally accepted tests applicable to a particular virus. It shall not be more than five passages away from the stock seed virus, unless otherwise prescribed for a particular virus. The stock seed virus shall be maintained by seed-lot system at specified passage level and tested for bacterial, mycoplasmal and extraneous viral contamination. The permanent record which the licensee is required to keep shall include a record of the origin, properties and characteristics of the seed virus from which the vaccines are made.] _______________________________________________________________________ Drugs and Cosmetics Rules, 1945 307 5. Tests- Viral vaccine shall be tested for sterility, safety and potency on suitable test animals and for viability in the case of live vaccines.

¹ Ins. by G.S.R. 659(E) ,dt. 31-8-1994.

² Subs., ibid.

(a) Sterility Test- All vaccines shall be tested for sterility in accordance with rules 115 to 119. If the vaccine contains added bactericides or bacteriostatic, a quantity of medium sufficient to render the growth inhibitor ineffective is added to the sample or a suitable substance is added in a concentration sufficient to render the growth inhibitor ineffective but not itself to inhibit the growth of micro-organisms.
(b) Safety Test- Suitable laboratory animals or large animals or birds may be employed to test the vaccine for safety. Details of the safety test are given in the individual monograph.
(c) Potency Test- All virus vaccines for which potency test has been prescribed shall be tested for potency and only those which pass the potency test shall be issued. Details of the potency test are given in the individual monograph. 6. Storage- Live viral vaccines shall be stored, protected from light at sub-zero

temperature as required. Other viral vaccines shall be stored at 2 ̊ C to 4 ̊ C but shall not be

frozen.

7. Condition of housing of animals- (i) The animals used in the production of vaccine

must be housed in hygienic conditions in premises satisfactory for this purpose.

(ii) Only healthy animals may be used in the production of vaccine. Each animal intended to be used as a source of vaccine must, before being passed for the production of vaccine be subjected to a period of observation in quarantine for at least seven days. During the period of quarantine the animal must remain free from any sign of disease and must be well kept.

1[(iii) The poultry birds from which eggs and cell culture for production of vaccines are

obtained should be housed in a manner so as to keep them free from extraneous infection and shall be screened at frequent intervals for common bacterial, mycoplasmal and viral infection. The record of the tests and their results shall be maintained by the manufacturers.]

8. Labelling- The provisions of “Labelling” as laid down for Bacterial Vaccines shall

also apply to Viral Vaccines. The following additional information shall also be included on the label of the outside container:

(i) The name and percentage of bacteriostatic agent contained in the vaccine.
(ii) If the vaccine as issued for sale contains any substance other than the diluent, the nature and strength of such substances. 9. Date of Manufacture- For the purpose of this part of the Schedule, the date of manufacture shall be what is given unless otherwise stated in the individual monograph, as defined in sub-clause (b) of sub-rule (3) of rule 109. Fowl Pox Vaccine Chick- Embryos Virus (Living) 1. Synonym- Egg adapted Fowl Pox Vaccine (Living). 2. Definition- Fowl-pox Vaccine, Chick-Embryo Virus (Living) is a suspension of a modified living virus (e.g. Mukteswar Strain) prepared from the chorioallantoic membrane

(CAM) of the infected embryo and is either freeze dried or is issued as glycerinated liquid vaccine. _______________________________________________________________________ Drugs and Cosmetics Rules, 1945 308 3. Preparation- Active chick-embryos obtained from Salmonella pullorum free flock, are used. 1[Twelve to thirteen days old embryos are injected with a suitable dilution of the suspension of the infected membrane (seed virus) of chick embryo adopted fowl pox virus.] The suspension of the stock seed virus is dropped on the CAM. After an incubation at 37 ̊C for a suitable period membranes showing discrete or confluent lesions (pocks) are harvested. These are homogenised with adequate quantity of antibiotics (penicillin and streptomycin) ampouled in 0.5 ml. quantities and freeze dried. 4. Standard-
(a) Description- Light mauve coloured scales.
(b) Identification- When reconstituted vaccine is applied to scarified area of the skin of a fowl it produces characteristic lesions of fowl pox. This product should afford protection against fowl pox.
(c) Moisture Content- Moisture Content in the finished product should not exceed 1.0 per cent.
(d) Safety Test- For testing each batch of fowl pox vaccine twelve healthy cockerels, or other suitable young chicken each weighing not less than 400 g. from the same source are taken. This group of twelve birds is immunized at least twenty-one days previous to the test, with fowl pox vaccine. The vaccine under test is reconstituted in 5 ml. of 50 per cent glycerine saline and administered to fowls as follows:- Three of the test birds are injected subcutaneously with 0.8 ml. or 10 times the field doses of the vaccine under test. This group serves to indicate whether the product is free from other viruses and bacteria causing septicaemia or not. Three of the test birds are injected intratrecheally with 0.3 ml. or 10 times the field dose of vaccine under test. This group serves to indicate whether the product is free from the virus of infectious laryngotracheitis and similar disease. Three of the test birds are injected intranasally with 0.2 ml. of the vaccine under

¹ Ins. by. GSR 659(E) , dt. 31-8-1994.

test. This group serves to indicate whether the product is free from the virus of Coryzai

and similar disease. The three remaining birds serve as controls. They are isolated and kept under observation for twenty-one days. The birds that succumb during the period of twenty-one days are subjected to a careful postmortem examination. The product is withheld from issue until the vaccine and the test birds are shown to be free from the causative agents of any extraneous disease.

(e) Sterility test- Complies with the tests for sterility as described under the general monograph on “Viral Vaccines”.
(f) Potency Test- For testing of potency three unsusceptible birds each weighing not less than 400 g. are vaccinated using the field dose by the stick method and examined for “takes”. Three weeks after vaccination these birds along with two unvaccinated controls are exposed to challenged virus and observed for fourteen days. The vaccinated birds should not manifest any reaction, while the controls should show active “takes”. 5. Labelling- Should comply with the requirement for “Labelling” as laid down in the general monograph on “Viral Vaccines”. 6. Storage and Expiry date- Freeze dried vaccine shall be expected to retain its potency for periods at temperatures as specified below:-

Room temperature– upto one month. __________________________________________________________________

1. Amended by. G.S.R. 659(E) , dt. 38-8-1994

Drugs and Cosmetics Rules, 1945 309 The liquid vaccine shall be expected to retain its potency for periods and temperatures as specified below:

2 ̊ C to 4 ̊C – six months.

Room temperature– seven days.

Fowl- Pox Vaccine, Pigeon Pox Virus (Living)

1. Synonym- Fowl Pox Vaccine (Pigeon pox scab). 2. Definition- Fowl Pox Vaccine, Pigeon-pox Virus (living) consists of pigeon pox virus in scabs collected from artificially infected pigeons and dried. 3. Preparation- Healthy pigeon are scarified on the legs and breast, with a suitable dilution of the suspension of pigeon-pox virus. The pigeons reacting satisfactorily and showing good takes are selected and the superficial skin layer scraped by means of sharp scalpel. The material so collected is freed from feathers, homogenised and dried or freeze

dried. The dried pulp is powdered, sieved and ampouled in 0.3 g. quantities and sealed

4. Standard-

(a). Description- Light cream coloured powder.

(b) Identification- When applied to feather follicles by vigorous rubbing, it produces mild reaction in fowls. The product should afford protection to fowls upto six weeks against fowl pox.
(c) Safety Test- For testing a batch of vaccine, twelve healthy cockerels, or other suitable young chicken from the same source are made available at the same time. This group of twelve birds is immunised at least twenty-one days previous to the test with fowl pox vaccine. The vaccine under test is reconstituted in 10 ml. of 50 per cent glycerine saline and administered to fowls as follows: - Three of the test birds are injected subcutaneously with 0.3 ml. or 10 times the field dose of the vaccine to be tested. This group serves to indicate whether the product is free from organisms of septicaemia disease. Three of the test birds are injected intranasally with 0.2 ml. of the vaccine to be tested. This group serves to indicate whether the product is free from virus of Coryza and similar diseases. 1[Three of the test birds are injected intratricheally with 0.3 ml or 10 times of the field dose of vaccine under test. This group serves to indicate whether the product is free from the virus of infectious laryngotracheitis and similar diseases.] The three remaining birds serve as controls. All the birds under test are isolated and held under observation for twenty-one days. All those that succumb are subjected to careful post-mortem examination. The product is withheld from issue until the vaccine and test birds are shown to be free from the causative agents of any extraneous diseases.
(d) Sterility Test- Complies with the tests for sterility described under the general monograph on “Viral Vaccines”.
(e) Potency Test- For testing the potency of a batch of vaccines three susceptible birds each weighing not less than 400 g. are vaccinated using the field dose by the follicular method and examined for ‘takes’. Three weeks after vaccination these birds and two healthy susceptible controls are exposed to challenge virus and are observed for

fourteen days. The vaccinated birds shall manifest no reaction, while the controls must

¹ Ins. by G.S.R .659(E), dt. 31-8-1994.

have active “takes”. _________________________________________________________________

Drugs and Cosmetics Rules, 1945 310

5. Storage and Labelling- Should comply with the requirements of ‘Labelling’ as laid down in the general monograph on ‘Viral Vaccines’. 6. Expiry date- The vaccine shall be expected to retain its potency for periods at temperature as specified below:-

Room temperature- Upto one month.

Fowl Pox Vaccine- Pigeon Pox- Chick Embryos Virus (Living) 1. Synonym- Chick embryo adapted pigeon pox vaccine (Living).

2. Definition- Fowl pox vaccine (Pigeon Pox virus) chick embryo adapted virus (living) is a suspension of a modified living virus prepared from the chorioallantoic membranes of the infected embryos and is freeze dried. 3. Preparation- Active chick embryos obtained from Salmonella Pullorum free stock are used. Twelve to thirteen days old embryos are injected with a suitable dilution of the suspension of the infected membrane (stock seed virus) of chick embryo adapted pigeon pox virus. The suspension of the stock seed virus is dropped on the membrane. The inoculated eggs are incubated at 37 ° C for four days. One of the fourth day embryos that are living, are removed to a refrigerator for chilling for about one hour. Membranes showing discrete lesions (Pocks) are harvested. These are homogenised with adequate quantities of antibiotics, ampouled in 0.5 ml. quantities and freeze dried. 4. Standards-

(a) Description- Light mauve coloured scales.
(b) Identification- When reconstituted vaccine is applied to scarified area of the skin of a fowl, it produces characteristics lesions of Fowl Pox. This product should afford protection against pox.
(c) Moisture content- Moisture content in the finished product should not exceed 1.0 per cent.
(d) Safety test- For testing each batch of chicks aged four to six weeks from the same source are taken. This groups of twelve birds is immunised at least twenty-one days previous to the test, with fowl-pox vaccine. The vaccine under test is reconstituted in 3 ml. of normal saline solution and administered as under:- ` Three of the test chicks are injected subcutaneously with 0.3 ml. or 10 times the field dose of the vaccine under test. This group serves to indicate whether the product is free from other viruses and bacteria causing of septicaemia or not. Three of the test chicks are injected intratracheally with 0.3 ml. or ten times the field dose. This group serves to indicate whether the product is free from the viruses of infections laryngeotracheitis and similar diseases. Three of the test chicks are injected with 0.2 ml 1/N of the vaccine under test. This group serves to indicate whether the product is free from the virus of coryza and similar diseases. The remaining three chicks serve as controls. They are isolated and kept under observation for twenty-one days. The birds that succumb during the period of Drugs and Cosmetics Rules, 1945 311 observation are subjected to careful post-mortem examination. The product is withheld from issue until the vaccine and the test birds are shown to be free from the causative agents of any extraneous disease. In addition to the above, similar groups of pigeons aged six to nine months old are also injected in a similar way to eliminate psittacosis.
(e) Sterility Test- Should comply with the tests for sterility described under the general monograph on ‘Viral Vaccine’.
(f) Potency test- For testing potency of a batch of vaccine three susceptible chicks of three to four weeks of age are vaccinated by feather forthicle method ( a few forthicles on one leg are injected) and these are examined for ‘takes’. Three weeks after vaccination these chicks along with two unvaccinated chicks are exposed to challenge virus (virulent fowl pox virus) and observed for fourteen days. The vaccinated chicks should not manifest any reaction while controls should show active ‘takes’.

6 Storage- The freeze dried product is expected to retain its potency for periods at temperatures as specified below:

-15 ° C to 20 ° C–two years.

2° C to 4 ° C–twelve months. Room temperature- up to one month.

Sheep Pox Vaccine (Living) 1. Synonym- Sheep Pox vaccine; Goat pox vaccine. 2. Definition- Sheep pox vaccine consists of sheep pox virus collected from sheep artificially infected with sheep pox virus and freeze dried. 3. Preparation- Healthy yearling sheep are infected artificially by subcutaneous infection on the undersurface of the previously shaved abdomen with 200- 300 cc. of the freeze dried sheep pox virus (seed material) diluted in 1 : 1 Normal saline solution. On the sixth or seventh day after injection oedematous swelling develops in the injected area with thermal reaction. The sheep which develop good swelling are slaughtered and the gelatinous material present under the skin in the infected area is collected under sterile conditions. This material is mixed with 2 parts by volume of sterile peptone broth of pH 7.2 and homogenised. The homogenised suspension is filtered, ampouled in 0.5 ml. quantities and freeze dried. 4. Standard:

(a) Description- White scales.
(b) Identification- Reconstituted vaccine when applied over the scarified area of the skin of the abdominal region of sheep will produce characteristic local lesion of pox.
(c) Moisture content- The moisture content should not exceed 1.0 per cent.
(d) Safety test- Two rabbits each weighing not less than 1 kg. are injected subcutaneously each with 1 ml. of 1 : 100 dilution of the vaccine in normal saline solution. These animals are observed for fourteen days. The animals should remain normal. Drugs and Cosmetics Rules, 1945 312
(e) Sterility Test- Complies with the tests for sterility described under the general monograph on ‘Viral Vaccines’.
(f) Potency Test- Four yearling sheep are vaccinated on the inner surface of the ear by scarification method. The contents of one ampoule of F.D. Sheep Pox vaccine are constituted in 10 cc. of 50 % glycerin saline solution, characteristic ‘takes’ develop in the scarified area with ulceration and scab formation. Three weeks later these and two more susceptible sheep (Controls) are challenged by scarifying with a suspension of the previous brow of the vaccine of the undersurface of the abdomen. The controls should develop typical lesions of pox and the vaccinated should remain normal. 5.Labelling- Should comply with the requirements of ‘labelling’ as laid down in the general monograph in ‘Viral Vaccine’. 6. Storage and expiry date- The vaccine is expected to retain potency for period and temperature as specified below:- -15 ° C to – 20 ° C– two years 2 ° C to 4 ° C–three months.

Room temperature- Fifteen days.

Horse Sickness Vaccine (Living) 1. Synonym- African Horse Sickness Vaccine, Mouse adapted Polyvalent Horse Sickness Vaccine (Living). 2. Definition- Horse sickness vaccine is a suspension of live mouse adapted strains of

Horse Sickness Virus (Onderstepoort) prepared from the brains of infected mice and is freeze

dried. 3. Preparation- Thirty to thirty-five days old white mice are infected intracerebrally with 0.05 ml. of a suitable dilution of the seed virus (6 or 7 types, as the case may be). Groups of large numbers of mice are injected separately with each type of the virus and are housed at 27 ° C to 32 ° C. A majority of these become paralytic on the third and fourth day when they are sacrificed and their brains collected and stored at – 15 ° C to – 20 ° C till the day of processing. For preparing the polyvalent vaccine, equal number of brains collected from mice infected with different types of the virus are homogenised with 5-10 times its volume of

sterile lactose buffer medium (pH 7.2 ) containing antibiotics. The suspension is centrifuged

at 1500 r.p.m. for five minutes. The supernatant liquid is distributed in ampoules in suitable quantities and freeze dried. 4. Standard:

(a) Description- White scaly material.
(b) Identification- This product affords protection to horse against horse sickness.
(c) Safety Test- Four healthy mice thirty to thirty-five days old are injected intraperitoneally with 0.2 ml. of 10:1 dilution of the vaccine and kept under observation for ten days. All the mice should remain normal throughout the period of observation.
(d) Sterility Test- Should comply with the test for sterility described under the general monograph on ‘Viral Vaccines’.
(e) Viability Test- Each batch of vaccine is titrated in tenfold dilutions using four mice of thirty to thirty-five days old for each dilution. Each mouse is injected intracerebrally with 0.05 ml and kept under observation for ten days. Mortality and survival ratios are noted and LD ml is determined. The minimum acceptable titre is 10–4 LD per 0.05 ml. Drugs and Cosmetics Rules, 1945 313

(5) Labelling - Should comply with the requirements of ‘labelling’ as laid down in the general monograph in ‘Viral Vaccines’.
(6) Storage- The vaccine may be expected to retain its potency for twelve months if

stored – 15 ° C to 20° C and about six months if stored in refrigerator at 2 ° C to 4° C.

Rabies Vaccine (Inactivated) 1. Synonym- Antirabic Vaccine (Inactivated)

2. Definition- Rabies vaccine is a suspension of the brain tissue of animals, that have

been infected with a suitable strain of rabies fixed virus, inactivated with phenol or some other suitable agent. 3. The following particulars relating to this vaccine are the same as those relating to Antirabic vaccine described in Part D of Schedule F to these rules, namely:-

(i) Strain of fixed Rabies Virus to be used;
(ii) Staff of Establishment;
(iii) Condition and housing of animals;
(iv) Precaution to be observed in preparation;
(v) Records;
(vi) Issue. 4. Preparation- Healthy sheep or any other suitable species of animal are inoculated subdurally or intracerebrally with an appropriate dose of suspension of a suitable strain of rabbit brain passaged rabies fixed virus. The sheep or animals which get paralysed from the sixth day onwards after the inoculation are sacrificed and their brains collected aseptically. Brain tissue is weighed individually and a suspension of suitable concentration of brain tissue prepared in buffered saline is strained through gauze. The suspension treated with phenol or some other suitable inactivating agent is incubated for an appropriate period. 5. Standard-

(a) Description- A grey to pale yellow opalescent suspension.
(b) Identification- Appropriate doses protect mice against subsequent intracerebral inoculation with suitable strain of fixed rabies virus.
(c) Safety test- Not less than five mice, each weighing at least 18 gm., are inoculated intracerebrally with not less than 0.03 ml. of the suitably diluted vaccine. None of the animals should show symptoms of rabies or die of the disease during period of observation of three weeks.
(d) Sterility Test- Should comply with the test for sterility described under the general monograph on ‘Viral Vaccine’. 6. Labelling- Should comply with the requirements of ‘Labelling’ as laid down in the general monograph on ‘Viral Vaccines’. In addition the label on the container shall indicate the percentage of brain tissue present in the vaccine. 7. Storage- The vaccine may be expected to retain its potency for about six months if

stored in refrigerator at 2 ̊ to 4 ° C.

Drugs and Cosmetics Rules, 1945 314 Rabies Vaccine (Living) 1. Definition- Rabies vaccine (living) is a freeze-dried suspension of chick-embryo tissue infected with a suitable attenuated strain of rabies virus. 2. Preparation- It may be prepared by the following method. Seed virus consisting of a suspension of the Flury or other suitable strain of chick adapted virus that has been maintained by passage in chick embryos is injected into the yolk-sacs of fertile eggs incubated for a suitable period. After incubation for a further ten days, the embryos are harvested and ground in water for injection to give 33 percent suspension. The suspension is centrifuged to remove coarse particles and the supernatant fluid is distributed into ampoules in 3 millilitre quantities, and freeze dried. The vaccine is reconstituted immediately before use by adding 3 millilitres of water for injection to the contents of an ampoule. 3. Standard- It complies with the requirements of general standard of viral vaccines for abnormal toxicity, sterility, and labelling with the following additions.

(a) Description- Dry honey-coloured flakes or powder, readily dispersible in water.
(b) Identification- It protects guinea pig against a subsequent inoculation of rabies street virus. It is distinguished from the inactivated Rabies vaccine by its ability to produce rabies encephalitic on intracerebral injection into mice.
(c) Safety- The guinea pigs used in the test for potency should not show any marked local or systemic reaction during the three weeks following injection with the vaccine.
(d) Sterility Test- Complies with the tests for sterility described under the general monograph on ‘Viral Vaccines’.
(e) Potency Test- The contents of an ampoule are dispersed in water for injection to give a 5 per cent suspension and not fewer than twenty guinea pigs, drawn from a uniform stock and each weighing 350 g. to 500 g., are each injected intramuscularly with 0.25 ml. of this suspension. Three weeks later, these guinea pigs and an equal number of similar unvaccinated control guinea pigs are each inoculated with 0.1 ml. of a suitable dilution of canine salivary gland suspension of street virus which is maintained as a 20 per cent suspension at 70 ° C or lower. The guinea pigs are observed for thirty days; not less than 80 per cent of the control guinea-pigs die of rabies and not less than 70 per cent of the vaccinated guinea-pigs are protected. 4. Storage- Freeze-dried vaccine should be stored at refrigeration temperatures of 2 ° C to 4 ° C. 5. Labelling- The life of the vaccine at room temperature and at refrigeration temperature should be stated on the label. 6. (a) Action and uses- Rabies vaccine (living) is used for the prophylactic inoculation of dogs against rabies; one injection should provoke a serviceable immunity lasting for at least a year. The vaccine has been used to a limited extent on cattle.
(b) Dose- By intramusclar injection: Dogs, the contents of one ampoule reconstituted in 3 ml. of water for injection; cattle five times the dog dose. Ranikhet Disease Vaccine (Living) 1. Synonym- New Castle Disease Vaccine (Living); pheumoenteritis Vaccine (Living). 2. Definition- Ranikhet Disease vaccine is a suspension of a modified living virus e.g. (Mukteswar strain) prepared from infected embryos and fluids and is freeze dried. Drugs and Cosmetics Rules, 1945 315 3. Preparation- Good fertile eggs obtained from Salmonella pullorum free flock are incubated in an egg incubator. Ten days old vigorous embryos are infected with 0.1 ml. of a suitable dilution of a suspension of the virus. Inoculation is done in the allantoic cavity. Embryos are incubated at a suitable temperature. Eggs showing dead embryos twenty-four hours after incubation are discarded. After forty-eight hours incubation the eggs are candled and those showing dead embryos are chilled for a suitable period of time, while embryos alive beyond forty-eight hours are discarded. The fluids and embryos are then collected and spot haemogglutination carried out. The material is homogenised in a blender and ampouled in aliquots of 0.5 ml. quantities and freeze-dried. 4. Standards-
(a) Description- Light brown scales.
(b) Identification- This product affords protection to fowls against Ranikhet Disease.
(c) Safety Test- For testing each batch of freeze dried Ranikhet Disease Vaccine, twelve healthy young chickens, all from the same source each weighing not less than 400 g. are taken and immunised against Ranikhet Disease. Fourteen days later, these birds, are tested as follows with the contents of one ampoule suspended in 100 ml. of normal saline. Three of the test birds are injected intratracheally with 0.1 ml. equivalent to ten times the field dose of the vaccine to be tested. This group serves to indicate whether the product is free from viruses or organisms of speticaemia disease. Three of the test birds are injected intratracheally with 0.1 ml. equivalent to ten times the field dose of he vaccine to be tested. This group serves to indicate whether the product is free from the virus of infectious laryngotracheitis,
- • * * and similar diseases. The three remaining birds serve as controls. 2[Three of the test birds are injected intranasally with 0.2 ml of the vaccine to be tested. This group serves to indicate whether the product is free from virus of Coryza and similar diseases.] All the treated birds and controls are observed daily for fourteen days. All the test birds that succumb are subjected to careful postmortem examination. The product is not issued until the birds under test are shown to be free from the causative agents of any extraneous diseases.
(e) Sterility Test- Should comply with the test for sterility described in the general monograph on ‘Viral Vaccine’.
(f) Potency Test- Four susceptible birds eight to twelve weeks old and each weighing not less than 400 g. are vaccinated by injecting subcutaneously 1 ml. of a 10 -5 dilution of the product. Two weeks after vaccination these birds and four non-protected birds are challenged by injecting subcutaneously each with 1.0 ml. of a 1: 100 dilution of

virulent virus (liver and spleen suspension) or 1.0 ml. of a 1 : 100 dilution of fluid from

the embryo infected with virulent Ranikhet Disease virus. The non-protected birds should show symptoms of Ranikhet Disease and die and all the protected birds should remain normal during an observation period of fourteen days. 5. Labelling- Should comply with the requirements of ‘Labelling as laid down in the general monograph on ‘Viral Vaccines’.

² Ins. by G.S.R. 659(E) ,dt.. 31-8-1994

______________________________________________________________ . The word “Coryza” omitted by. GSR 659(E) ,dt.. 31-8-1994.

Drugs and Cosmetics Rules, 1945 316

6. Storage- The vaccine when stored at – 15° C to 20° C. may be expected to retain

the potency for about one year and about three months if stored in a refrigerator at 2° C to 4° C. The product should not be used if stored for more than ten days outside the refrigerator.

Ranikhet Disease Vaccine F strain (Living) 1. Synonyms- New castle disease vaccine F Strain (Living). 2. Definition- Ranikhet disease vaccine F. strain is a suspension of a naturally modified living virus (F strain) prepared from the infected embryos, devoid of beaks and eyes and fluids in a frozen state. 3. Preparation- Good fertile eggs obtained from Salmonella pullorum free flock are incubated in an egg incubator. Eight days old vigorous embryos are infected with 0.1 ml. of 1 : 100 suspension of Ranikhet disease vaccine F strain virus. Inoculation is done via the allantoic cavity. Embryos are incubated at 37° C. Eggs are candled every day upto four days and the dead ones are discarded. Final candling of the embryos is carried out on the fourth day and only the living ones are chilled in a refrigerator for one hour. The fluids embryos are collected separately. The fluids are tested for spot haemagglutination and sterility test is carried out. The beaks and eye balls of the embryos are removed. The materials are homogenised with adequate quantities of antibiotics in a cool warning blender and ampouled in aliquots of 0.5 ml. quantity and freeze dried. 4. Standard-

(a) Description- Light brown scales.
(b) Identification- This product affords protection to baby chicks against Ranikhet disease.
(c) Moisture content- The moisture content should not exceed 1[1.0] per cent.
(d) Potency test- For testing each batch of the vaccine twelve one-day old chicks are given two drops 1/N o the field dose of the vaccine (5 ampoules selected at random may be reconstituted in 50 ml.) of cold normal saline solution. These are observed for fourteen days and the vaccinated chicks should remain normal throughout the period of observation. This serves the safety test also. On the fourteenth days the vaccinated chicks are challenged two drops with 1:50 virulent Ranikhet disease virus alongwith 8 control chicks. Four of the controls receive two drops 1/N of the virulent virus while the rest of the four receive 0.5 ml. of the virulent virus. The control chicks should succumb to the challenge virus showing symptoms of Ranikhet Disease while the protected chicks should remain normal throughout the observation period of fourteen days.
(e) Sterility Test- Should comply with the tests for sterility described in the general monograph on ‘Viral Vaccines’

the potency for about one year and about three months if stored in a refrigerator at 2 ° C to 4° C. When removed from the refrigerator, the product should not be used later than ten days.

¹ Ins. by G.S.R. 659(E) ,dt.. 31-8-1994

_______________________________________________________________

Drugs and Cosmetics Rules, 1945 317 Rinderpest Goat adapted Tissue Vaccine (Living) 1. Synonym- Goat-adapted Cattle Plague Vaccine; Goat Tissue Vaccine (Living). 2. Definition- Rinderpest Goat-adapted Tissue Vaccine is the homogenised freeze dried preparation of spleen pulp of goats artificially infected with the suitable strain of rinderpest virus. 3. Preparation- Healthy susceptible goats are quarantined for a period of ten days.

After this period a batch of selected goats are injected subcutaneously with 2 ml. of a suitable

dilution of the suspension of the seed virus. The donor goats are sacrificed after a suitable period when the titre of the virus in the animal body is expected to be maximum, usually four days, and the spleen from animals free from any pathological change or signs are collected under sterile conditions. Smear from each spleen is examined microscopically to exclude

spleen which are contaminated from the production batch.

The spleen is freed from fat and fascia and is blended into a smooth pulp in a grinder. The pulp is spread on a shallow dish of glass or stainless steel and is freeze dried. The freeze dried pulp is then ground into a fine powder and sieved. The powder is ampouled in 0.25 g. or 0.125 g. quantities and freeze dried. 4. Standard:

(a) Description- Dark brown or chocolate coloured scales or powder.
(b) Identification- The product affords protection to susceptible animals against rinderpest.
(c) Moisture content- Not more than 1.0 per cent.
(d) Safety Test- Each batch of vaccine shall be tested for safety in laboratory animals and cattle or buffalo calves as follows:-
- (i) Small animals- At least two guinea pigs each weighing 300 g. to 450 g. and two adult rabbits each weighing 1 kg. to 1.5 kg. should be injected each with 1 ml. of 1: 100 suspension of the vaccine subcutaneously and kept under observation for seven days. None of the animals should die. Alternatively, a batch of six white mice each weighing not less than 18 g. may be used, each mouse receiving 0.5 ml. of a dilution 1 : 100 suspension subcutaneously. None of the animals should die.
- (ii) Large animals- Either cattle of good grade of susceptibility (hill cattle) or buffalo calves may be employed. For each batch of vaccine, three animals should be injected subcutaneously with 1 ml. of 1 : 8000 dilution of the vaccine. These animals should be kept under observation for twelve to fourteen days. None of the animals should show any untowards reactions.
(e) Sterility Test- Complies with the tests for sterility described under the general monograph in ‘ Viral Vaccines’.
(f) Potency Test- The animals receiving 1 ml. of 1 : 8000 dilution of vaccine used under safety test mentioned above and kept under observation for fourteen days, should be challenged with 1 ml. of 1 per cent suspension of stock Rinderpest Virulent virus. None of the animals should die of rinderpest within a period of ten days. This test serves as a short potency test for each of the batches. For conducting a detailed potency test the following procedure may be followed:-

Dilution 1: 8000, 1: 12,000 and 1 : 16,000 shall be tested and for each dilution

three susceptible cattle or buffalo calves should be used. Each animal is inoculated subcutaneously with 1 ml. of a dilution of the vaccine, followed twelve to fourteen days later with a standard challenge dose of virulent rinderpest bull virus containing

Drugs and Cosmetics Rules, 1945 318

in 1 ml. of a 1 : 100 suspension of spleen tissue. Two unvaccinated bovines, each

receiving the same quantity of the challenge dose acts as controls. These are kept under observation for fourteen days. The end point of protection titre is assessed on the death or survival rate and the dose contained in one gramme of vaccine calculated on the basis of 20 to 40 minimum protective doses being equivalent to one vaccinating dose.

(g) Virulence and Viability Test- Two to four goats each weighing not less than 18 kg. are injected with 2 ml. of 1 : 100 suspension of the vaccine and kept under

observation for ten days. These animals should show reaction characterised by pyrexia

(rise of about 2 ̊ C) anorexia and dullness. 5. Labelling- Should comply with the requirement of ‘Labelling’ as laid down in the general monograph on ‘ Viral Vaccines’. 6. Storage- The vaccine may be expected to retain its potency for twelve months if

stored at - 15 ̊ C to -20 ̊ C or about three months if stored at 2 ̊C to 4 ̊ C.

Rinderpest Lapinised Vaccine (Living) 1. Synonym- Rabbit Adapted Cattle Plague Vaccine (Living) Lapinised Vaccine (Living). 2. Definition- Rinderpest lapinised vaccine is a suspension of a modified living virus (e.g. Nakamura III Strain) prepared with the blood, spleen and mesenteric lymph glands of infected rabbits and is freeze dried. 3. Preparation- Adult rabbits possibly from a known stock, each weighing not less than 1 kg. free from cocidiosis and snuffles, are injected intravenously with 1 ml. of a suitable dilution of a suspension of the stock seed virus. Donor rabbits are sacrificed after a suitable period when the titre of the virus in the animals is expected to be the maximum usually the third day. Ten millilitres of blood is collected from each rabbit in a defibrinating flask under aseptic condition. Later the animals are sacrificed and the spleen and mesenteric lymph glands collected. Each rabbit is subjected to a thorough post-mortem examination to observe lesions of rinderpest infection. After harvesting, the blood and the organs (spleen and glands) are homogenised in a suitable proportion if necessary. Adequate quantities of penicillin and streptomycin may be added. The homogenized material is ampouled in suitable quantities and freeze dried. 4. Standard-

(a) Description- Dark chocolate coloured mass.
(b) Identification- This product affords protection to susceptible animals against rinderpest.
(c) Moisture content- Not more than 1.0 per cent.
(d) Safety Test- For testing a batch 2 guinea pigs each weighing not less than 300 g. are injected subcutaneously with 1 ml. of a 1 : 100 suspension of the vaccine. Alternatively, a group of six white mice each weighing not less than 18 g. is used. Each animal receives subcutaneously 0.5 ml. of 1 : 100 suspension of the vaccine. None of the test animals should die within a period of seven days.
(e) Sterility Test- Should comply with the tests for sterility described in the general monograph on ‘Viral Vaccines’. If antibiotics have been added the inoculum should be neutralised before doing the test. Drugs and Cosmetics Rules, 1945 319
(f) Potency Test- Dilution 1: 100, 1 : 200, 1 : 400 and 1 : 800 shall be tested and for each dilution 2 susceptible cattle ( hill bulls) or buffalo calves should be used. Each animal is inoculated subcutaneously with 1 ml. of a dilution of the vaccine, followed twenty-one days later with a standard challenge dose of a virulent rinderpest bulls virus contained in 1 ml. of a 1 : 100 suspension of spleen tissue. Two unvaccinated bovines each receiving the same quantity of the challenge virus serve as controls. These animals are kept under observation for fourteen days. The end point of the protecting titre is assessed on the death or survival rate and the dose contained in one gramme of vaccine calculated on the basis of twenty minimum protective doses being equivalent to one vaccinating dose.
(g) Virulence and Viability Test- Four rabbits each weighing 1 to 1.5 kg. are injected subcutaneously with 1 ml. of 1 : 100 suspension of the vaccine. The animals should react typically showing all the symptoms of rinderpest in rabbits.

5. Labelling- Should comply with the requirements of ‘Labelling’ as laid down in the

general monograph on ‘Viral Vaccines’. 6. Storage- The vaccine may be expected to retain its potency for six months if stored

1. Synonym- Lapinised Avianised Vaccine (Living). 2. Definition- Rinderpest Lapinised Avianised Vaccine is a suspension of a modified live rinderpest virus of low virulence prepared either with the whole chick embryo or the viscera of the infected chick embryo. 3. Preparation- Twelve or thirteen days old active chick embryos from a flock free from Salmonella pullorum infection are injected intravenously with a suitable dilution of the suspension of the stock seed virus in six per cent glucose solution. The embryos are incubated at 38.5 ̊ C for five days. At the end of this incubation period, eggs which show living embryos are selected for the preparation of the vaccine. The viscera of the chicks are harvested, care being taken to reject the gizzard and gall bladders. The material is homogenised in a blender with adequate quantities of antibiotics (penicillin and streptomycin added if necessary), and primary freeze dried done. This freeze dried material is ground into a fine powder, ampouled in suitable quantities and finally subjected to secondary freeze drying and sealed under vacuum. 4. Standard-

(a) Description- Pale cream or yellow coloured sterile powder.
(b) Identification- This product affords good grade of immunity to susceptible animals against rinderpest.
(c) Moisture content- Not more than 1.0 per cent.
(d) Safety Test- For testing each batch, a group of six mice each weighing not less than 18g. is used. Each mouse is injected subcutaneously with 0.5 ml. of a 1 : 100 suspension. Alternatively, two guinea pigs each weighing not less than 300 g. and two rabbits each weighing not less than 1 kg. are injected with 1 ml. of 1 : 100 suspension subcutaneously. These animals should not show any untoward reaction during the period of observation for seven days.
(e) Sterility Test- Should comply with the test or sterility as laid down in the general monograph on ‘Viral Vaccines’.
(f) Potency Test- Healthy highly susceptible cattle (hill bulls) or buffalo calves should be used for testing the potency of each batch of vaccine in suitable dilution. For

each dilution two highly susceptible animals should be used. Each animal is inoculated

Drugs and Cosmetics Rules, 1945 320 subcutaneously with 1 ml. of a dilution of the vaccine, followed twenty-one to twenty- eight days after with a standard challenge dose of a virulent rindepest bull virus

contained in 1 ml. of a 1 : 100 suspension of spleen tissue. Two unvaccinated bovines,

each receiving the same quantity of the challenge virus serve as controls. All these

calculated on the basis of forty minimum protective doses being equivalent to one vaccinating dose.

5. Labelling- Should comply with the requirements of ‘Labelling’ as laid down in the

general monograph on ‘Viral Vaccines’.

6. Storage and Expiry date- The vaccine shall be expected to retain its potency for the

period at temperatures as specified below:-

Sheep and Goat Pox Vaccine (Living)

1. Synonym- Sheep Pox Vaccine. Goat Pox Vaccine (Living). 2. Definition- Sheep and Goat Pox Vaccine consists of the virus contained in the scabs collected from sheep artificially infected with the virus. 3. Preparation- Healthy yearling sheep are infected artificially on the shaved portion of the abdomen with a suitable dilution of the suspension of the stock seed virus 50 per cent glycerine saline solution. The material from the semi-dried areas where the pock lesions are evident is collected and dried over calcium chloride or phophorus pentoxide under vacuum. Dry scabs are powdered, sieved, ampouled in suitable quantities and sealed. 4. Standard:

(a) Description- Light cream coloured powder.
(b) Identification- This product when applied to scarified area of the skin of the sheep or goats produces characteristic local lesions of pox and should afford protection to sheep and goat against Sheep and Goat Pox.
(c) Safety Test- Two rabbits each weighing not less than 1 kg. are injected subcutaneously each with 1 ml. of a 1 : 100 dilution of the vaccine in normal saline solution. These animals are observed for fourteen days. The animals should remain normal.
(d) Sterility Test- Complies with the tests for sterility described under the general monograph on ‘Viral Vaccines’.
(e) Potency Test- Four yearling sheep are inoculated with 1 : 100 suspension of the vaccine in 50 per cent glycerine saline on a scarified area on the abdomen. Fourteen days later, these and two more susceptible sheep are inoculated by the same method with stock virus and observed for a period of fourteen days. The control animals should develop typical lesions of pox and vaccinated animals should remain normal. 5. Labelling- Should comply with requirement of ‘Labelling’ as laid down in the general monograph on ‘Viral Vaccines’. 6. Storage and Expiry date- The vaccine shall be expected to retain its potency for

Drugs and Cosmetics Rules, 1945 321 Fowl Spirochaetosis Vaccine ( Chick Embryo Origin) 1. Synonym- Tick Fever Vaccine. 2. Definition- The vaccine consists of a merthiolated suspension of chorioallantoic membrane, internal viscera and blood of chick embryos infected with a vaccine strain of spirochaetes and freeze dried. 3. Preparation- Eleven days old developing chick embryos are infected with 0.2 ml. of sterile fresh blood containing spirochaetosis via the chorioallantoic membrane. The inoculated embryos are incubated at 37 ̊C and candled daily and the dead one are discarded. On the seventh day the living embryos are chilled in the refrigerator for two hours. The chilled embryos are harvested separately and necrotic lesions in liver noted. Representative samples of blood should be examined for teaming spirochaetes. The internal viscera, chorio-allantoic membranes and the blood are collected. The material is pooled, weighed and held in deep

freeze at – 15 ̊C to –20 ̊C for a period of one week. Thereafter the material is blended with

equal quantity of Merthiolate (final concentration of merthiolate in the suspension should be 1 : 10, 000) thoroughly for three times, each time the motor running at full speed and the vaccine is ampouled in 2 ml. quantities and freeze dried. 4. Standard-

(a) Description- Light brownish scales.
(b) Identification- The vaccine affords protection when inoculated into the fowls against spirochetosis.
(c) Moisture content- The moisture content should not exceed 1.0 per cent.
(d) Safety and potency test- Six healthy cockerals ten to twelve weeks old are used for this purpose. Each ampoule of vaccine is reconstituted in 10 ml. of cold distilled water and the six cockerals are injected intramuscularly each with 1 ml. of the reconstituted vaccine and the birds are observed for a period of ten days and the vaccinated birds should remain normal throughout the period of observation. The vaccinated birds are challenged with 0.2 ml. intramuscularly with virulent spirochaete

blood along with two susceptible controls. Temperature and blood smear examination of

the challenged birds and controls should be carried out daily for a period of ten days. The blood smears of vaccinated birds should remain negative for spirochaetes during the entire period of observation. The controls should react and show spirochaetes in the blood.

(e) Sterility Test- Complies with the tests for sterility described in the general monograph on ‘ Bacterial Vaccine’. 5. Labelling- Should comply with the requirement of ‘Labelling’ as laid down in the general monograph on ‘Viral Vaccines’.

Swine Fever Vaccine Crystal Violet 1. Synonym- Crystal Violet Swine fever vaccine, Hog Cholera Vaccine. 2. Definition- Swine fever vaccine, crystal violet is a suspension of blood of swine that have been infected with a suitable virulent antigenic strain of swine fever virus, inactivated

with 0.25 per cent crystal violet ethylene glycol at 37 ̊C for fourteen days.

3. Preparation- Susceptible healthy pigs of six to seen months of age belonging to a

well established strain or bred are used. Body weight of these animals at this age may vary

according to the breed but optimum weight is considered as between 75 to 100 kg. Animals used for production may be procured from well established farms and kept under quarantine

Drugs and Cosmetics Rules, 1945 322 for fourteen days. These are injected intramuscularly with a suitable dilution of the

suspension of the virulent blood viruses. Bleeding of the clinically injected animals is carried

out on the sixth day. The defibrinated blood from each animal is strained and stored

separately in sterile glass containers. To the four parts of defibrinated blood, one part of 0.25

per cent crystal violet- ethylene glycol is added and the suspension after thorough mixing, is stored at 37 ̊ C ( + 0.5) for two weeks. The product is filled in 20 ml. volumes in sterile vials and labelled on the completion of tests. 4. Standard-

(a) Description- Very dark violet suspension.
(b) Identification- This product affords protection against swine fever but not against African Swine Fever.
(c) Safety Test- Two young pigs weighing about 15 to 30 kg. are injected subcutaneously each with 40 ml. of the vaccine batch to be tested. In addition, one unvaccinated susceptible pig is placed in contact.
(d) Sterility Test- Should comply with the test for sterility described under general monograph on ‘Viral Vaccines’.
(e) Abnormal toxicity test- Two guinea pigs are given 1 ml. of vaccine intramuscularly.

Two guinea pigs are given 2 ml. of the vaccine intraperitoneally.

Two mice are given 0.5 ml. of the vaccine subcutaneously.

(f) Potency Test- Four susceptible pigs weighing between 20-30 kg. are injected with 5 ml. of the vaccine subcutaneously. After twenty-one days these are challenged with 1 ml. of suitable dilution of the challenge virus subcutaneously. The dose must contain at least 1000 minimum infective doses. At least two control pigs should be used. 5. Labelling- - Should comply with requirement of ‘Labelling’ as laid down in the

general monograph on ‘Viral Vaccines’.

6. Storage- The vaccine may be expected to retain its potency for twelve months if

stored in refrigerator at 2 ̊C to 4 ̊C.

Swine Fever Vaccine Lapinised (Living) 1. Synonym- Lapinised swine fever vaccine, freeze dried lapinised swine fever vaccine. 2. Definition- Swine fever lapinised vaccine consists of the suspension of a

are collected with sterile precautions. The collection is later homogenised in a blender using ten per cent yolk phosphate buffer as a diluent. The suspension is ampouled in 0.5 ml. quantities and freeze dried.

Drugs and Cosmetics Rules, 1945 323 4. Standard-

(a) Description- Light scales.
(b) Identification- This product affords protection against swine fever.
(c) Moisture content- The moisture content should not exceed 1.0 per cent.
(d) Safety Test- Six mice are injected each with 0.5 ml. of a 1 : 100 suspension of the vaccine. These are kept under observation for seven days. Non should die.
(e) Viability Test- Two healthy rabbits are injected intramuscularly with 1 ml. of 1 : 100 suspension of the vaccine. These animals show thermal reaction.
(f) Sterility Test- Should comply with the test for sterility described under the general monograph on ‘Viral Vaccines’.
(g) Potency Test- The vaccine batch under test should be tested on susceptible healthy pigs weighing between 20-30 kg. Two animals for each dilution may be used.

The dilutions tested are 1 : 10, 1 : 25, 1 : 50 and 1 : 100. One millilitre of each of these

dilutions is injected subcutaneously. One healthy, susceptible, unvaccinated in contact animal should be kept along with the vaccinated animals. Fourteen to twenty-one days later these animals along with two controls are injected subcutaneously with 1 ml. of the challenge virus containing at least 1000 minimum infective doses. 5. Labelling- Should comply with requirements of ‘Labelling’ as laid down in the

general monograph on ‘Viral Vaccines’.

6. Storage- The vaccine may be expected to retain its potency for six months if stored at temperature ranging between – 10 ̊ C to - 15 ̊ C and for seven days at 2 ̊ C to 4 ̊ C in the refrigerator.

1[Foot and Mouth Disease Vaccine (Inactivated)

1. Synonym. – Inactivated Tissue culture mono or polyvalent Foot and Mouth Disease

Vaccine. 2 Definition. – Foot and Mouth Disease Vaccine is a liquid product or preparation containing one or more types of foot and mouth disease virus which have been inactivated in

such a way that its immunogenic property is maintained. It may also contain an adjuvant. The

vaccine is described as monovalent, bivalent, trivalent or polyvalent depending on the number of types of virus used. 3. Preparation. – The virus is propagated in suitable cell culture. The cell culture is infected with an appropriate inoculum of virus and incubated at a suitable temperature for multiplication of virus. The virus is harvested and cellular debris removed by filteration. Inactivation is carried out by a suitable agent such as formaldehyde solution or aziridine compound. The adjuvant may be aluminium hydroxide and/or saponin. In case of inactivated gel vaccine the antigen is concentrated by sedimentation at plus 4 degree C. For preparing a polyvalent vaccine, monovalent antigens are mixed in appropriate quantities to give the final mixture which is the formulated vaccine.

4. Standards :

(a) Description :- Aluminium hydroxide gel vaccines settle down to variable degree on storage leaving the supernatant clear. _____________________________________________________________ Drugs and Cosmetics Rules, 1945 324
(b) Identification – It protects cattle against Foot and Mouth Disease due to homologous type/subtype of virus.
(c) Sterility test – It shall comply with the tests for sterility as prescribed under the “general monograph on “Viral Vaccines”.
(d) Safety test - The test is carried out on fully susceptible cattle not less than 12 months of age and which have not been sensitized either by vaccination or previous infection. Inoculate 3 susceptible cattles each with 2 ml. of finished product at multiple sites on tongue by intradermal route and observe for 4 days. The same animals are inoculated on 4th day with 3 cattle doses subcutaneously and are observed for a further period of 6 days. The animals should not develop any signs of FMD and remain normal.
(e) Potency test – Each batch of the vaccine is to be tested in susceptible cattle of not less than 15 months of age. The potency test in cattle can be done either by :–
- (i) PD Method : The vaccine shall be tested by the determination of PD in susceptible cattle by challenging animals vaccinated with appropriate dilution of the vaccine made in adjuvanted or non-adjuvanted diluent as appropriate. A minimum of 5 animals should be used per dilution and 2 unvaccinated animals to be included as controls to the challenge. All animals are needle challenged with 10,000 ID of the homologous strain of virus by inoculation on the tongue on the 21 st day of post-vaccination. The control animals are to be similarly challenged. Animals are observed for 10

¹ Ins. by G.S.R. No. 659(E) ,dt.. 31-8-1994.

days for the development of lesions. Unprotected animals show generalised lesions

due to FMD. Control animals must shown generalized lesions. From the number of animals protected in each group the PD content of the vaccine is calculated. The vaccine passes the test if an observed PD value of 3 or greater is obtained in the test.

(ii) Percentage protection method in which groups of ten health susceptible cattle are each injected subcutaneously with the vaccinating dose and 14 – 21 days later the cattle are challenged by intradermal injection into three separate sites on the tongue with 10,000 ID of the strain of virus used in the preparation of the vaccine. The vaccine can be passed if atleast seven out of the ten in the group are protected against the development of generalized infection whereas all the controls should react by developing primary and secondary lesions observable in the mouth and feet. For other reasons if cattle testing is not possible then the potency of the vaccine may be assed in guineapigs either by Lucam ‘C’ index or PD method by challenging those which have been previously vaccinated, provided that the correlation has been established between guineapig challenge test and cattle challenge results. The estimation of the serum neutralizing antibody titre cattle may be considered as a supportive test to evaluate potency of vaccine. However, potency testing of vaccines, in cattle, of batches whenever by other accepted methods of testing is in doubt, at aleast one out of every five batches, be undertaken. 5 Labelling :- It is labelled as described under the requirements of ‘labelling’ as laid down in the general monograph, with the additional requirements that the label on the container states the virus types used in the preparation. 6. Storage :- It should be protected from the light and stored between 4 o C to 8 o C. Under these conditions it may be expected to retain its potency for not less than 12 months. Freezing of aluminium hydroxide vaccine must be avoided. The frozen product will not be fit for use. Drugs and Cosmetics Rules, 1945 Canine Hepatitis Vaccine (Living) 1. Synonyms : Infectious Canine Hepatitis Vaccine (Living), Canine Hepatitis Cell Culture Vaccine. 2. Definition : Canine Hepatitis Vaccine (Living) is a freeze dried preparation of tissue culture fluid containing the cell culture adopted canine hepatitis virus. 3. Preparation : Canine hepatitis vaccine shall be prepared from virus bearing cell culture fluid. Only stock seed virus which has been established as pure, safe and immunogenic shall be used in the preparation of the vaccine.

Immunogenicity test : Each lot of stock seed virus shall be tested for immunogenicity

as follows : Thirteen canine hepatitis susceptible dogs, 8-14 weeks old shall be used for the test (10 vaccinates and 3 controls). Blood samples may be drawn from these animals and individual serum samples tested for the presence of antibodies, against canine hepatitis virus. Ten dogs shall be injected subcutaneously with predetermined quantity of the virus and remaining 3 dogs are kept as unvaccinated controls. The dose calculation will be based on virus titration in suitable cell culture system. Not less than 14 days post vaccination, the vaccinated and control shall each be challenged intravenously with virulent infectious canine hepatitis virus and observed daily for 14 days. At least 2 out of 3 controls should die and the survivors shall show the clinical signs of canine hepatitis. Nine out of ten vaccinated dogs shall survive and shall not show any signs of infectious canine hepatitis during the observation period. The stock seed virus shall be tested once in 5 years and maintained under standard conditions as prescribed. The stock seed virus may be inoculated on a suitable tissue culture system and may be incubated for five to seven days. The tissue culture fluid is then harvested and titrated in cell culture system for virus content. After appropriate dilution and pooling, the material is stored at minus 20 o C until freeze dried. Each vaccine dose shall contain not less than 10 3.5 TCID dose. 4. Standards :- (a) Description. – The dried product is a pinkish cream material readily dispersible in water. The reconstituted vaccine is a pinkish liquid.

(b) Identification.- It causes characteristic cytopathic effect in dog, pig and ferret kidney monolayers. This can be neutralized by specific antiserum. When inoculated into dogs, the development of specific neutralizing antibodies can be demonstrated by suitable serological tests.

(d) Sterility Test.-- Shall comply with the tests of sterility as described under the general monograph on “Viral Vaccines”.

(e)

Safety Test.-- Mouse safety test – Vaccine prepared for use as recommended on

Drugs and Cosmetics Rules, 1945 the label shall be tested. Eight mice shall be inoculated intracerebrally with 0.03 ml and 8 mice shall be inoculated intraperitoneally with 0.5ml. Both the groups shall be observed for seven days. If unfavourable reaction attributable to the product occurs in two or more mice in either group during their observation period, the batch is unsatisfactory.

(f)

Dog Safety Test.-- Each of the two susceptible pups aged 8 – 14 weeks shall be

injected with vaccine equivalent of 10 vaccinating doses from the batch reconstituted with sterile diluent and administered in the manner recommended on the label and observed for 21 days. None of the pups shall show any unfavourable reaction during the period of observation.

(g) Potency test, Virus Titration: – Samples of finished product shall be tested for virus titre in suitable cell culture system. The batch shall have a virus titre of not less than 10 3.5 TCID dose.

(h) Potency test in dog:– Two healthy susceptible dogs of 8-14 weeks of age shall be injected subcutaneously with one Vaccine dose. 14 days after vaccination, specific neutralizing antibodies from both the dogs shall be demonstrable by serological tests.

5 Labelling:

Shall comply with the requirement for labelling as laid down in the general monograph on “Viral Vaccines”.

. Storage: The dry product shall be stored at temperature of minus 20 o C or below. The vaccine is expected to retain its potency for about 6 months in the freezing chamber of the refrigerator (temperature) approximately minus o C Duck Plague Vaccine 1 Definition.- Duck plague vaccine is a suspension of modified living virus prepared from infected chick embryos.

. Preparation.- Fresh fertile hen’s eggs obtained from salmonella free flocks are incubated in an incubator. Nine days old embryos are injected with 0.2 ml of the suitable dilution ( 1 in 100) of the suspension of the virus on the CAM and incubated at 37 o C for 5 days post-inoculation. Dead embryos of the 3rd, 4th and 5th days post-inoculation are harvested. The embryos (devoid of head and legs). Clear fluid and the membranes are collected and homogenized in a Blender, ampoulded in 0.5ml quantities and freeze dried.

. Standards:-

(a) Description.- Light brown scales.

(b) Identification.- This product affords protection to the ducks against duck plague.

Drugs and Cosmetics Rules, 1945

(c) Safety Test.- Four healthy, 8 to 12 weeks old ducks weighting not less than 600 gms are inoculated subcutaneously with 1ml of 10 -1 dilution of the vaccine and observed for a period of 14 days. During the period of observation, the ducks shall not show any untoward reaction.

(d) Sterility.- Shall comply with the test for sterility described in the general monograph on “Viral Vaccines”.

(e)

Potency Test.- Six susceptible ducks 8 to 12 weeks old each weighing not less than

600 gms are inoculated subcutaneously with 1 ml of 10 -3 dilution of the vaccine. The minimum virus contents in 1 ml. dose of the vaccine shall be 10 3.5 EID 50. days later these ducks are challenged subcutaneously each with 1 ml. of 10 -2

dilution of the virulent duck plague virus (1000 DEID

) along with 2 unprotected

young ducks of about 8-12 weeks age. The unprotected ducks shall show symptoms of duck plague and die within 10 days, while the protected ducks shall remain normal during the observation period of 14 days. 4. Labelling.- Should comply with the requirements of labelling as laid down in the general monograph on “Viral Vaccine”.

5. Storage.- Vaccine when stores at minus 15 o C to minus 20 o C may be expected to retain its potency for one year and about three months if stored in the freezing chamber of Refrigerator i.e. minus 5 o C. Avian Encephalomyelitis Vaccine (Living) 1. Synonyms.- Avin-encephalomyelitis Vaccine Freeze dried.

2. Definition.- A virus bearing tissue and fluid suspension from embryonated hen’s legs.

3. Preparation.- The stock seed virus which has been established as pure, safe and immunogenic shall be used for preparing the vaccine.

(i) Each lot of stock seed virus shall be tested for pathogenicity by chicken embryo inoculation test:

(a) One dose of the seed lot shall be mixed with 9 volume of sterile heat inactivated specific, antiserum to neutralize vaccine virus in the product.
(b) After neutralization, 0.2 ml of serum vaccine mixture shall be inoculated into each of at least 20 fully susceptible chicken embryos (0.1ml of the inoculum shall be inoculated on CAM of 9-11 days old embryos and 0.1 ml in the allantoic sac).
(c) Eggs shall be candled for 7 days. Deaths occurring during first 24 hours shall be discarded but at least 18 viable embryos shall survive 24 hours post inoculation for a valid test. All embryos and CAMs from embryos which die after the first day shall be examined. Drugs and Cosmetics Rules, 1945
(d) If the death or abnormality attributable to inoculums occur, the seed lot is unsatisfactory.
- (ii) Immunogenicity test.- Avian encephalomyelitis susceptible chicks, all of same age 8 weeks old) shall be used 20 chickens shall be inoculated with the field dose of the virus by prescribed route. Ten additional chickens of same age and flock shall be held as unvaccinated controls. At least 21 days post vaccination, the controls and vaccinates shall be challenged intracerebrally with Virulent avian encephalomyelitis virus and observed each for 21 days. At least 80 percent of controls shall show signs of avian encephalomyelitis or die. At least 19 to 20 vaccinates shall remain free from clinical avian encephalomyelitis during the observation period for the stock seed virus to be satisfactory 4. Standards:- (a)

Description:- Greyish white flakes easily dispersible in the diluent.

(b)

Identification:- At least 5–6 days old embryonated eggs (from hens with no history of

infection with avian encephalomyelitis) shall be inoculated with 0.1 ml of undiluted vaccine into the yolk sac and kept in incubator and then transferred to the brooder where they are allowed to hatch. The hatched chicks shall be raised for 7 days. More than 5 per cent of hatched chicks shall manifest the typical symptoms (weak-leg, leg paralysis tremor etc.) at the end of this period.

(c)

Moisture Content: - Shall not exceed 1.0 per cent.

(d) Sterility Test: - Shall comply with the test for sterility described under general monograph on “Viral Vaccines”. (e) Safety Test: - At least 25 avian encephalomyelitis susceptible birds (6-10 weeks of age) shall be vaccinated with 10 field doses by the recommended route and observed each day for 21 days. If unfavourable reactions attributable to the vaccine occur during the observation period, the batch of vaccine is unsatisfactory.

(f) Potency Test: - (i) The vaccine shall be titrated for virus content. To be eligible for release, the batch shall have a virus titre of at least 10 2.5 EID per dose. (ii) At least 10 susceptible chickens shall be vaccinated with the field dose of the vaccine by prescribed route and 10 chickens from same batch and source shall be kept as unvaccinated controls. At least 21 days post-vaccination, both the groups shall be challenged intracerebrally with Virulent avian encephalomyelitis virus and observed for 21 days. At least 8 out of 10 controls shall develop recognizable signs or lesions of avian encephalomyelitis and at least 8 out of 10 vaccines should remain normal 5. Labelling: Shall comply with the requirement of labelling as laid down in general monograph on “Viral Vaccines”. Drugs and Cosmetics Rules, 1945 Marek’s Disease Vaccine (Living) 1. Synonyms.- Herpes virus of Turkey Vaccine HVT vaccine (Living). 2. Definition:- Marek’s disease vaccine is a suspension of cell free fluid containing live virus. 3. Preparation.- The stock seed virus which has been established as pure, safe and immunogenic in avian species shall be used for preparing the seed virus for vaccine production. (i) Safety Test – The stock seed virus shall be non-pathogenic for chickens as determined by the following procedure: The groups of at least 25 chickens each at one day of age shall be used. These chickens shall be of the same source and batch be susceptible to Marek’s disease and be kept in isolated group. Group 1: Each chicken shall be injected with 0.2 ml of 10 times as much viable virus as will be contained in one dose of vaccine by intramuscular route. Group II : Shall serve as controls. At least 20 chickens in each group shall survive for four days postinjection. All chickens that die shall be necropsied and examined for lesions of Marek’s disease and cause of death. The test shall be judged according to the following : At 120 days o age, the remaining chicken in both the groups shall be weighted, killed and necropoised. If at least 15 chicken in each of these two groups have not

survived the 120 days period if any of the chicken of Group-I have gross lesions of

Marek’s disease at necroposy or if the average body weight of the chickens in Group-I is significantly (statistically) different from the average of Group-II at the end of 120 days, the lot of stock seed virus is unsatisfactory.

(ii)

(iii) Purity test – Shall conducted in chickens and no lesions other than those typical of Turkey Herpes virus shall be evidenced.

Immunologenicity test – Sixty susceptible day old chicks are used. Thirty of them inoculated with the seed virus in a dose corresponding to the field dose of the final vaccine and 14-21 days later challenged by intrabdominal route with virulent Marek’s diseas virus, alongwith the other 30 non-vaccinated control chicks. At the end of the observation period when the chicks are 20 weeks old, the surviving chickens are examined for the presence of antibody against Marek’s disease by serological tests and postmortem inspection for lesions of Marek’s disease.

Any bird dead is thoroughly examined and the cause of death ascertained by necropsy/histopathological examination. All the surviving birds are killed and necropsied. The protection index (P1) is determined by following procedure :

No. with MD lesions

1. Percent MD =

_________________________ x 100 No. with MD lesions + No. of –ve Su-viviours (effective No.)

Percent MD in controls –

Drugs and Cosmetics Rules, 1945 Percent MD in vaccinated 2. P.I. = _______________________________ x 100 Percent MD controls

Master seed virus should have P.1 of at least 80 per cent. Eighty per cent of the chicks in the control group must fall ill specifically. If more than 80 per cent of the vaccinated chickens do not show symptoms or signs of Marek’s disease, the seed virus is regarded as sufficiently effective and can be used for production of vaccine. The seed virus is propagated in duck embryo fibro-blast cell culture, chick embryo fibroblast or any other suitable cell culture (specific pathogen free SPF flock) and when the peak passage level is attained the cell monolayer is suspended in cold diluent of the following composition: SPGA Stablizer 0.218% Sucrose. 0.0038% monosodium phosphate. 0.0072% dipotassium phosphate. L Monosodium glutanate 0.0049 M. 1 per cent bovine albumin fraction (V). 0.25 per cent EDTA (Sterilised by Seitz filteration and stored at minus 10 o C). The virus is freed from cell by ultrasonication for 3 minutes interrupted after every 30 seconds) at 100 MA and freeze dried at times 60 o C preferably in shelf freeze dried

in convenient volumes.

The doses per ampoule vial is calculated after titrating the freeze dried product in terms of plaque forming units (PFU) in the corresponding cell monolayers.

4. Standards:

(a) Description: - The cell free freeze dried HVT vaccine look uniformly grayish in colour and easily dispersible in the specified diluent.

(b) Identification. - The vaccine on inoculation in suitable cell culture system shall cause cytopathic effect typical of Herpes virus of Turkey. Specific antiserum of Herpes virus of Turkey shall neutralize the cytopathic effect.

(d) Sterility test. - Shall comply with the test prescribed in general monograph on “Viral Vaccines”.

(e) Safety Test.- At least 25 one day old chickens shall be injected with ten times of the field dose of vaccine by intramuscular route. The chickens shall be observed each day for 21 days. Chickens dying during the period shall be examined, cause of death determined and the results recovered as follows :

(i) If at least 20 chickens do not survive the observation period, the test is inconclusive.
(ii) If lesions of any disease or cause of death are directly attributable to the vaccine the vaccine is unsatisfactory. (f)

Potency test. - The sample shall be titrated in the cell culture system. A satisfactory batch

shall contain at least 1500 plaque forming units (PFU) as per dose at the time of release

Drugs and Cosmetics Rules, 1945 and maintain at least 1000 PFU till the end of expiry period.

5. Labelling. - Shall comply with the requirements of labelling as laid down in general monograph on “Viral Vaccines”.

Storage and expiry date. - The freeze-dried cell free HVT vaccine may be stored at 4

o C for 6 months.

Goat Pox Vaccine (Living Cell Culture)

Synonym. - Goat Pox Vaccine (living), Attenuated Goat Pox Vaccine.

Definition. - Goat Pox vaccine is freeze-dried preparation, prepared by growing attenuated

goat pox virus in kid kidney/testicular cell culture.

3. Preparation. - Primary kidney/testicular cell cultures of disease free kid are used. The monolayers infected with the seed virus are incubated at 37 o C. The cultures are harvested by

three cycles of freezing and thawings 6 to 7 days post infection when more than 80 per cent

cells show CPE. The suspension is centrifuged at 1000 rpm for 10 minutes to remove cellular debris being stored at minus 20 o

C. The suspension is freeze dried after addition of

5 per cent Lactalbumin hydrolysate and 10 per cent sucrose.

4. Standards:

(a)

Description. - Light yellow colour.

(b)

Identification - The product affords protection to goat against goat pox.

(c)

Moisture content. - The moisture content shall not exceed 1.0 per cent.

(d) Safety tests.- (i) Laboratory animals. - Six mice, 3 guinea pigs and 3 rabbits are inoculated with 0.2ml intraperitoneally, 0.5 ml and 1.0 ml subcutaneously, respectively with 10 field doses of the vaccine. The inoculated animals during the observation period of 80 days shall remain normal.
- (ii) Goat. - Two susceptible goats of 6 to 8 months of age are inoculated in postaxillary region by subcutaneous route with one-hundred field doses of the vaccine. The inoculated animals shall not develop more than a local reaction of 2 to 3 cms. These animals shall be observed for 10 days. (e) Sterility test.- Shall comply with the test for sterility described under the general monograph on “Viral Vaccines”. (f) Titration in cell culture.- Four randomly selected samples are inoculated in kid kidney cell cultures using 5 tubes for each dilution. The titration shall be repeated thrice. One thousands TCID is used as a field dose. (g) Potency Test.- The three susceptible goats (8-10 months) are inoculated with 1/10th field

dose and 3 susceptible goats (8-10 months) with one field dose, subcutaneously. Three

in contract controls are also kept with the inoculated goats. These animals are observed for a period of 14 days and their body temperature recorded daily. The vaccinated

Drugs and Cosmetics Rules, 1945 animals shall not show any termal, local or generalized reaction. Twenty one days post infection, the vaccinated and controls and challenged with 10,000 TCID of virulent goat pox virus by intradermal route. The temperature of these goats are recorded for a period of 14 days. The vaccinated goats shall not develop localized or generalized reaction while control goats shall develop high fever, localized reaction or even generalized reaction in some cases.

5. Labelling .- Shall comply with requirements of labelling as laid down in the general monograph on “Viral Vaccines”.

6. Storage and expiry date.- The vaccine is expected to retain its potency for 12 months if stored at minus 15 o C to minus 20 o C and for three months at 2 o C to 4 o C.

Sheep Pox Vaccine (Inactivated)

Synonym .- Formal gel sheep pox vaccine.

2. Definition .- Sheep pox vaccine is a formaline inactivated gel treated tissue vaccine.

3. Preparation.- Healthy susceptible sheep of 8-12 months of age are inoculated subcutaneously with 500 ml of the 1:100 dilution of the Russian Virulent Sheep Pox Virus. Seven to eight day post inoculation skin of the abdomen alongwith the oedema is collected. The infected tissues are homogenized in 10 percent concentration in phosphate buffer (pH 7.4-7.6) which after the extraction of the virus is mixed with sterile gel and buffer in the following proportion :-

6 percent aluminium hydroxide gel-50 per cent. Phosphate Buffer (pH 7.6)- 35 per cent. 10 per cent suspension – 15 per cent

This is later formalized and kept at 20-25 o C/10 o C for varying periods.

4. Standards.-

(a)

Description .- It is a greyish white suspension. During storage the gel settles at the bottom,

upper layer of the suspension is clear.

(b)

Identification.- This product affords protection to sheep against sheep pox.

(c) Safety test.- This is carried out by inoculating 2 white mice with 0.2 ml., one guinea pig with 1.0 ml and one rabbit with 3,0 ml of vaccine. The animals should remain clinically healthy for 10 days.

(d)

Sterility test.- This is done by seeding the vaccine on usual bacterial media. The plates and

tubes are incubated for 10 days at 37 o

C. If the pathogenic bacteria are found, the vaccine is

rejected while with non-pathogenic bacteria the vaccine is passed for field use.

(e) Potency test.- This is done by inoculating 4 non immune susceptible sheep preferably exotic breed of 1-2 years with 3 ml of vaccine in the thigh, subcutaneously.

The vaccinated sheep are challenged 15 days after inoculation alongwith 3 controls each with 0.1 ml of virulent virus containing 200 infective doses intradermally under the tail.

Drugs and Cosmetics Rules, 1945 The sheep are observed for 10 days and their skin reaction recorded. The vaccine is considered potent if all the vaccinated, sheep do not show thermal or local skin reaction. Vaccine is also potent if 3 vaccinated animals do not develop any reaction and one shows abortive skin reaction, while at least 2 of the 3 controls develop typical sheep pox reaction at the site of inoculation.

5. Labelling.- Shall comply with the requirements of labelling as laid down in the general monograph on “ Viral Vaccines”.

Storage.- The vaccine shall be stored at 4

o C to 5 o C. it keeps well at above temperature upto 12 months. Sheep Pox Vaccine (Living Cell Culture)

Synonym.- Sheep pox vaccine (Living), attenuated sheep pox vaccine.

Definition.- Sheep pox vaccine is freeze dried preparation prepared by growing attenuated

sheep pox virus in lamb kidney/testicular cell cultures.

o C. The cultures are harvested by 3 cycles of freezing and thawing 6 to 7 days post infection when more than 80 per cent Cells show C.P.E. The suspension is centrifuged at 1000 r.p.m. for 10 minutes to remove cellular debris before being stored at minus 20 o C. The suspension is freeze dried

after addition of 5 per cent Lactalbumin hydrolysate and 10 per cent sucrose.

Standards:-

(a)

Description.- Light yellow colour.

(b)

Identification.- The product affords protection to sheep against sheep pox.

(c)

Moisture contents.- The moisture contents should not exceed 1.00 per cent.

(d) Safety tests.-
- (i) Six mice, 3 guinea pig and 3 rabbits are inoculated with 0.2 ml intraperitoneally 0.5ml and 1.0 ml subeutaneously, respectively containing 10 field doses of the vaccine. The inoculated animals during the observation period of 10 days should remain normal.
- (ii) One hundred field doses of the vaccine are inoculated subcutaneously into each of 2 susceptibles sheep in postaxillary region. Inoculated animals shall not develop more than a local reaction of 2 to 3 cms. (e) Sterility test. - Shall comply with the test for sterility as described under the general monograph on “Viral Vaccines”. (f) Titration in cell culture. - Four randomly selected samples reconstituted in a maintenance medium are inoculated in lamb kidney cell cultures using 5 tubes for each dilution. The titrations shall be repeated thrice. The TCID to be calculated by Read and Muonch method. One thousand TCID is calculated as one field dose. (g)

Potency test. - Three susceptible sheep 8-10 months old are inoculated with 1/10th, field

dose and 3 susceptible sheep with one field dose, subcutaneously. Three in contact controls are also kept with the inoculated sheep. These animals are observed for a period

Drugs and Cosmetics Rules, 1945 of 14 days and their temperature is recorded daily. The vaccinated animals should not show any thermal, local or generalize reactions. Twenty-one days post infection the

intradermal route. The temperature of these sheep are recorded for a period of 14 days. The vaccinated sheep should not develop localised or generalized reaction while control sheep should develop high fever, localized reaction or even generalized reaction in some cases.

5. Labelling.- Shall comply with requirements of labelling as laid down in the general monograph on “Viral Vaccines”.

6. Storage and expiry date.- The vaccine is expected to retain its potency for 12 months if stored at minus 15 o C to minus 20 o C and three months at 2 o C to 4 o C

Tissue Culture Rinderpest Vaccine

Synonyms.- Cell Culture Rinderpest Vaccine.

2. Definition.- Tissue Culture Rinderpest Vaccine is a freeze dried preparation of live modified rinderpest virus adapted to and propagated in cell culture.

changes shall be used. When secondary cultures are used they shall have retained their original morphology and Karyotype. Kabete ‘O’ stain of Rinderpest virus developed by East African veterinary Research Organisation (Plowrights strain between the passage levels of 99th and 100th passages) shall be used. The virus harvested from cell monolayer culture prepared from the kidneys of a single calf or serially cultivated bovine kidneys cells (Not more than 10 passages away from the Primary) inoculated with the same seed and harvested together, will be freeze dried with stabilizers in suitable quantities.

Standards.- It complies with the requirements of general standards of viral vaccines:

(a) Description.- Dry light yellow coloured flakes readily soluble in chilled and saline or buffered saline.

(b) Identifications.-
- (i) Protects cattle against a subsequent challenge with virulent or caprinised rinderpest virus.
- (ii) It is titrable in tissue culture systems capable of supporting the multiplication of this virus. The test shall be made on at least three separate occasions using a cell culture derived from different animals.
- (iii) Specificity test shall be performed using an appropriate scrum neutralization test. (c) Sterility test. - Each batch shall be tested for bacterial and mycotic sterility as given in general monograph on “Viral Vaccines”. (d) Innocuity test.- Shall be made on each batch in at least two guinea pigs and six mice. These animals shall be observed for at least two weeks for any untoward reaction. (e) Safety and efficacy test.- The test for safety and efficacy shall be performed using the pooled reconstituted contents of not less than 4 ampoules taken at random. The vaccine Drugs and Cosmetics Rules, 1945 shall be injected subcutaneously into each of at least two susceptible cattle free from specific antibodies using the quantity containing not less than 100 fields doses and two

further cattle and using 1/10th of the field dose (calculated on the basis of 1000 TCID

one field dose). The animals shall be housed with at least two unvaccinated animals and observed for a period of three weeks. The vaccine passes the safety test if the cattle show

no signs of unusual clinical reactions.

At the end of three weeks all the four animals will be challenged alongwith two in contact cattle with a challenge dose of not less than 10th

ACID of virulent Rinderpest virus. The vaccine passes the potency/efficacy test if the in contact animals develop rinderpest and all the vaccinated animals remain normal.

5 Labelling.- Shall comply with general monograph on “Viral Vaccines”. Each ampoule or

at least 50 percent ampoules in a lot shall contain at least following print :

(i) TCRP Volume.
(ii) Batch No. with year.
(iii) General instructions for use. 6 Storage .- The vaccine when stored at minus 20 o C and plus 4 degree C will maintain its titre for 2 years and 6 months respectively. Canine Distemper Vaccine

1. Synonyms.- Cannine Distemper Vaccine (Living)- Freeze-dried.

2. Definition.- It is freeze dried preparation of either tissues from chick embryo containing

eggs adapted strain of cannine distemper virus or the cell culture in which modified virus has been cultivated.

3. Preparation.- Canine distemper vaccine shall be prepared from virus bearing cell culture, fluid or infected chroioalantoic membrane. Only stock seed virus which has been established as pure, safe and immunogenic shall be used for preparation of vaccine. Stock seed virus propagated in chicken embryo shall be tested for pathogen by chicken embryo test. One volume of the virus shall be mixed with 9 volume of specific sterile heat inactivated serum to neutralize the virus. Mixture shall be inoculated into twenty (9 to 11 days old ) chicken embryo (with 0.1 ml on CAM and 0.1 ml in alantoic sac). Embryonated eggs shall be candled for 7 days daily. Death occurring in the first 24 hours shall be discarded. CAMS of embryos which die after 24 hours shall be examined. When necessary embryo sub-culture shall be made to determine the cause of death. The test should be concluded on the 7th day cost inoculation.

The surviving embryos and their CAMS are examined. If deaths or abnormality due to the inoculums occur, the seed virus is unsatisfactory.

Immunogenicity test : Thirteen susceptible dogs 8-14 weeks old shall be used for the test

(ten vaccinates and 3 controls). Blood samples are drawn from these animals and individual sample is tested for antibodies against canine distemper. Ten dogs shall be injected with a predetermined quantity of the virus and remaining 3 dogs are used as unvaccinated controls. The dose shall be based on the virus tiltration. At least 21 days cost infection the vaccinated and controls shall be challenged intramuscularly with the same dose of virulent canine distemper virus and the animals are observed each day for 21 days. At least 2 out of 3 controls should die and survivor should show the symptoms typical of canine distemper. At least 9 out of 10 vaccinated animals should survive and should not show any clinical signs of canine distemper during the observation period. The stock seed

Drugs and Cosmetics Rules, 1945 virus should be tested for immunogenicity at least once in 5 years, if maintained under suitable conditions of storage. Eight days old chicken embryos from a healthy flock are inoculated on their chorioallantoic membrane with bacteriologically sterile virus suspension of egg adapted strain. After incubation for a period of five days, infected membrane and embryos are harvested. The individual embryo is tested for bacterial sterility. Those free from bacterial contamination are made into a 20 percent suspension in a suitable medium. The suspension is distributed in a single dose quantity into the ampoules of vials and freeze-dried.

The ampoules are sealed under vacuum or with pure dry sterile nitrogen before sealing. Alternatively, the virus may be grown on the suitable cell culture. Cells along with the suspending fluid is harvested, distributed in single dose quantity in ampoules and freeze dried.

4. Standard.-

(a) Description. - It is a dry product, pinkish cream material, readily dispersible in water or a suitable solvent.
(b) Identification. - It infects CAM of fertile eggs. This is neutralized by canine distemper antiserum. It does not cause distemper after injection into susceptible ferrets or dogs but immunizes them against the disease.
(c) Moisture content. - Moisture content in the finished product shall not exceed more than 1.0 per cent.
(d) Sterility test. - Shall comply with the test for sterility as described in the general monograph on “Viral Vaccines.”
(e) Safety tests. - (i) Mice safety test: Reconstituted vaccine as recommended on the label shall be tested. Eight mice, 4 weeks old shall be inoculated intracerebally with 0.03 ml and 8 mice shall be inoculated intraperitoneally with 0.5ml. Both groups shall be observed for 7 days, if unfavourable reaction attributable to the product in either 2 or more mice in either group is observed during observation period, the batch is unsatisfactory.
- (ii) Dog Safety test.-Inject two healthy dogs eight to fourteen weeks old that have previously been shown to be free from distemper virus-neutralising antibodies by the recommended route with twice the dose stated on the label and observe for 21 days. No significant local or general reaction develops.
- (i) Potency test. - (i) Titration : Final samples of finished product shall be tested for virus titre, and when tested at any time within the expiry period, it should contain not less than 10 ID per dose.
- (ii) It shall be carried out in dogs. Two healthy susceptible dogs each of 8-14 weeks of age free from distemper neutralizing antibodies are injected subcutaneously each within one vaccination dose. Serum samples shall be collected from each dog 14 days after vaccination and these shall have specific neutralizing antibodies at a dilution of 1: 100.

6. Labelling.- Shall comply with the requirements of labelling as laid down in the general

monograph on “Viral Vaccines”.

Drugs and Cosmetics Rules, 1945

7. Storage and expiry date. - For the freeze-dried product the expiry date is one year when

stored at minus 20 o C.

Avian Infectious Bronchitis Vaccine (Living)

1. Synonyms. - Avian Infectious Bronchitis Vaccine (Living) freeze-dried.

2. Definition. - It is a freeze-dried product of low virulent Avian Infectious Bronchitis Virus grown in embryonated hen’s eggs of cultivated in cell culture.

3. Preparation. - Only stock seed virus which has been established as pure, safe and immunogenic shall be used. Each jot of stock seed virus shall be tested for other pathogens by chicken embryo inoculation tests as follows: -

A lot of seed virus shall be mixed with 9 volumes of sterile heat inactivated specific anti- serum to neutralize and the vaccine virus serum mixture shall be inoculated into each of at least 20 fully susceptible chicken embryos of 9-11 days old (0.1 ml on CAM and 0.1 ml in the allantoic sac). Eggs are candled daily for 7 days. Deaths occurring during first 24 hours shall be discarded but at least 18 viable embryos shall survive 24 hours post inoculation for a valid test. All embryo and CAMS from embryos shall be examined which die after 24 hours. If necessary embryo subcultures shall be made to determine the cause of death. The test shall be concluded on the 7th day post inoculation and surviving embryos including the CAM shall be examined. If death and or abnormality attributable to the stock seed virus occur, the seed lot is unsatisfactory.

Each lot of stock seed virus shall be tested for immunogenicity as below: -

Bronchitis susceptible chickens of the same age and source shall be used. For each method of administration recommended on the label and for each serotype against which protection is claimed, 20 chicks shall be used as vaccinates. Ten additional chickens for each serotypes against which protection is claimed shall be held as unvaccinated controls. 21 to 28 days post vaccination all vaccinates and controls shall be challenged by eye drops with virulent Bronchitis virus. A separate set of vaccinates and controls shall be used for each serotype against which protection is claimed. The challenge virus shall have a titre of at least 10 4.6 EID per ml. Trachea swabs shall be taken once 5 days post challenge from each vaccinated and controls. Each swab shall be placed in test tube containing 3 ml of tryptose phosphate broth and antibiotics. The tubes and swabs shall be swirled thoroughly and stored at minus 40 o C pending egg inoculation. For each chicken swabs at least 5 chicken embryos, 9-11 days old shall be inoculated in the allantoic cavity with 0.2 ml of broth from each tube. All the embryos surviving 3rd day post inoculation shall be used in

evaluation. A tracheal swab shall be positive for virus recovery when any of the embryos

show typical infections bronchitis virus lesions such as stunting, curling, kidney urates, clubbed down or death during 4-7 days post inoculation period.

90 percent of the controls should prove positive for virus recovery. If less than 90 per cent of the controls are negative for virus recovery, the stock seed is unsatisfactory. The stock seed virus should be tested for immunogenicity once in 5 years provided it is maintained under standard conditions of the bronchitis virus storage.

4. Standards. -

(a) Descriptio: It is greyish-white product easily dispersible in the diluent. Drugs and Cosmetics Rules, 1945
(b) Identification: (i) The contents of the ampoule are suspended as per the instructions for the field use. The 0.2ml of the suspension shall be inoculated in the allantoic cavity of 9-11 days old chicken embryo and are incubated for 7 days. The lesions typical of infectious bronchitis shall be observed in the embryos at the end of incubation period. The allantoic fluid shall not agglutinate the chicken RBC's.
- (ii) Spectilie antisera against avian infectious bronchitis virus should neutralize the vaccine virus.
(c) Moisture content. - Moisture content in the finished product should not exceed 1.0 per cent.
(d) Sterility test. - Complies with the test for sterility as described under the general monograph on “Viral Vaccines”.
(e) Safety test. - Ten healthy susceptible chickens 5-10 days old from the same source batch shall be vaccinated with ten field dose of the vaccine and along with five chicks from same batch as unvaccinated controls by the prescribed route and observed 7 or 21 days post vaccination. Neither severe respiratory symptoms nor death shall occur to more than one experimental chicks, none of the unvaccinated control shall show any clinical symptoms.
(f) Potency test. - The minimum virus content of the freeze-dried product shall not be less than 10 3.5 EID per bird. The virus content of the vaccine shall be titrated as below: Serial ten-fold dilution of the freeze-dried material will be made in tryptose phosphate broth. Three to five embryonated eggs (9-11 days old) shall be in inoculated with 0.1 ml of each dilution into the allantoic cavity and observed daily for 7 days. Deaths occurring during the first 24 hours shall be discarded. The surviving embryos are examined for the evidence of infection and EID shall be calculated by the Reed and Muench Method/spearman and Karber method.

5. Labelling .- Shall comply with the requirement of labelling as laid down in the general

monograph on “Viral Vaccine”.

6. Storage and expiry date.- Shall be stored at 4

o C for six months]. PART II –ANTISERA Provisions applicable to the production of all Sera from Living Animals

1. Definitions- (i) This Part of the Schedule applies to antibacterial sera, anti-viral sera and

anti-toxic sera which are prepared by injecting bacteria or viruses or their products into buffalo- bulls or other suitable animals so as to produce active immunity which is manifested by the formation of anti-body.

(ii) For the purpose of this Part of the Schedule an anti-serum means sterile liquid anti- serum concentrated and unconcentrated, solutions of globulins or their derivatives or solid forms which can be reconstituted when necessary. 2. Staff of Establishment- The establishment shall be under the direction and control of a competent expert in bacteriology and serology with adequate training in immunology and standardisation of biological products and knowledge of animal management. He shall be assisted by a staff adequate for carrying out the tests required during the course of preparation of the sera and standardisation of the finished products. 3. Proper Name- The proper name of he antiserum shall be the recognised scientific name of the diseases or its causative organism or some generally recognised abbreviations thereof preceded by the prefix ‘anti’, and followed by the word ‘serum; as for example, ‘Anti- Anthrax serum’. The proper name of any antitoxin may be formed from the word ‘Anti-toxin’ preceded by the name of the organism from which the toxin was prepared, and followed, if desired, by a term indicating the source or the strain of that organism provided where there is no Drugs and Cosmetics Rules, 1945 special provision in the Schedule, the name as approved by the Licensing Authority may be adopted.

4. Records-

(1) The permanent records which the licensee is required to keep shall include the following particulars: -
- (a) As to the culture- Evidence of the identity and specificity of the cultures.
- (b) As to the procedure used in immunising the animals;
  - (i) The method of preparing the cultures or antigen used for immunisation.
  - (ii) The dosage and methods employed in administering the culture or antigen.
  - (iii) The period in the course of immunisation at which blood is withdrawn for the preparation of the serum.
- (c) Any test which may have been applied to the serum to determine its content of specific antibodies or its specific therapeutic potency and purity.
(2) If the licensee desired to treat the performance of any tests recorded under sub- paragraph (i) (c) of this paragraph as determining the date of completion of manufacture for the purpose of rule 109 he shall submit full particulars of the proposed test to the Licensing Authority and obtain his approval. 5. Cultures- The cultures used in immunising the animals shall be at all times open to inspection, and specimens shall be furnished for examination at the request of the Licensing Authority.

6. Quantity -

(a) Any antiserum shall be issued for veterinary use in the form of either.
- (i) Actual serum, i.e., the liquid product of decantation of the coagulated blood or plasma without any addition, other than antiseptic or subtraction, or
- (ii) A solution of the purified serum proteins containing the specific antibodies.
(b) At the time of issue, the liquid shall be clear or show at the most a slight opalescence or precipitate. Preparations of the natural serum shall not contain more than 10 per cent of solid matter. A solution of serum protein shall not contain more than 20 per cent of solid matter. 1. Precautions to be observed in preparations-
- (i) Laboratories where sera are exposed to the air in the course of the process

of preparation must be separated by a sufficient distance from stables and animals

houses to avoid the risk of aerial contamination with bacteria from animal excreta, and must be rendered fly proof to prevent such contamination by insects. Such laboratories must have impervious walls and floors and must be capable of being readily disinfected when necessary.

(ii) A special room with impervious walls must be provided for the collection of blood from the living animals.
(iii) An efficient system of manure removal must be used which will prevent its accumulation in the vicinity of any room where blood or serum is collected or handled. Drugs and Cosmetics Rules, 1945
(iv) An adequate number of sterilizers must be provided for the sterilization of all glassware or other apparatus with which the serum may come into contact in the course of its preparation.
(v) All processes to which the serum is subjected during and after the collection from the animals, must be designed to preserve its sterility, but in the case of a artificially concentrated sera, it shall suffice that the process of concentration is conducted with scrupulous cleanliness and in such a manner as to avoid unnecessary dangerous contamination.
(vi) The laboratories in which the testing of sera for potency, sterility and freedom from abnormal toxicity are carried out must be adequate for the purpose. An adequate supply of animals for use in such tests and suitable housing for such animals must be provided.
(vii) Provision must be made for complying with any special conditions which may be laid down in the Schedule relating to the production and issue of the particular serum, in respect of which the licence is granted. 8. Unhealthy or Infected Animals- If an animal used in the production of sera is found to be suffering from an infection except one produced by living organisms against

which it is being immunized, or shows signs of serious or persistent ill health not reasonably

attributable to the process of immunisation, the licensee shall immediately report the matter to the Licensing Authority and shall, if the authority orders an inspection and the Inspectors so directs, cause such animals to be killed and a postmortem examination of it to be made, and take steps to prevent any serum obtained from the animal being sold or offered for sale until permission is given by the Licensing Authority. If the result of the postmortem is such as to bring under suspicion, the health of any of the other animals used for the production of sera, the Licensing Authority may prohibit the use of those animals for the production of sera or may take such other steps as may be necessary to prevent the issue of sera which may be dangerous to animal health. Provided in the case of emergency, the person in charge of the establishment may order the destruction of an animal used in the production of sera and suspected of infection, and shall in that case given notice forthwith to the Licensing Authority and shall permit an Inspector to be present at the postmortem examination.

9. Conditions and Housing of animals:

(i) The animals used in the production of sera should be adequately housed under hygienic environments.
(ii) Only healthy animals free from disease should be used in the preparation of sera.
(iii) Every animal intended to be used as the source of serum must be subjected to a period of observation in quarantine for at least seven days before being admitted to the animal sheds in which the serum yielding animals are housed.
(iv) In case of horses and other equidae, every animal used as source of serum shall either be actively immunized against tetanus or shall be passively immunized against the disease by injection of tetanus antitoxin in such doses as to ensure the constant presence of that antitoxin in the blood during the whole period of the use of the animals as a source of serum. Anti-Sera and their General Standard Anti-sera contain the immune substances that have a specific prophylactic or therapeutic action when injected into animals exposed to or suffering from a disease due to a

specific microorganism or its toxin. Anti-sera are classified into three groups.

Drugs and Cosmetics Rules, 1945

(i) Antitoxic sera (Antitoxin)
(ii) Antibacterial sera.
(iii) Antiviral sera. Antisera are usually issued in an unconcentrated form for animal use but may be concentrated and also freeze dried. However, for the purpose of the Schedule the word ‘antisera’ is also used for the unconcentrated liquid sera. A suitable bacteriostatic agent in a concentration sufficient to prevent the growth of microorganisms is added to the liquid serum. General Standard 1. Description- Liquid native or unconcentrated antisera are yellow or yellowish brown in colour. They are initially transparent but may become turbid with age. They are almost odourless except for the odour of any bacteriostatic agent that may have been added. 2. Identification- The test for identity is described in the individual monograph.

from abnormal toxicity.

(a) Two healthy mice each weighing not less than 18 g. are injected subcutaneously each with 0.5 ml. of the sample and observed for five days. None of the mice should show any abnormal reaction or die.
(b) Two healthy guinea pigs each weighing 300 g. to 450 g. are injected subcutaneously each with 5 ml. of the sample and observed for seven days. None of the guinea-pigs should show any abnormal reaction or die. 5. Sterility- All anti-sera shall comply with the tests for sterility described in rules 115 to 119. 6. Potency- The potency of each preparation, when the available methods permit, is determined by the appropriate biological assay, and it is described under the individual monograph. 7. Total Solids- Native antisera should not contain more than 10 per cent solid matter. 8 Labelling- Should comply with the provisions for ‘Labelling’ as laid down for ‘Bacterial Vaccines.’ 9. Storage- Liquid preparations of antisera shall be stored, protected from light at

in the individual monograph in this part is as defined in clause (b) of sub-rule (3) of rule 109.

11. Containers- All antisera are distributed in sterilised containers of a material which is

inert towards the substance and which are sealed to exclude micro-organisms.

12. Expiry Date- The expiry date of potency of all sera shall not be more than twenty-

four months after the date of a manufacture.

Anti-Anthrax Serum 1. Synonym- Bacillus Anthracis Anti-serum. 2. Definition- Anti-anthrax serum is the serum of animals that confers a specific protection against Baccillus anthracis.

Drugs and Cosmetics Rules, 1945 3. Preparation- The antiserum may be prepared in buffalo bulls after repeated

injections of cultures of B. anthracis of a virulent strain.

4. Standard- It complies with the requirements in the general provisions for antisera under Description, Acidity or Alkalinity, Abnormal Toxicity, Sterility, Solids,

Labelling, Storage and Expiry date.

Identification – It protects animals against infection with B. Anthracis Anti-Blackquarter Serum 1. Synonym- Blackleg Antiserum, Clostridium Chauvoei-Anti serum 2. Definition-Anti-Blackquarter serum is the serum of suitable animals containing the Substances that have a specific neutralising effect on Clostridium Chauvoei. 3. Preparation- It is prepared by injecting subcutaneously or intramuscularly increasing doses of formolised cultures of Cl. Chauvoei into buffalo bulls. 4. Standards- It complies with the requirements described in the general provisions for antisera under Description, Acidity or Alkalinity, Abnormal Toxicity, Sterility, Solids,

Labelling, Storage and Expiry date.

Identification- It protects susceptible animals against infection with virulent strains of Cl. Chauvoei.

Anti-Fowl-Cholera Serum

1. Synonym- Pasteurella Septica Antiserum (Avian). 2. Definition- Fowl Cholera Antiserum is the serum of animals containing the substances that confer a specific protection to fowls against virulent strain of Pasteurella Septica (Avian). 3. Preparation- Antiserum is prepared from buffalo bulls after they have been subjected to an injection of killed cultures of virulent strain of Pasteurella Septica (Avian) followed by injections of living cultures of the same organism. 4. Standard- It complies with the requirements described in the general provision for anti-sera under Description, Acidity or Alkalinity, Abnormal Toxicity, Sterility, Solids,

Labelling, Storage and Expiry date.

Identification- It protects susceptible fowls against infection with Pasteurella Septica (Avian) and its homologous strains. Anti- Haemorrhagic Septicaemia Serum 1. Synonym- Pasteurella Septica Antiserum. 2. Definition- Anti-Haemorrhagic Septicaemia Serum is the serum of animals containing the substances that confer a specific protection to susceptible animals against virulent strains of Pasteurella Septica. 3. Preparation –

The antiserum is prepared from buffalo bulls after they have been

subjected to repeated injections of formolised cultures of standard strain Pasteurella Septica

with adjuvants, followed by suitable doses of virulent culture of the organism.

4. Standard.-It complies with the requirements described in the general provisions for antisera under Description, Acidity or Alkalinity, Abnormal Toxicity, Sterility,

Solids, Labelling, Storage and Expiry date.

Drugs and Cosmetics Rules, 1945 Identification- It protects susceptible animals against infection with homologous strains of Pasteurella Septica. Anti-Rinderpest Serum

1. Synonym- Cattle Plague Antiserum

2 Definition- Anti-Rinderpest Serum is the serum of buffalo bulls containing the substances that confer a specific protection to susceptible animals against virulent strains of

of virulent rinderpest virus, which is injected simultaneously with a predetermined quantity of anti rinderpest serum so as to control the severity of the reaction (serum-simultaneous- method).

4 Standard- It complies with the requirements described in the general provisions for

antisera under Description, Acidity or Alkalinity, Abnormal Toxicity, Solids, Labelling, Storage and Expiry date.

(i) Identification- It protects susceptible animals against rinderpest.
(ii) Potency-Five Buffalo-calves of about one year of age in good condition are used for the test. Three are injected subcutaneously with the anti-rinderpest serum under test at the rate of 10 ml. per 46 kg. body weight, subject to a minimum of 20 ml. per animal. These together with the two remaining, are simultaneously injected subcutaneously at a different site with 1 ml. of a 1: 100 dilution of spleen suspension of virulent bull-virus. The animals should be observed for fourteen days during which time the serum treated animals should exhibit no symptoms of rinderpest other than rise in temperature and slight intestinal disturbances, while the controls develop more severe symptoms or die. Salmonella Pullorum Anti Serum

1. Synonym- Salmonella Pullorum Anti Serum.

2. Definition- Salmonella Pullorum anti-serum is the sera from fowls and contains antibodies against Salmonella Pullorum. It is used for standardizing batches of Salmonella Pullorum antigens and also used as a control along with the sera suspected for pullorum disease. 3. Preparation- The serum is prepared after intravenous inoculation with smooth culture suspension of Salmonella Pulloram in healthy birds. 4. Standards- It complies with the requirements in the general provisions for anti- sera under Description, Acidity, Alkalinity, Sterility, Solids, Labelling, Storage and Expiry date. 5 . Identification- It should give positive agglutination with Salmonella pullorum antigen. Standard Anti-Brucella Abortus Serum 1. Synonym- National counterpart of standard anti-Brucella Abortus serum.

2. Definition- Standard Anti-Brucella abortus serum is the serum which contains

1000 International Units (I.U) per ml. and is used for standardizing batches of brucella antigens and is also used as a control along with the sera suspected for brucellosis.

3. Preparation- The serum is prepared after intravenous inoculation of suspension of smooth culture of B. abortus (strain 99) in rabbits or cattle and subsequently diluting it suitably with brucella-free healthy serum so that when tested with standardized Brucella abortus tube test antigen, it gives 50% agglutination at 1/500 final serum dilution.

Drugs and Cosmetics Rules, 1945

4. Standard- It complies with the requirements in the general provision for anti- sera under Description, Acidity, Alkalinity, Sterility, Solids, Labelling, Storage and Expiry date. Identification- It should give agglutination with Brucella antigen.

PART III- DIAGNOSTIC ANTIGENS Provisions Applicable to the Manufacture and Standardisation of Diagnostic Agents (Bacterial Origin) 1 Definition- This Part of the Schedule applies to reagents of bacterial origin employed for various tests. 2 Staff of establishment- A competent expert in bacteriology with sufficient experience in the manufacture and standardisation of veterinary biological products shall be in charge of the establishment responsible for the production of various diagnostic agents of bacterial origin and he may be assisted by a staff adequate or carrying out the tests required during the preparation and standardisation of various diagnostic agents. 3 Proper Name- The proper name of any diagnostic agent is the name of micro- oraganism from which it is made, followed by the word ‘antigen’ unless the Schedule otherwise provides, or, it may be derived from the name of the organism responsible for the causation of the disease or if there is no special provision in the Schedule, the name approved

by the Licensing Authority. In the case of the undermentioned preparations the proper name

of the diagnostic agent may be as follows:

4. Records- Cultures used in the preparation of diagnostic agents of bacterial origin must, before being manipulated into an agent be thoroughly tested for identity by the generally accepted tests applicable to the particular micro-organism. The permanent record which the licensee is required to keep shall amongst other include a record of the origin, properties and characteristics of the cultures. 5. Preparation- Diagnostic agents of bacterial origin are prepared from selected cultures after their careful examination for the identity, specificity, purity and antigenicity. They may be prepared in the following manner:

(a) Formolised Antigens- The selected pure culture strain grown in a suitable medium at an optimum temperature for an appropriate period. The pure growth is then exposed to the action of a solution of Formaldehyde I.P. in a suitable

concentration and at an appropriate temperature for a suitable period.

Drugs and Cosmetics Rules, 1945

(b) In some cases, the diagnostic agents are prepared by growing the organisms on suitable media and then deriving specific protein constituents of the bacteria by various methods.

6. General Standard:-

(a) Description- Diagnostic agents may be clear opalescent or coloured liquids.
(b) Identification- Some exhibit specific agglutination when mixed with the serum of the animals infected with homologous organisms and others when injected into the animal body in appropriate doses cause specific reactions like hypersensitiveness, local and general reaction, if the animal is infected with homologous organisms.
(c) Sterility Test- All antigens shall be tested for sterility in accordance with rules 114 to 119.
(d) Standardisation- It is carried out either by determining the definite concentration in the product or by observing the general and local reactions in healthy and artificially infected animals with various standard dilutions of the product.

Abortus Bang Ring (A.B.R.) Antigen 1. Synonym- Milk Ring Test Antigen. 2. Definition- The antigen is a suspension of pure growth culture of standard strain of Brucella abortus strain 99 strained supravitally with 2,3,5, triphenyl tetrazolium chloride suspended in 0.85 per cent saline containing 1 per cent glycerol and 1 per cent phenol. 3. Preparation- Smooth strain of Brucella abortus strain 99 is grown in potato infusion agar for 48 to 72 hours in Roux flasks, at 37 ̊ C. Condensation fluid if any is pipetted off before washing. Each flask is washed with about 20 ml. of normal saline. The pooled washing is filtered through a gauze and the filtrate is collected in a measuring cylinder. To every 500 ml. of the filtrate 1 g. of 2, 3, 5, triphenyl tetrazolium chloride is added immediately. The container is shaken for thirty minutes till the tetrazolium salt is dissolved. The product is taken out and kept at 37 ̊ C for two hours. After incubation the product is heated at 65 ̊ C in a water bath for thirty minutes. It is cooled and centrifuged at 3000 r.p.m for one hour. The supernatant is pipetted off and sediment is suspended in normal saline

containing 1 per cent glycerol and 1 per cent phenol and filtered through sterile cotton wool.

This forms concentrated antigens.

Drugs and Cosmetics Rules, 1945 Standardization of the Strained Antigen An aliquot portion of the microbial suspension stained with phenylte-trazolium is taken, representing the initial undiluted suspension. 1 ml. per tube of this initial undiluted stained suspension is added to six test tubes, followed by increasing quantities of the glycerolphenol diluent as follows:- __________________________________________________________________________

Tube Undiluted Stained Suspension Diluent

__________________________________________________________________________ 1 1 0.6 2 1 0.8 3 1 1.0 4 1 1.2 5 1 1.4 6 1 1.6 _________________________________________________________________________

The contents of each tube are then diluted tenfold with the same diluent and serve as antigen for a tube agglutination test with the Standard Serum (or its national counterpart). In this way, six sero-reactions will be carried out. During this procedure, the concentrated

strained microbial suspension should be kept in the refrigerator at 4 ̊ C.

The agglutination reactions are read after forty-eight hours at the agglutination titre of the Standard Serum, previously determined with the usual unstained antigen in the tube test, corresponding to the correct dilution of the standard antigen.

The next step, therefore, is to dilute the concentrated stained suspension to the same extent as the tube whose tenfold dilution has given the correct agglutination titre, i.e. the concentration of antigen in the tube before the tenfold dilution had been made.

4. Standard:

(a) Description- It is a red colour liquid containing dead bacteria in suspension.
(b) Identification- It shows formation of a specific cherry red coloured ring in the cream layer when mixed with pooled samples of milk taken from animals suffering from burcellosis.
(c) Sterility Test- Should comply with tests for sterility described in the general monograph on ‘Diagnostic Antigen’. The test shall, however, be done before colouring. 5. Labelling and Storage- Should comply with the requirements of ‘Labelling’ and ‘Storage’ as laid down in the general monograph on ‘Diagnostic Antigens’. 6. Expiry Date- The date of expiry of potency shall be not more than nine months

from the date of manufacture when stored 2 ° C to 4° C.

Brucella Abortus Coloured Antigen

1. Synonym- Brucella abortus Cotton Strain 99 coloured Antigen.

2. Definition- Brucella Abortus colured Antigen, is a suspension of pure smooth cultures of Brucella abortus strain 99 in phenolised glycerine saline, the bacteria being

Drugs and Cosmetics Rules, 1945 coloured by the addition of crystal violet and brilliant green. This antigen is used for plate test for serological diagnosis of brucella infection. 3. Preparation- Seventy-two hours old growth of Brucella Abortus strain ninety-nine in smooth form on potato infusion agar medium in Roux flasks is washed with phenolised glycerine saline (containing 12 per cent sodium chloride, 20 per cent glycerine and 0.5 per cent phenol). The washed growth is filtered through a pad of absorbent cotton wool and the suspension is coloured by the addition of 1 ml. each of 1 per cent aqueous solution of crystal violet and brilliant green for very 250 ml. of the suspension. The product is heated for sixty minutes in a water bath at 60° C before it is standardised.

4. Standard:

(a) Description- It is a greenish violet liquid containing dead bacteria in suspension.
(b) Identification-It gives specific agglutination when mixed with the serum of the animal infected with brucella organism.
(c) Sterility Test- Should comply with the tests for sterility described in the general monograph on ‘Diagnostic Antigens’
(d) Standardisation- 0.5 ml. of the antigen is mixed with 4.5 ml of normal saline solution in Hopkins graduated tube. The mixture is centrifuged at 3000 r.p.m. for sixty minutes and the percentage of bacterial cells present in the original antigen is assessed by noting the height of the cell deposit. The antigen is then standardised so as to contain 10 per cent cell deposit. 5. Labelling and Storage- Should comply with the requirements of ‘Labelling’ and ‘Storage’ as laid down in the general monograph on ‘Diagnostic Antigens’. 6. Expiry Date- The date of expiry of potency shall be not more than nine months

from the date of manufacture when stored at 2 ° C to 4°C.

Brucella Abortus Plain Antigen 1. Synonym- Brucella Abortus Strain 99 Plain Antigen. 2. Definition- Brucella Abortus Plain Antigen is a suspension of a pure smooth culture of Brucella abortus strain 99 in phenol-saline. 3. Preparation- Seventy-two hours old growth of Br. Abortus strain 99 in smooth form on potato infusion agar medium in Roux flasks is washed with normal saline solution. The washed growth is filtered through a pad of absorbent cotton wool and the suspension is kept at 60 ° C per cent. for sixty minutes on a water bath to kill the organisms. It is then preserved by the addition of phenol in a final concentration of 0.5 per cent. 4. Standard:

(a) Description- An opalescent liquid containing dead bacteria in suspension.
(b) Identification –It gives specific agglutination when mixed with the serum of animals infected with brucella organism.
(c) Sterility Test- Should comply with the tests for sterility described in the general monograph in ‘Diagnostic Antigen’.
(d) Standardisation- Mix the concentrated antigen well and dilute 1 ml. with 0.5 per cent phenol saline until it corresponds to about Tube 4 of Brown’s opacity tubes. Further dilutions of the antigen adjusted to opacity tube No. 4 are made. The particular dilution that gives 50 per cent agglutination with anti-brucella abortus serum ( containing 1000 International Units) at 1 : 500 final serum dilution, is assessed as the diluting factor for the concentrated antigen. The bulk of the concentrated antigens is accordingly diluted for issue as standard antigen. Drugs and Cosmetics Rules, 1945 Labelling and Storage- Should comply with the requirements of ‘Labelling and Storage’ as laid down in the general monograph on ‘Diagnostic Antigen’. 5. Expiry Date- The date of expiry of potency shall be not more than nine months

from the date of manufacture when stored at 2° C to 4° C.

Johnin 1. Definition- Johnin is a preparation of a fluid medium in which Mycobacterium Paratuberculosis has been grown in artificial culture and which has been freed by filtration from the bacilli. 2. Preparation- Young culture of selected strain of Myco-Paratuberculosis of bovine origin is grown on synthetic medium and incubated at 37 ° C for ten to twelve weeks. Flasks showing nutrient and pure growth are steamed for three hours thereafter kept at room temperature overnight. The contents are filtered through fine meshed sieve. The filtrate is concentrated over a steam bath to one-tenth of its original volume and kept in cold storage for fourteen days before being filtered through Seitz filter. The product is dispensed in ampoules and hermetically sealed.

3. Standards:-

(a) Description- A yellowish brown to brownish liquid.
(b) Identification- It produces hot, painful and oeodemateus swelling at the site

of inoculation in animals infected with Myco-paratuberculosis organism.

(c) Sterility Test- Should comply with the test for sterility described in the general monograph on ‘Diagnostic Antigens’.
(d) Potency Test- Two animals, previously infected with Myco-paratuberculosis and two healthy animals are each injected intrademally in the neck region with 0.1 ml. of the product. Forty-eight hours later, the injection is repeated at the same site. The product should produce a typical reaction in the infected animals in the form of a hot painful and oedemetous swelling at the site of inoculation persisting for at least forty-eight hours after the second injection. Control animals should not show such reaction. 4. Labelling and Storage- Should comply with the requirements of ‘Labelling’ and ‘Storage’ as laid down in general monograph on ‘Diagnostic Antigens’.

Malleins 1. Definition- (i) Malleins are preparations of fluids media in which the Actinobacillus mellei has been grown in artificial culture and which have been freed by filtration from the bacilli.

(ii) For the purposes of this Schedule malleins are classified into (a) Mallein-

(a) Mallein Subcutaneous- Three to four weeks old pure growth of standard strain of A. mallei grown on synthetic medium is steamed for one hour in Koch’s steam sterilizer. One part of 5 per cent phenol solution is added to every nine part of the dead culture which is then filtered through Seitz filter. Drugs and Cosmetics Rules, 1945
(b) Mallein Concentrated. - The procedure is the same as for Mallein Subcutaneous except, that the filtrate is evaporated in porcelain dish over steam to half the original volume before addition of phenol. Five per cent phenol solution is added in sufficient quantity to the concentrated product, to give a final concentrated of 0.5 per cent.

3. Standards:

(a) Description- A yellowish to brown viscous liquid.
(b) Identification- It produces hot tense, painful swelling when injected into the

animals infected with A. mallei organisms.

(c) Sterility Test- Should comply with the tests for sterility described in the general monograph on ‘Diagnostic Antigens’.
(d) Potency Test: -
- (i) Mallein subcutaneous- Two ponies, previously sensitised with A. Mallei and controls, are injected each with 1 ml. of the product subcutaneously in the neck region. The animals are observed for local reaction and rise in temperature. Local reaction is manifested by a hot tense, painful swelling becoming prominent within twenty-four hours. The rise in temperature is observed by recording the body temperature at the time of inoculation and subsequently at short intervals. A rise in temperature of 1 ̊ C or more above normal is indicative of infection.
- (ii) Mallein Intra-dermo-Palpebral (I.D.P.)- Two ponies, previously sensitized with A. mallei and two healthy ponies are injected intradermally with 0.2 ml. of the product near the rim of the lower eye lid of one eye. Typical reactions such as painful swelling of the palpebral tissue with mucopurulent discharge from the eye is indicative of infection. The two healthy ponies should not show such reactions. Similar test in other eye is performed with a previously determined patient mallein using as a standard. When the local reactions produced by intradermo palpebral infections of the two preparations are comparable the batch is passed for issue. 4. Labelling and Storage- Should comply with the requirement of ‘Labelling’ and ‘Storage’ as laid down in the general monograph on ‘Diagnostic Antigen’.

Salmonella Abortus Equi ‘H’ Antigen

1. Synonym- Equine Abortion Diagnostic Antigen.

2. Definition- Salmonella Abortus Equi Antigen is suspension of a pure smooth culture of actively motile Salmonella Abortus equi in formal saline. 3. Preparation- Standard strain of S.abortus equi is grown on nutrient agar in Roux flasks at 37 ̊ C for twenty-four hours. The pure growth in Roux flasks is washed with normal saline and diluted to contain approximately 800 million organisms per ml. Solution of Formaldehyde I.P. is added to give a final concentration 0.5 per cent and the formolised product is incubated at 37 ̊ C for twenty-four hours. The final product is dispensed in suitable containers.

4. Standards:-

(a) Description- A slightly opalescent liquid containing dead bacteria in suspension.
(b) Identification- It gives specific agglutination when mixed with the serum of the animals infected with S.abortus equi organisms. Drugs and Cosmetics Rules, 1945
(c) Sterility Test- Should comply with the test for sterility described in the general monograph on ‘Diagnostics Antigens’. 5. Labelling and storage- Should comply with the requirements of ‘Labelling’ and ‘Storage’ as laid down in the general monograph on ‘Diagnostic Antigens’.

Salmonella Pullorum Coloured Antigen

1. Synonym- Bacillary White Diarrhoes (B.W.D) Antigen.

2. Definition- The antigen is a suspension in a solution containing 1 per cent Formaline, 1 per cent KH PO and 0.85 per cent Sodium Chloride of pure smooth culture of standard strain of Salmonella Pullorum. 3 Preparation- Standard strain of S. Pullorum is grown on sulphur agar medium in Roux flasks for five days at 37 ̊ C. The pure growth is washed with 1.0 per cent Formal Saline. Standardisation The antigenic cell suspension is then centrifuged (preferably in cold centrifuge) for half an hour at 4000 rotations per minute and the packed cell volume determined. The packed cell is then re-suspended in a solution containing 1 per cent formalin, 1 per cent KH

PO and 0.85 per cent sodium chloride, 1 ml. of packed cell is suspended in 10 ml. of the resuspendiary solution, mixed thoroughly and is passed through a cotton wool pad. The turbidity of the antigenic suspension is usually between 100 to 125 times Mac Farland scale standard and optimum 3 cc. of a 1 per cent aqueous solution of crystal violet are added to

100 ml. of the antigenic suspension. After making the dye the antigen is allowed to stand

forty-eight hours before use. The average yield per Roux flasks of culture medium is about

50 ml. The antigen should be bottled in 10 ml. or 20 ml. quantity in amber-coloured bottles

and corked with rubber caps and paraffin sealed and preserved until required for use within the expiry period. This antigen reacts instantly with the blood of all carrier birds and remains permanently negative with that of non-infected birds. This antigen gives good reactions with positive sera whose titre is even as low as 1 : 20.

4. Standard:-

(a) Description- Violet coloured liquid containing dead bacteria in suspension.
(b) Identification- It gives specific agglutination when mixed with the serum of birds in infected with S. Pullorum infection. It is used for carrying out plate agglutination tests for serological diagnosis for S. Pullorum infection in birds.
(c) Sterility Test- Should comply with the test for sterility described in the general

monograph on ‘ Diagnostic Antigen’. The tests shall be done before addition of ‘Crystal

Violet’. 5. Labelling and Storage- Should comply with the requirements of ‘Labelling’ and

‘Storage’ as laid down in the general monograph 0n ‘Diagnostic Antigens’.

6. Expiry Date- A six month expiration date for this antigen is recommended. However, it is advisable to use fresh ones as far as possible. This antigen should be preserved at 4 ̊ C to 6 ̊ C in dark place in the refrigerator and should not be exposed to hot weather

condition for longer than necessary before use in the field.

Salmonella Pullorum Plain Antigen

1. Synonym- Bacillary White Diarrhoes (B.W.D) Plain Antigen.

Drugs and Cosmetics Rules, 1945 2. Definition- The antigen is a suspension of pure smooth culture of Salmonella pullorum in phenol saline. 3. Preparation- Forty-eight hours old pure culture of smooth strain of S. Pullorum is washed with 0.5 percent phenol saline and the pooled suspension is adjusted to contain approximately 800 million organisms per ml. by the addition of more carbol saline. The suspension is kept at room temperature of twenty-four hours, and dispensed in suitable containers.

4. Standard: -

(a) Description- An opalescent liquid containing dead bacteria in suspension.
(b) Identification- It gives specific agglutination when mixed with the serum of birds infected with S. Pullorum.
(c) Sterility Test- Should comply with the tests for sterility described in the general monograph on ‘Diagnostic Antigen’. 5. Labelling and Storage- Should comply with the requirments of ‘Labelling’ and ‘Storage’ as laid down in the general monograph on ‘Diagnostic Antigens’. 6. Expiry Date- The date of expiry of potency shall be not more than nine months

from the date of manufacture when stored at 2 ̊ C to 4 ̊ C.

Tuberculin 1. Definitions:

(i) Tuberculins are preparations of fluid media on which Mycobacterium tuberculosis

has been grown in artificial culture and which has been freed by filtration from the bacilli.

(ii) For the purposes of the Schedule tuberculins are classified in (a) Tuberculin- Subcutaneous (b) Heat Concentrated Synthetic Medium (H.C.S.M) Tuberculin (c) Avian tuberculin. 2. Preparation:-

(a) Tuberculin subcutaneous- Flasks containing Henley and Dorset synthetic medium are inoculated with standard human strains of Myco-Tuberculosis previously grown on glycerol- beef broth medium for ten days. After ten to twelve weeks of

incubation at 37 ̊ C, flasks containing pure growth are steamed for three hours. The

contents are filtered through fine meshed sieve and the volume is made up to its original with phenolised distilled water such that the final concentration of phenol is 0.5 per cent. It is then filtered through Seitz filter.

(b) Heat Concentrated Sythetic Medium (H.C.S.M) Tuberculin- To the strained liquid obtained after sieving as in the method of preparation of Tuberculin subcutaneous, glycerol is added in the proportion of 122 ml. per litre of the original volume of medium used. The mixture is evaporated to one-fifth of the original

volume on a steam bath. An equal volume of 1 per cent phenol in distilled water is

added after the mixture is cooled. The product is stored at 47 ̊ C for fourteen days before it is filtered through Seitz filter. It is then dispensed in ampoules.

(c) Avian Tuberculin Concentrated- The procedure is the same as for Tuberculin Concentrated (H.C.S.M) except that standard strain of Myco-tuberculosis (Avian) is used in its preparation. 3. Standard:-
(a) Description- A yellowish brown viscous liquid.
(b) Identification- When injected intradermally into the animal infected with tuberculosis diffused swelling occurs depending upon the allergic status of the animal, the Drugs and Cosmetics Rules, 1945

magnitude of dose and specificity of the product. In non-infected animals this reaction is

not observed.

(c) Sterility Test- Should comply with the test for sterility described in the general monograph on ‘Diagnostic Antigens’.
(d) Potency Test- (i) Tuberculin subcutaneous-Six large white guinea-pigs each weighing not less than 300-450 g. are individually inoculated intramuscularly with 0.5 mg. (Moist growth from solid plants) of Mycobacterium tuberculosis three weeks prior to test of each batch of tuberculin; the following dilutions of (a) test tuberculin and (b) standard tuberculin are used:- 1 in 200, 1 in 400, 1 in 800 and 1 in 1600. The six sensitized guinea pigs are depilated on one flank and after about twenty- four hours each animal inoculated intradermally with 0.2 ml. of each dilution of the two tuberculins in two rows. The reactions are read after twenty-four and forty-eight hours. When the local reactions produced by the graded inter-dermal injections of the two preparations are comparable the brew is passed for issue.
- (ii) Heat Concentrated Synthetic Medium (H.C.S.M) Tuberculin-Six adult white guinea-pigs each weighing not less than 300-450 g. and sensitized three weeks previously with 0.5 mg. (moist growth from solid plants) of Myco-Tuberculosis bovine type, injected intramuscularly are used for test of each batch. The following dilutions of
(a) test tuberculin and (b) standard tuberculin are used: - 1 in 500, 1 in 1000, 1 in 2000 and 1 in 4000. The six sensitized guinea pigs are depilated on one flank and after about twenty- four hours each animal is inoculated intradermally with 0.2 ml. of each dilution of the two tuberculins in two rows. The reactions are read after twenty-four and forty-eight hours. When the local reactions produced by the graded inter-dermal injections of the two preparations are comparable, the test tuberculin is passed for issue. The tuberculin is dispensed in ampoules.
- (iii) Avian Tuberculin- Six adults fowls, with well developed wattles, sensitized at least three weeks previously by intramuscular injection with 10 mg. moist weight (from solid plants) of twenty-one days old culture of Mycobacterium tuberculosis (Avian Type) are used for potency test of each batch. In each fowl, one wattle is inoculated with 0.2 ml. of undiluted test tuberculin and the other wattle with similar quantity of undiluted standard tuberculin. The reactions in each fowl are read after twenty-four hours and forty-eight hours and if comparable the product is passed for issue. 4. Labelling and Storage- Should comply with the requirments of ‘Labelling’ and ‘Storage’ as laid down in the general monograph on ‘Diagnostic Antigens’. 5. Expiry Date- The date of expiry of potency shall be not more two years months

from the date of manufacture when stored at 2 ̊ C to 4 ̊ C.

PART IV GENERAL 1. For the purpose of this Schedule any test or method of testing described in the British Veterinary Codex shall be deemed to be a method approved by the Licensing Authority. 2. The Licensing Authority shall publish in the official Gazette from time to time particulars of any test or method of testing approved by him.]

Drugs and Cosmetics Rules, 1945 353

F (II)

(See Rule 124-C) STANDARDS FOR SURGICAL DRESSINGS Synonyms: Bandage Cloth, Bleached Bandage Cloth, Rolled Bandage, Open Wove Bandage, Cotton Bandage Cloth. Bandage Cloth consists of cotton cloth of plain weave made from machine spun yarn of suitable count to comply with a bleached count between 20 tex and 25 tex for warp and between 25 tex and 30 tex for weft. The fabric contains no filling, sizing or dressing material. It may be supplied uncut and folded or cut to suitable size and rolled. Description for uncut bandages: Uncut bandages are cotton cloth of plain weave, in one continuous length showing no joints or seams, with well-formed selvedges. The cloth is bleached to a good white, is clean and odourless and reasonably free from weaving defects and from seed and leaf debris. Description for cut bandage: Same as for uncut bandages, except for selvedges which shall not be included in cut bandages. In addition, both the extremes and edges of cut bandages shall be straight and evenly cut, with reasonable freedom and loose threads. Threads per dm: – Warp not less than 150 and weft not less than 85. Weight in g/m

the length and width stated on the label. For cut bandages, each of the bandages in a packing complies with this requirement.

Foreign matter: - Not more than 2 per cent.

Fluorescence: When viewed under screened ultra-violet light, not more than occasional points of fluorescence are observed. Packing, Labelling and Storage: Bandage Cloth shall be packed securely so as to allow normal handling and transport

without tearing and exposing the contents. In packages of cut and rolled bandages, each

bandage shall also individually be wrapped in a suitable paper. The net content is stated on the label in terms of length and width. Bandage Cloth must be stored in packed condition protected from dust. The packings of Bandage Cloth shall be labelled prominently with the words “Non-Sterile”. Absorbent Gauze.

Synonyms.- Gauze; Unmedicated Gauze; absorbent Cotton Gauze.

Absorbent Gauze is cotton fabric of plain weave, supplied in various widths and lengths. The Gauze is bleached and free from any sizing, dressing or filling material. The yarn used is machine spun cotton yarn, of suitable count to comply with a bleached count between 17 and 25 tex in the finished fabric.

¹ Ins. by G.S.R. No.318(E), dt.. 1-5-1984.

___________________________________________________________________________

Drugs and Cosmetics Rules, 1945 354 Description: Cotton cloth, plain weave, with a simple selvedge present on both sides to prevent unravelling of yarn. The cloth is bleached to a good white, is clean, odourless, reasonably free from fabric defects and adhering sand debris from cotton seeds and leaves, or any other foreign matter. Threads per dm:.- Warp not less than 75 and weft not less than 55. Weight in g/m

label. Absorbency:- Average sinking time not more than 10 seconds. Fluorescence:- When viewed under screened ultra-violet light not more than occasional points of fluorescence are observed.

Foreign matter:- Not more than 1 per cent.

Sterility:- If sterile, the contents comply with the test for sterility.

Packing, Labelling and Storage:

Absorbent Gauze is folded and packed with such materials and so securely as to protect its absorbency and allow normal handling and transport without tearing and exposing the contents. The net content is stated on the label in terms of length and width. The packages shall be labelled prominently with the words “Non-Sterile”. If sterile, it shall be so stated on the label, and the packing method and material shall be such as to maintain the sterility. The Absorbent Gauze must also comply with the Sterility Test. Absorbent Gauze must be stored in packed conditions protected from moisture and dust.

METHODS OF TEST Defect in fabric:. The sample is unfolded, opened and held against diffused daylight or spread on black topped table to locate and identify prominently visible defects in yarn and fabric construction. The fabric shall be reasonably free from holes, slubs, snarls and naps as well as the following: - Odour.- Misty odour, or any objectionable smell like that of chemicals or materials used in sizing and bleaching.

Skewness.- (For Bandage Cloth only) A condition where warp and weft do not keep

at right angles to each other. Defective Selvedge. - The selvedge tearing and allowing yarn to unravel and loop formation at selvedge.

yarn due to loose widing. Measurement of length and width. Length is the distance from end to end, along one edge of the fabric, and width is the perpendicular distance from one edge to the opposite edge. Length. - Fix a meter scale to a table or mark off the division of one metre on a table edge. Starting from one end, spread the fabric flat on that table in a single layer keeping one

Drugs and Cosmetics Rules, 1945 355 selvedge parallel to the scale; smoothen the fabric without stretching it, to avoid creases, and mark off with a coloured pencil, on the selvedge exactly one metre. Shift the fabric and measure the same way the second metre and so on for the entire length of the fabric making a mark at each metre. Note down the total length in metres. Repeat this at the opposite selvedge, as well as on the fabric folded approximately about the middle. The average of the three readings is the length. For cut bandages, one measurement at the middle of the bandages by folding it length-wise will suffice.

Width. - Lay the portion of the fabric to be measured flat and smooth on the tables,

but do not stretch fabric except sufficiently to render it creaseless. At the place where mark had been made on the selvedge in measuring the length measure the perpendicular distance to the opposite selvedge with a metre scale. Note the width, repeat this at every mark made in measuring the length. The average of all the readings is the width of the fabric. For cut bandages, width shall be measured at every 50 cms., and average reported as width.

Threads per dm.- (For examples not less than 15 m. in length).

Weft. - At the third metre from one extreme locate three places one at about 5 cm. below the top selvedge, a second in the middle and third at about 5 cm. below the top selvedge, a second in the middle and third about 5 cm. above the bottom selvedge, all three in a vertical row. Take a rectangular plate (made of suitable material such as plastic or aluminium) with the rectangular opening of 5 cm. x 10 cm. cut in it. Keep the plate on the fabric horizontally so that the left 5 cm. side and bottom (10 cm. side) edges of the opening coincides with a weft and warp yarns within the opening for the length of 10 cm.. Repeat this at the other two selected places, and note down the average of three readings. Repeat this at every third metre in the sample and calculate the average weft per dm. Warp.- Keep the rectangular plate, this time vertically with left (10 cm. side) and bottom (5 cm. side) edge of opening coinciding with a weft and warp yarn respectively. Count the number of warp yarns within the opening for 10 cm. and note down. Repeat this for about 10 selected places in the samples taking care that the same set of warp yarns is not counted more than twice and calculate the average warp per dm. Magnifying glass mounted on stand may be used for counting. For samples less than 15 m. in length, locate as many different places as the dimension of the fabric permits, the total being not less than 10 for each sample and calculate the warp and weft per dm. as above. For cut bandages, all the warp threads in the samples are counted, taking care to leave 5 mm at the cut edge, and weft is counted at every 50 cm. at any place about the middle of the bandage. Weight per unit area. For samples not less than 15 m. in length, cut out pieces of fabric from the entire length of sample, representative places being taken from areas at every third or fourth metre so that the total area of all the pieces so collected is not less than 3 sq. metre. Weigh the pieces accurately, measure the dimension of each of the pieces and calculate the area and weight of all the pieces. From the average area and average of weight thus obtained, calculate

the area per sq. metre.

For samples less than 15 m. length, take pieces in such a manner that the total area of the selected pieces is not less than 20 per cent of the total area of the sample. For cut bandages, pieces of 50 cm. in length, cut from 5 different cut bandages in a packing should be taken and weight calculated as an average of 5 readings. Absorbency. - Take a glass trough of approximate size length 30 cm. x width 30 cm. x depth 25 cm. with straight thick walls and flat bottom. Fill it almost full with distilled water leaving only about 5 cm. from the top rim of trough. Maintain the water at 27 o C ± 1 o C.

Drugs and Cosmetics Rules, 1945 356 Cut out from any five places located equidistant down the length of the entire sample, square pieces, each weighting one gm. (±10 per cent). Fold each piece in such a manner that a square of approximately 5 cm. x 5 cm. is obtained. Keep one of the folded test specimen between two glass plates and place 1 kg weight on the top for 10 minutes. Remove the weight. Lift the specimen with forceps and gently place it on to the surface of water (the specimen should be lightly pinched in the middle with a blunt forceps having no serrations). As soon as the specimen touches the water surface start a stopwatch which is stopped when the entire sample disappears below the surface of the water. Record the time taken. Repeat the test with the other four-test specimens. Calculate the average time in seconds. Foreign Matter Dry about 5 g. of the sample to constant weight at 105 o C and weigh the dried sample accurately. Extract the dried sample with chloroform for one hour in an apparatus for the continuous extraction of drugs. Remove the extracted sample to a beaker and allow the evaporation of residual chloroform. Wash the material 12 times with hot water, using about 1000 ml. for each washing and wringing the material by hand after each washing; pass all water through a fine sieve (100 mesh). Place the washed material and any loose threads or fibres from sieve in a beaker, cover with a 0.5 per cent aqueous solution of diastase and maintain at 50 o C until free from starch. Allow to cool, filter the solution through a sieve; return sample and loose fibre to a beaker. Repeat the washing process as before with hot water. Dry the material to constant weight at 105 o C, and determine the loss in weight. Calculate the percentage of foreign matter, which is equal to the loss in weight, with reference to the sample dried to constant weight, at 105 o C. If the sample is tested with iodine and is known to be free from starch, the treatment with solution of diastase and the second series of washing with hot water may be omitted. Cloth for manufacture of Plaster of Paris Bandages, cut and uncut.

Synonyms.- Bleached Bandage Cloth for Plaster of Paris, Rolled Bandage for Plaster

of Paris. Cloth for Plaster of Paris Bandages shall consist of cotton cloth of leno weave made from yarn of suitable count. It may be supplied cut or uncut of various widths and lengths. Description

(a) For uncut bandages.- Cotton cloth of leno weave, in one continuous length showing no joints or seams, and with selvedges. The cloth is bleached to a good white, is clean and odourless and reasonably free from weaving defects as well as from seed and leaf debris; the cloth may be dressed if necessary and if so, shall not dust off when unrolled.
(b) For cut bandages. - Same as for uncut bandages except for selvedges which shall not be included and the bandages shall be cut evenly with straight edges and be reasonably free from loose threads. Threads per dm:

Warp. - Average not less than 150/dm; and Weft.- average not less than 75/dm.

Weight in gm/m : - 35 ± 5 Length and width: The length and width for uncut bandages shall not be less than 98 per cent each of the length and width stated. For cut bandages a tolerance of ±5 cm. in length and ±0.5 cm. in width may be allowed, and each of the bandages in packing complies with these requirements. Fluorescene When viewed under screened ultra-violet light not more than occasional points of fluorescence are observed.

Drugs and Cosmetics Rules, 1945 357 Packing, Labelling and Storage Bandage Cloth for Plaster of Paris shall be packed securely so as to allow normal handling and transport without tearing and exposing the contents. In packages of cut and rolled bandages, each bandage shall also individually be warpped in suitable paper. The package shall be labelled as “Cloth for Plaster of Paris Bandage”. The net content is stated on the label in terms of number of rolls and length and width. Bandage Cloth for Plaster of Paris must be stored in packed condition protected from dust.

Drugs and Cosmetics Rules, 1945 358

F (III)

(See rule 124-D) STANDARDS FOR UMBILICAL TAPES

(A) Standards for Sterilised Umbilical Polyster Tape. Description. - A uniform strand of Polyester yarn prepared by braiding and may be finished with a suitable silicone finishing material, white to yellowish-white in colour. Tape shall be sterilized by Gamma Radiation or other suitable method approved by the Licensing Authority. Other requirements. - The Umbilical Polyester Tape shall conform to the claims made on the label in respect of length and width. Tensile strength. - The Umbilical Polyester Tape shall have Tensile strength of not less than 4 kg. on straight pull. Packing and labelling. - The Umbilical Polyester Tape shall be packed in sealed Polythene bags or sealed plastic containers which ensure that when packed, the tape is sterile. The packing shall protect the tape from contamination and damage. Every packing offered for sale shall bear a clear and permanent marking with the following particulars: -
- (i) The proper name of the drug i.e. Umbilical Polyester Tape ‘Sterile’
- (ii) Manufacturer’s name and address.
- (iii) Batch number.
- (iv) Licence number under which the tape is manufactured.
- (v) Date of manufacture and date of expiry.
- (vi) Length and width of the Tape.

Storage condition. - It should be stored in a cool place protected from light.

(B) Standards for Sterilised Umbilical Cotton Tape– Description. - A uniform strand of cotton yarn prepared by braiding and may be finished with a suitable silicone finishing material, white to yellowish-white in colour. The tape shall be sterilized by Gamma Radiation or by any other suitable method approved by the Licesing Authority.

Other Requirement. - The Umbilical Cotton Tape shall conform to the claims made

on the label in respect of length and width. Tensile strength. - The Umbilical Cotton Tape shall have a Tensile strength of not less than 4 kg. on straight pull. Packing and labelling. - The Umbilical Cotton Tape shall be packed in sealed Polythene bags or sealed plastic containers which ensure that when packed the tape is sterile. The packing shall protect the tape from contamination and damage. Every packing offered for sale shall bear a clear and permanent marking with the following particulars:-

(i) The proper name of drug i.e. Umbilical Cotton Tape “Sterile”.
(ii) Manufacturer’s name and address. ______________________________________________________________ Drugs and Cosmetics Rules, 1945 359
(iii) Batch number.
(iv) Licence number under which the tape is manufactured.
(v) Date of manufacture and the date of expiry.
(vi) Length and width of the Tape.

¹ Ins. by G.S.R. No.1115(E), dt.. 30-9-1986.

Storage condition.- It should be stored in a cool place protected from light.]

Drugs and Cosmetics Rules, 1945 360

FF

( See rule 126-A) Standards for ophthalmic preparations. Part-A. Ophthalmic Solutions and suspensions. Ophthalmic Solutions and Suspensions shall-

(a) be sterile when dispensed or when sold in the unopened container of the manufacturer, except in case of those ophthalmic solutions and suspensions which are not specifically required to comply with the test for ‘Sterility’ in the Pharmacopoeia;
(b) contain one or more of the following suitable substances to prevent the growth of micro-organisms:-
- (i) Benzalkonium Chloride, 0.01 per cent (This should not be used in solutions of nitrates or salicylates).
- (ii) Phenyl mercuric nitrate, 0.001 per cent.
- (iii) Chlorbutanol 0.5 per cent.
- (iv) Phenyl ethyl alcohol 0.5 per cent. Provided that solutions used in surgery shall not have any preservative and be packed in single dose container.

Provided further that the Licensing Authority may in his discretion authorise the use

of any other preservative or vary the concentration prescribed on being satisfied that its use affords equal guarantee for preventing the growth of micro-organisms:-

(c) be free from foreign matter;
(d) be contained in bottles made of either neutral glass or soda glass specially treated to reduce the amount of alkali released when in contact of aqueous liquids, or in suitable plastic containers which would not in any way be incompatible with the solutions; The droppers to be supplied with the containers of ophthalmic solutions and suspensions shall be made of neutral glass or of suitable plastic material and when supplied separately shall be packed in sterile cellophane, or other suitable packings; (e ) In addition to complying with the provisions of labelling laid down in the rules the following particulars shall also be shown on the label:-

(1) of the containers
- (i) The statement ‘Use the solution within one month after opening the container’.
- (ii) Name and concentration of the preservative, if used.
- (iii) The words ‘N OT FOR INJECTION’. _________________________________________________________________ 1. Amended by Ministry of Health, F.P., W.H. and U.D. Notification No. F-1-13/69-D , dt.. 3-1-1970.
(2) of container or carton or package leaflet Drugs and Cosmetics Rules, 1945 361
- (i) Special instructions regarding storage, wherever applicable.
- (ii) A cautionary legend reading as “WARNING
- (i) if irritation persists or increases, discontinue the use and consult the phycian.
- (ii) Do not touch the dropper tip or other dispensing tip to any surface since this may contaminate solutions”.

Part B: Ophthalmic Ointments

Ophthalmic Ointments shall-

(a) be sterile when dispensed or when sold in the unopened container of the manufacturer;
(b) be free from foreign matter;
(c) in addition to complying with the provisions for labelling laid down in the rules the following particulars shall be shown on the container or carton or package leaflet-
- (i) Special instructions regarding storage wherever applicable;
- (ii) A cautionary legend reading “Warning :- If irritation persists or increases discontinue the use and consult Physicians”]. Drugs and Cosmetics Rules, 1945 362

G]

(See Rule 97) Aminopterin L-Asparaginase Bleomycin Busulphan; its salts Carbutamide Chlorambucil;its salts Chlorothiazide and other derivatives of 1, 2, 4 benzothiadiazine Chlorpropamide; its salts Chlorthalidone and other derivatives of Chlorobenzene compound.

2[(Cis-Platin)] Cyclophosphamide; its salts

2[(Cytarabine)] Daunorubicin Di-Isopropyl Eluorophosphate Disodium Stilboestrol Diphosphate Doxorubicin Hydrochloride Ethacrynic Acid, its salts Ethosuximide Glibenclamide Hydantoin; its salts; its derivatives, their salts Hydroxyurea Insulin, all types

2[(Lomustine Hydrochloride)] Mannomustine; its salts Mercaptopurine; its salts Metformin; its salts Methsuximide Mustine, its salts Paramethadione Phenacemide Phenformin; its salts 5-Phenylhydantoin; its alkyl and aryl derivatives; its salts Primadone

2[(Procarpazine Hydrochloride]) __________________________________________________________

¹ Subs.. by G.S.R. No.462(E) , dt. 22-6-1982 (w.e.f. 22.6.1982).

² Ins. by G.S.R. No.626(E) , dt. 2-7-1987 w.e.f. 2-7-1987.

Drugs and Cosmetics Rules, 1945 363 Quinthazone Sarcolysine

1[(Sodium-2-Mercaptoethanesulfonate Tamoxiten Citrate)] Testolactone Thiotepa Tolbutamide Tretamine; its salts Troxidone Antihistaminic substances the following, their salts, their derivatives, salts of their derivatives Antazoline Bromodiphenhydramine Buclizine Chlorcyclizine Chlorpheniramine Clemizole Cyproheptadine Diphenhydramine Diphenylpyraline Doxylamine Succinate Isothipendyl Mebhydrolin Napadisylate Meclozine Phenindamine Pheniramine Promethazine Thenalidine Triprolidine Substances being tetra-N-Subs. derivatives of Ethylene Diamine or Prophylenediamine.

Note . – Preparations containing the above substances excluding those intended for topical or external use are also covered by this Schedule.]

¹ Ins. by G.S.R. No.626(E) , dt. 2-7-1987 (w.e.f. 2-7-1987).

___________________________________________________________________

Drugs and Cosmetics Rules, 1945 364

H

(See Rules 65 and 97)

PRESCRIPTION DRUGS

Acebutolol Hydrochloride Aclarubicin Inj Actilyse Acyclovir Adrenocorticotrophic hormone (ACTH) Alclometasone Dipropionate Allopurinol Alphachymotrypsin Alprazolam Amantadine Hydrochloride Amikacin Amineptine Amiloride Hydrochloride Aminoglutethimide Tab. Aminosalicylic Acid Amiodarone Hydrochloride Amitriptyline, its salts Amoscanate Amoxapine_ Amrinone Lactate Analgin Androgenic, Anabolic, Oestrogenic and Progestational Substances Antibiotics Aprotinin Organic Compound of Arsenic for inj. Articaine Hydrochloride Astemizole Atenolol Atracurium Besylate Injection Auranofin Azathioprine Bacampicillin Barbituric acid, its salts, derivative of Barbituric acid, their salts Benserazide Hydrochloride Betahistine Dihydrochloride Bethanidine Sulphate Bezafibrate Biclotymol Biperiden Hydrochloride Bitoscanate Bleomycin Oil Suspension Bromhexine Hydrochloride _________________________________________________________________________

¹ Subs. by G.S.R. No.282(E), dated 16.7.1996 .

Drugs and Cosmetics Rules, 1945 365

Bromocriptine Mesylate Budesonide Bupivacaine Hydrochloride Buprenorphine Hydrochloride Buspirone Captopril Carbidopa Carbocisteine Carboplatin Injection Carboquone Carisoprodol L. Carnitine Cefadroxyl Cefatoxime Sodium Cefazolin Sodium Ceftazidime Pentahydrate Ceftizoxime Sodium Sterile Cefuroxime Cefuroxime Axetil Centbutindole Centchroman Chlordiazepoxide, its salts Chlormezanone Chlorpromazine, its salts Chlorzoxazone Ciclopirox Olamine Cimetidine Cinnarizine Ciprofloxacin HCL Monohydrate/lactate Clavulanic Acid Clindamycin Clidinium Bromide Clobetasol Propionate Clobetasone 17-Butyrate Clofazimine Clofibrate Clonidine Hydrochloride Clopamide Clostebol Acetate Clotrimazole Codeine, its salts and derivatives Colchicine Corticosteroids, their esters, their derivatives and their dosage forms Cotrimoxazole Cyclandelate Cyclosporin Oral Solution Danazol Dapsone, its salts and derivatives Desogestrol Dextranomer

Drugs and Cosmetics Rules, 1945 366 Dextropropoxyphene, its salts Diazepam Diazoxide Diclofenac Sodium Digoxine Dilazep Hydrochloride Diltiazem Dinoprostone Diphenoxylate, its salts Disopyramide Domperidone Dopamine Hydrochloride Dothiepin Hydrochloride Doxapram Hydrochloride Doxepin Hydrochloride Econozole Enalapril Maleate Enfenamic Acid Epinephrine, its salts Epirubicine Inj. Ergot, alkaloids of, whether hydrogenated or not, their homologues, any salt of any substance falling within this item. Estradiol succinate Estramustine Phosphate Capsule Ethacridine Lactate Ethambutol Hydrochloride Ethamsylate Ethinyloestradiol Ethionamide Etomidate Etoposide Cap. & Inj. Famotidine Flavoxate Hydrochloride Flufenamic acid, its salts, its esters, their salts Flunarizine Hydrochloride Flupenthixol Fluphenazine Enanthate and Decanoate Flurazepam Flurbiprofen Flutamide Fluoxetine Hydrochloride Galanthamine Hydrobromide Gallamine, its salts, its quaternary compound Gemfibrozil Genodeoxycholic Acid Gliclazide Glucagon Glycopyrrolate Glydiazinamide Guanethidine Gugulipid

Drugs and Cosmetics Rules, 1945 367 Halogenated Hydroxyquinolines Haloperidol Heparin Hepatitis B. Vaccine Hyaluronidase Hydrocortisone 17-Butyrate Hydrotalcite Hydroxyzine, its salts Ibuprofen Imipramine, its salts Indapamide Indomethacin, its salts Insulin Human Interferon Alpha Inj. Intralipid (intravenous Fat Emulsion) Iohexol Sterile Solution Iopamidol Sterile Solution Iopromide Iron Preparation for parenteral use Isocarboxazid Isoflurane Isonicotinic acid hydrazine and other hydrazine derivatives of isonicotinic acid, their derivatives, their salts Isosorbide Dinitrate Isosorbide Mononitrate Isoxsurprine Ketamine Hydrochloride Ketoconazole Acetate Ketoprofen Labetalol Hydrochloride Levarterenol, its salts Levodopa Lidoflazine Lithium Carbonate Lofepramine Decanoate Loperamide Lorazepam Loxapine Mebendazole Mebeverine Hydrochloride Medroxy Progesterone Acetate Tablets Mefenamic Acid, its salts, its esters, their salts Megestrol Acetate Meglumine Iocarmate Melagenina Lotion Mephenesin, its esters Mephentermine Mesterolone Methicillin Sodium Methocarbamol Met-oclopramide

Drugs and Cosmetics Rules, 1945 368 Metoprolol tartarate Metrizamide Metronidazole Mexiletine Hydrochloride Mianserin Hydrochloride Miconazole Minocycline Minoxidil Mitoxantrone Hydrochloride Mometasone Furoate Morphazinamide Hydrochloride Narcotic Drugs listed in the Narcotic Drugs and Psychtropic Substances Act, 1985. Nadolol Nalidixic Acid Naproxen Natamycin Netilmicin Sulphate Nicergoline Nifedipine Nimustine Hydrochloride Nitrazepam Nitroglycerin Injection Norethisterone Enanthate Inj. Norfloxacin Ofloxacin Orphenadrine, its salts Orthoclone Sterile Oxazepam Oxazolidine, its salts Oxethazaine Hydrochloride Oxolinic Acid Oxprenolol Hydrochloride Oxyfedrine Oxymetazoline Oxyphenbutazone Oxytocin Ozothine Pancuronium Bromide Para amino benzene sulphonamide, its salts and derivatives. Para amino salicylic acid, its salts, its derivatives D-Penicillamine Pentazocine Pentoxiflylline Pepleomycin Inj. Phenelzine, its salts Phenothiazine, derivatives of and salts of its derivatives Phenobarbital Phenylbutazone, its salts Pimozide Pindolol Piracetam

Drugs and Cosmetics Rules, 1945 369 Piroxicam Pituitory gland, the active principles of, not otherwise specified in this Schedule and their salts Polidocanol Injection Polyestradiol Phosphate Inj. Praziquantel Prednimustine Tablets Prednisolone Stearoylglycolate Prenoxdiazin Hydrochloride Promazine Hydrochloride Propafenon Hydrochloride Propranolol Hydrochloride Protriptyline Hydrochloride Pyrazinamide Pyrvinium, its salts Quinidne Sulphate Ranitidine Rauwolfia alkaloids, their salts,derivatives of the alkaloids of rauwolfia, their salts Reproterol Hydrochloride Rosoxacin Salbutamol Sulphate Salicylazosulphapyridine Satranidazole Septopal Beads & Chains Serratio Peptidase Sisomicin Sulphate. Sodium Cromoglyate Sodium Hyaluronate Solution Sodium and Meglumie Iothalamates Sodium Valproate Sotalol Spectinomycin Hydrochloride Spironolactone Sucralfate Sulphadoxine Sulphamethoxine Sulphamethoxypyridazine Sulphaphenazole Sulprostone Inj. Teratolol Hydrochloride Terbutaline Sulphate Terfenadine Terizione Testosterone Undecoanoate Tiaprofenic Acid Timolol Maleate Tinazoline Tinidazole Thiacetazone Thiopropazate, its salts Tobramycin

Drugs and Cosmetics Rules, 1945 370 Tranylcypromine, its salts Trazodone Tretinoin Trifluperazine Trifluperidol Hydrochloride Trimetazidine Dihydrochloride Trimipramine Tripotassium Dicitrato Bismuthate Urokinase Vasopressin Vecuronium Bromide Inj. Verapamil Hydrochloride Xipamide Zidovudine Cap.

NOTE : 1. Preparations exempted under proviso to para 2 of Note to Schedule X shall also be covered by this Schedule.

1[2. Preparations containing the above substances excluding those intended for topical/or external use (except ophthalmic and ear/nose preparations containing antibiotics and /or steroids)

are also covered by this Schedule. The inclusion of a substance in this Schedule does not imply

or convey that the substance is exempted from the provisions of rule 122-A of the Drugs and Cosmetics Rules, 1945.]

¹ Subs. by G.S.R. 904(E), dt. 1.2.2000

_________________________________________________________________________

Drugs and Cosmetics Rules, 1945 371

(Omited)

J

(See rule 106)

Diseases and ailments (by whatever name described) which a drug may not purport to prevent or cure or make claims to prevent or cure.

8. Cancer and Benign tumour 9. Cataract 10. Change in colour of the hair and growth of new hair.

15. Diseases and disorders of uterus. 16. Epilepticfits and psychiatric disorders 17. Encephalitis 18. Fairness of the skin 19. Form, structure of breast 20. Gangrene 21. Genetic disorders 22. Glaucoma 23. Goitre 24. Hernia 25. High/low Blood Pressure 26. Hydrocele 27. Insanity 28. Increase in brain capacity and improvement of memory. 29. Improvement in height of children/adults. 30. Improvement in size and shape of the sexual organ and in duration of sexual performance 31. Improvement in the strength of the natural teeth. 32. Improvement in vision 33. Jaundice/Hepatitis/Liver disorders 34 Leukaemia 35. Leucoderma 36. Maintenance or improvement of the capacity of the human being for sexual pleasure. 37 Mental retardation, subnormalities and growth 38. Myocardial infarction 39. Obesity 40. Paralysis

¹ Omitted by G.S.R 462(E) , dt. 22.6.1982

² Subs. by G.S.R. 21(E) , dt. 11.1.1996.

___________________________________________________________________________________

Drugs and Cosmetics Rules, 1945 372 41. Parkinsonism 42. Piles and Fistulae 43. Power to rejuvinate 44. Premature ageing 45. Premature greying of hair 46. Rheumatic Heart Diseases 47. Sexual Impotence, Premature ejaculation and spermatorrhoea 48. Spondylitis 49. Stammering 50. Stones in gall-bladder, kidney, bladder 51. Vericose Vein. ]

373 Drugs and Cosmetics Rules, 1945

K

[See rule 123] __________________________________________________________________________

Class of Drugs Extent and Conditions of Exemption

__________________________________________________________________________

Drugs falling under clause (b)(i) of Section 3 of the Drugs and Cosmetics Act not intended for medicinal use.

All the provisions of Chapter IV of the Act and the Rules thereunder subject to the conditions that the

drug is not sold for medicinal use or for use in the

manufacture of medicines and that each container is labelled conspicuously with the words “NOT FOR MEDICINAL USE”.

• * *
• * * * * 2[2A Quinine and other antimalarial drugs. Persons selling the drug by retail under arrangements made by State Government for sale and distribution of the drugs will be exempted from the requirement to take out licences for retail sale under clause (c) of Section 18 of the Act.
• * *
• * * * * 3[5.
• * * Drugs supplied by a registered medical practitioner to his own patient or any drug specified in Schedule C supplied by a registered medical practitioner at the request of another such practitioner if it is specially prepared with reference to the condition and for the use of an individual patient provided the registered medical practitioner is not (a) keeping an open shop or (b) selling across the counter or (c) engaged in the importation, manufacture, distribution or sale of
• * * * *

All the provisions of Chapter IV of the Act and the

Rules made thereunder, subject to the following ditions: con

5[(1)The drugs shall be purchased only from a

dealer or a manufacturer licensed under these rules and records of such purchases showing the names and quantities of such drugs together with their batch numbers and the names and addresses of the manufacturers shall be maintained. Such records shall be open to inspection by an Inspector appointed under the Act, who may, if necessary, make enquiries about purchases of the drugs and may also take samples for test.

¹ Omitted by Government of India Notification No. F.1-56/47-D, dt. 16.1.1950).

___________________________________________________________________________ 2. Added by Notification No .F. I-2/47-D dt. 13-2-1950. 3. Amended by Notification No. F. I-22/59-D dt.. 9-4-1960.

4 Omitted by Notification No. F.I-6/62-D dt. 2-7-69.

5. Amended by Min. of Health & F.W. Notification No. X- 11013/3/76-D & MS, dt. 19-8-1978 .

Drugs and Cosmetics Rules, 1945

Class of Drugs Extent and Conditions of Exemptions

drugs in India to a degree which render him liable to the provisions of Chapter IV of the Act and the rules thereunder.

(2) In the case of medicine containing a substance specified in 1[Schedule G, H or X] the following additional conditions shall be complied with]:
- (a) the medicine shall be labelled with the name and address of the registered medical practitioner by whom it is supplied;
- (b) if the medicine is for external application, it shall be labelled with the words
  - • * * “For external use only” or if it is for internal use with the dose;
- (c) the name of the medicine or ingredients of the preparation and the quantities thereof, the dose prescribed, the name of the patient and the date of supply and the name of the person who gave the prescription shall be entered at the time of supply in register to be maintained for the purpose;
- (d) the entry in the register shall be given a number and that number shall be entered on the label of the container;
- (e) the register and the prescription, if any, on which the medicines are issued shall be preserved for not less than two years from the date of the last entry in the register or the date of the prescription, as the case may be. 3[(3)The drug will be stored under proper storage conditions as directed on the label.] 5A. Drugs supplied by a hospital or dispensary maintained or supported by Government or local body
  - • * * The provisions of Chapter IV of the Act and the Rules thereunder which require them to be covered by a sale licence, subject to the following conditions : _______________________________________________________________________ 2. Omitted G.S.R. 462(E) , dt. 22.6.1982. Drugs and Cosmetics Rules, 1945

¹ Subs. by G.S.R. 462(E) , dt. 22.6.1982.

³ Ins. G.S.R. 460(E) , dt. 22.6.1984.

⁴ Omitted G.S.R. 812(E) , dt. 14.11.1994.

Class of Drugs Extent and Conditions of Exemptions

(1) the dispensing and supply of drugs shall be carried out by or under the supervision of a 1[registered pharmacist];
(2) the premises where drugs are supplied or stocked shall be open to inspection by an Inspector appointed under the Drugs and Cosmetics Act who can, if necessary, take samples for test.
(3) the drugs shall be stored under the proper storage conditions. 2[(4) The drugs shall be purchased from a manufacturer or a dealer licensed under these rules or received as transferred stocks from hospital stores for distribution. Records of such purchases or receipts shall be maintained.] 3[5B. Whole Human Blood I.P. and/or its components stored for transfusion by a First Referral Unit Community Health Centre, Primary Health Centre and Hospital. The provisions of Chapter IV of the Act and the rules made thereunder which require obtaining of a licence for operation of a blood bank or processing Whole Human Blood and/or its components subject to the following conditions, namely:–
(1) The First Referral Unit, Community Health Centre, Primary Health Centre and/or any Hospital shall be approved by the State/Union Territory Licensing Authority after satisfying the conditions and facilities through inspection.
(2) The captive consumption of Whole Human Blood I.P or its components in the First Referral Unit, Community Health Centre, Primary Health Centre and/or any Hospital shall not be more than 2000 units annually.
(3) The Whole Human Blood and/or its components shall be procured only from Government Blood Bank and/or Indian Red Cross Society Blood Bank and/or Regional Blood Transfusion Centre duly licensed.
(4) The approval shall be valid for a period of two years from the date of issue unless sooner suspended or cancelled and First Referral Unit, Community Health Centre, Primary Healthy Centre or the Hospital shall apply for renewal to the State Licensing Authority three months prior to the date of expiry of the approval.
(5) The First Referral Unit, Community Health ________________________________________________________________________________________ Drugs and Cosmetics Rules, 1945

¹ Subs. by G.S.R. 676(E), dt. 6.9.1994.

² Ins. by G.S.R. 648(E), dated 16.9.2002 (w.e.f. 1.10.2002).

³ Ins. by G.S.R. 909(E), dated 20.12.2001.

Class of Drugs Extent and Conditions of Exemptions

Centre, Primary Health Centre and/or any Hospital shall have the following technical staff for storage of blood or its components:-

(a) A trained Medical Officer for proper procurement, storage and cross matching of blood and/or its components. He/she shall also be responsible for identifying haemolysed blood and ensure non-supply of date expired blood or its components.
(b) A blood bank Technician with the qualification and experience as specified in Part XII B of Schedule F or an experienced laboratory technician trained in blood grouping and cross matching.

(6) The First Referral Unit, Community Health Centre, Primary Health Centre and Hospital shall have an area of 10 sq metres. It shall be well lighted, clean and preferably air-conditioned. Blood bank refrigerator of appropriate capacity fitted with alarm device and temperature indicator with regular temperature monitoring shall be provided to store blood units between 2 o C to 8 o C and if the components are proposed to be stored, specialized equipments as specified in Part XII B of Schedule F shall also be provided.
(7) The First Referral Unit, Community Health Centre, Primary Health Centre and Hospital shall maintain records and registers including details of procurements of Whole Human Blood I.P and/or blood components, as required under Part XII B of Schedule F.
(8) The First Referral Unit, Community Health Centre, Primary Health Centre and Hospital shall store samples of donors blood as well as patients sera for a period of seven days after transfusion.]
- • * * * * * Drugs and Cosmetics Rules, 1945

Class of Drugs Extent and Conditions of Exemptions

(i) the colour of the drug may be pink, owing to its being coloured with an edible pink colouring matter;
(ii) the B.P tests for readily carbonisable substances produce a yellow colour of an intensity about four times the colour produced with quinine sulphate conforming to the B.P. standard;
(iii) other Cinchona alkaloids present shall not exceed six per cent; and
(iv) the residue on incineration shall not exceed 0.14 per cent.

1[9. Magnesium Sulphate The provisions of sub-clause (i) of clause (ii) of section

18 of the Act to the following extent: –

water.] water.] _______________________________________________________________________________________________________

1. Item 6 omitted by G.S.R. 681(E), dated 5.12.1980.

2[10.

as well as drugs:– All the provisions of Chapter IV of the Act and the Rules thereunder.

(i) all condensed or powdered milk whether pure skimmed or malted, fortified with vitamins and minerals or otherwise
(ii) Farex, Oats and all other similar cereal preparations whether fortified with vitamins or otherwise excepting those for parenteral use.
(iii) Virol, Bovril, Chicken essence and all other similar predigested foods.
(iv) Ginger, Pepper, Cumin. Cinnamon and all other similar spices and condiments unless they are specially labelled as conforming to the standards in the Indian Pharmacopoeia or the official pharmacopoeias and Drugs and Cosmetics Rules, 1945

Class of Drugs Extent and Conditions of Exemptions

official compendia of drug standards prescribed under the Act and rules made thereunder.

12. Substances intended to be used for destruction of vermin or insects, which

cause disease in human beings or animals viz. Insecticides and Disinfectants.

The provisions of Chapter IV of the Act and the Rules thereunder which require them to be covered

by a sale licence

1[subject to the conditions that

provisions of condition (17) of rule 65 of the Drugs and Cosmetics Rules, 1945 are complied with by the person stocking or selling such substances].

13.

2[The following household remedies,

namely:–

3[(1) Asprin Tablets.]

4[(2) Paracetamol Tablets.]

(3) Analgesic Balms.
(4) Antacid Preparations
(5) Gripe Water for use of infants.
(6) Inhalers, containing drugs for

treatment of cold and nasal

congestion.

The provision of Chapter IV of the Act and the Rules thereunder which require them to be covered with a sale licence in Form 20-A subject to the following conditions: -

(a) the drugs are sold only in a village having population of not more than one thousand persons and where there is no licenced dealer under the Drugs and Cosmetics Act;
(b) the drugs do not contain any substance specified in 5[Schedule G, H or X];

(7) Syrups, lozenges, pills and tablets for cough.
(8) Liniments for external use.
(9) Skin ointments and ointments for burns.
(10) Absorbent cotton wool, bandages, absorbent gauze and adhesive plaster.
(11) Castor Oil, liquid Paraffin and Epsom Salt.
(12) Eucalyptus Oil
(13) Tincture Iodine, Tincture Benzoin Co.and Mercurochrome solution in

containers not exceeding 100 ml.

(14) Tablets of Quinine Sulphate I.P.
(15) Tablets of Iodochlorohydroxy quinoline – 250 mg.]
- (c) the drugs are sold in the original unopened containers of the licensed manufacturers;
- (d) when the drugs are sold under clause (a) condition 3 under “Conditions of licence” of Form 20-B shall not apply. ___________________________________________________________________________ 1.. Added by Notification No.F.I-19/50-DS , dated 30.3.1953 2. .Added by. Notification No. DR/Sch. Ddk/F. I-40/54-DS , dated 27.1.1955. 3. Amended by Notification F. 1-20/60-D, dt.24.1.1964. Drugs and Cosmetics Rules, 1945

Class of Drugs Extent and Conditions of Exemptions

14. Mechanical Contraceptives

The provisions of Chapter IV of the Act and rules thereunder, which require them to be covered by a sale licence,

7[subject to the

condition that the provisions of condition (17) of rule 65 of the Drugs and Cosmetics Rules, 1945 are complied with by the person stocking or selling mechanical contraceptives.]

1[14A. Vaginal contraceptive pessaries

containing Nonoxynol.

The provisions of Chapter IV of the Act and the rules made thereunder which require them to be covered by a sale licence subject to the condition that the

provisions of clause (17) of rule 65 of the Drugs and

Cosmetics Rules, 1945 are complied with by the person stocking or selling this contraceptive.]

2[15. Chemical contraceptive having the following composition per tablet:-

(2) Levonorgestrel – 0.15 mg.

Ethinylestraditol – 0.3 mg.

(3) Centchroman – 30 mg.

3[(4) Desogestrel -- 0.150 mg.

Ethinyloestradiol – 0.030 mg

(5) Levonorgestrel -- 0.1 mg.

Ethinyloestradiol -0.02 mg.]

The provisions of Chapter IV of the Act and the rules made thereunder which required them to be covered with a sale licence.]

4[16 Cosmetics.

The provisions of Chapter IV of the Act and the Rules made thereunder, which require them to be covered by a licence for sale provided that the cosmetics sold, if of Indian origin, are manufactured by licensed manufacturers.]

5[17. Ophthalmic ointments of the Tetracycline group of drugs.

• * * * Persons authorised by the Government to distribute or sell the drugs under the National Trachoma Control Programme shall be exempted from the provisions of Chapter IV of the Act and the rules made thereunder, which require the drugs to be covered by a sale licence.
• * * * 7[19 Hair Fixers, namely mucilagenous preparations containing gums, used by men for fixing beard. The provisions of Chapter IV of the Act and the rules thereunder.] ____________________________________________________________________

² Ins. by Notifn No. F.1-19/59/D, , dated 13.6.1961.

⁴ Subs. by Notifn No. 1060(E) , dated 5.9.1986.

⁵ Subs. by G.S.R. 462(E), dated 22.6.1988.

⁶ Ins. by Notifn No. F. 1-39/61-D, dated 23.3.1964.

⁷ Subs. by G.S.R. 926, dated 16.7.1977.

Drugs and Cosmetics Rules, 1945

Class of Drugs Extent and Conditions of Exemptions

¹ Ins. by G.S.R. 784(E) , dt. 28.8.1989.

_______________________________________________________________________________

³ Ins. by G.S.R. 648(E) , dt. 16.9.2002.

⁴ Ins. by Notification No. 1-36/64-D , dt. 17.8.1964.

⁵ Ins. by . Notification No. I-21/63-D , dt. 4.1.1965.

⁶ Omitted by Notification No. G.S.R. 1594 , dt. 13.11.1976.]

⁷ Ins. by Notification No. S.O.2139 , dt. 12.8.1971.

2 . Subs. by G.S.R. 730 (E) , dt. 10.12.1991 and corrected by G.S.R. 305(E) , dt. 4.3.1992.

1[20 Radio Pharmaceuticals.

All the provisions of Chapter IV of the Act and the rules made hereunder.]

2[21 Tablets of Chloroquine Salts.

The provisions of Chapter IV of the Act and the Rules thereunder, which require them to be covered by a sale licence, provided the drug in strip pack is sold under the Commercial Distribution Scheme of the National Malaria Eradication Programme and duly labelled as “National Malaria Eradication Programme–Ministry of Health and Family Welfare, Government of India.”]

3[22 Sales from restaurant cars of trains and from coastal ships of household remedies, which do not require the supervision of a registered pharmacist for their sale.

The provisions of Chapter IV of the Act and the rules thereunder which require them to be covered with a sale licence, subject to the following conditions, namely:-

(a) the records of purchase and sale of drugs shall be maintained by the person in charge of sale of such drugs, which shall be available for inspection by an Inspector appointed under the Act;
(b) the place where such drugs are stocked shall be open to inspection by an Inspector appointed under the Act who can, if necessary, take samples for test.] 4[23. Drugs supplied by : (i) Multipurpose Workers attached to Primary Health Centres/Sub-Centres, (ii) Community Health Volunteers under the Rural Health Scheme *** (iii) Nurses, Auxiliary Nurse, Midwives and Lady Health Visitors attached to Urban Family Welfare Cenres/Primary Health Centres/Sub-Centres and 6[(iv) Anganwadi Workers.] The provisions of Chapter IV of the Act and the Rules thereunder which require them to be covered by a sale licence, provided the drugs are supplied under the Health or Family Welfare Programme of the Central or State Government.] Drugs and Cosmetics Rules, 1945

Class of Drugs Extent and Conditions of Exemptions

¹ Ins. by. G.S.R. 926 , dt. 16.7.1977.

² Ins. by. G.S.R. 697(E) , dt. 11.11.1977.

³ Ins. by G.S.R. 1241(E) , dt. 15.9.1979.

⁴ Ins. by. G.S.R. 540(E) , dt. 22.9.1980

⁵ Omitted by. G.S.R. 784 (E) , dt. 28.8.1989

______________________________________________________________________________________ 6. Added by G.S.R. 784, dt. 28.8.1989.

1[24.

Homoeopathic medicines supplied by a registered Homoeopathic medical practitioner to his own patient or Homoeopathic medicines supplied by a registered Homoeopathic medical practitioner at the request of another such practitioner provided the registered Homoeopathic medical practitioner is not (a) keeping an open shop, or (b) selling across the counter or, (c) engaged in the importation, manufacture, distribution or sale of Homoeopathic medicines in India to a degree which renders him liable to the provisions of Chapter IV of the Act and the rules made thereunder.

All the provisions of Chapter IV of the Act and the rules made thereunder subject to the following conditions:-

(1) The Homoeopathic medicines shall be purchased only from a dealer or a manufacturer licensed under the Drugs and Cosmetics Rules 1945.
(2) The premises where the Homoeopathic medicines are stocked shall be open to inspection by an Inspector appointed under the Act, who may, if necessary, “take samples for test”.] 2[25. Preparations applied to human body for the purpose repelling insects like mosquitoes. The provisions of Chapter IV of the Act and Rules thereunder which require them to be covered by a sale licence subject to conditions that such a product has been manufactured under a valid drug manufacturing licence. 26. 3[Medicated Dressings and Bandages for First Aid.] The provisions of Chapter IV of the Act and rules thereunder which require them to be covered by a sale licence subject to the conditions that such a product has been manufactured under a valid drug manufacturing licence.] 4[27 Oral Rehydration Salts (Manufactured as per the following formula) : Sodium chloride 3.5 g/litre.
- • Trisodium citrate dihydrate 2.9 g/litre. Potassium Chloride 1.5 g/litre *May be replaced by Sodium bicarbonate (Sodium hydrogen Carbonate) 2.5 g/litre, The provisions of Chapter IV of the Act and rules thereunder which require them to be covered by a sale licence, subject to the conditions that such a product has been manufactured under a valid drug manufacturing licence.] Drugs and Cosmetics Rules, 1945

Class of Drugs Extent and Conditions of Exemptions

when citrate salt is not available.

________________________________________________________________________________________ 1.

² Ins. by. G.S.R. 1060(E) , dt. 5.9.1986.

³ Subs. by. G.S.R. 371(E) , dt. 24.3.1988.

⁴ Ins. by. G.S.R. 677(E) , dt. 2.6.1988.

Ins. by G.S.R. 680(E) , dt. 5.12.1980.

1[28

White or Yellow Petroleum Jelly I.P. (Non-perfumed).

The provisions of Chapter IV of the Act and the rules made thereunder which require them to be covered by a sale licence, subject to the condition that such a product has been manufactured under a valid drug manufacturing licence.]

2[29 Morphine Tablets

The provisions of Chapter IV of the Act and the rules made thereunder which require them to be covered by a sale licence, subject to the following conditions, namely:-

(i) The drug shall be supplied by the Palliative Care Centres approved by the State Government to terminally-ill cancer patients.
(ii) The drug shall be kept under the custody of the Medical Officer in-charge of the said centre.
(iii) The drug shall be purchased from a dealer or a manufacturer who holds licence under these rules, and records of such purchases showing the names and quantities together with their batch numbers, and names and addresses of the manufacturers or dealers and the names and addresses of the patients to whom supplies have been made shall be maintained. Such records shall be open to inspection by an Inspector appointed under the Act, who may also take samples for test. 30 Whole Human Blood collected and transfused by Centres run by Armed Forces Medical Services in border areas, small mid-zonal hospitals including peripheral hospitals, Field Ambulances, Mobile medical units and other field medical units including blood supply units in border, sensitive and field areas. All the provisions of Chapter IV of the Act and rules made thereunder which require them to be covered by a licence to operate a Blood Bank for collection, storage and processing of whole human blood for sale or distribution subject to the following conditions-
(i) These Centres shall collect, process and transfuse blood in emergent situations which require life saving emergency surgeries/or transfusion.
(ii) These Centres shall be under the active direction and personal supervision of a qualified Drugs and Cosmetics Rules, 1945

Class of Drugs Extent and Conditions of Exemptions

Medical Officer, possessing the qualifications and experiences specified in condition (i) of rule 122-G.

(iii) Each blood unit shall be tested before for freedom from HIV I and II antibodies, Hepatitis B surface antigen, malarial parasites and other tests specified under the monograph “Whole Human Blood” in current edition of Indian Pharmacopoeia. ________________________________________________________________________________________
(iv) These Centres shall have adequate infrastructure facilities for storage and transportation of blood.
(v) The blood collected and tested by such Centres shall be transfused by the Centre itself and may be made available for use of other peripheral Armed Forces hospitals or centers during operational circumstances.] 1[31. The following Homoeo- pathic Medicines, namely:-

¹ Ins. by G.S.R. 753(E) , dt. 4.11.1999.

² Ins. by. G.S.R. 6(E) , dt. 4.1.2001

(a) Arnica Montana Hair Oil
(b) Homeopathic ointments, each in 15 gm. Tube: The provisions of Chapter IV of the Act and the Rules made thereunder which require them to be covered with a sale licence in form 20-C subject to the following conditions:-
- (i) Arnica Montana
- (ii) Calendula Officinalis
- (iii) Cantharis
- (i) These homoeopathic medicines shall be sold in the original sealed small quantity packings of the licensed manufacturers.
- (iv) Rhus Toxicodendron
- (ii) These medicines may be stocked and sold by retail dealers of medicines licensed under Rule 61.
(c) Biochemic tissue remedies in tablets forms, in generic names only, each in 20 gm. Packing in 3x and 6x trituration :
- (iii) These medicines shall be stored separately from other allopathic drugs.
- (iv) These medicines shall be purchased from a manufacturer or a dealer licensed under these Rules.
- (i) Calcarea Phosphorical
- (ii) Calcarea Sulphurica
- (iii) Ferum Phosphoricum
- (iv) Kali Muriaticum
- (v) Kali Phosphoricum Drugs and Cosmetics Rules, 1945

Class of Drugs Extent and Conditions of Exemptions

___________________________________________________________________________________

1 Ins. by . Notification No. G.S.R. 218(E) , dt. 28.3.2001.

(vi) Kali Sulphuricum (vii)Magnesium Phosphoricum
(v) The purchase and sale records of these medicines shall be maintained by the dealer for a minimum period of three years.
(vi) These medicines shall be labelled in generic/pharmacopoeial names only.]
(viii) Megnesia Sulphurica
(ix) Natrum Muriaticum
(x) Natrum Phosphoricum
(xi) Natrum Sulphuricum
(xii) Silicea (d) Homoeopathic medicines, mentioned below, in pills, each in 30 C potency, in sealed original packing of manufacturer of 8 gms:–
(i) Arnica Montana
(ii) Aconitum Napellus
(iii) Arsenicum Album
(iv) Aloe Socotrina
(v) Apis Mellifica
(vi) Allium Cepa
(vii) Bryonia alba
(viii) Borax
(ix) Belladonna
(x) Cantharis
(xi) Carbo Vegetabilis
(xii) Cina
(xiii) Colocynthis
(xiv) Calendula Officinalis
(xv) Caulophyllum Thalictroides
(xvi) Cocculus Indicus
(xvii) Drosera Rotundifolia
(xix) Hypericum Perforatum
(xx) Hepar Sulphur

(xxi) Ipecacuanha
(xxii) Ledum Palustre (xxiii) Millefolium
(xxiv) Mercurius Solubillis
(xxv) Nux Vomica
(xxvi) Pulsatilla Nigricans (xxvii) Podophyllum Peltatum Drugs and Cosmetics Rules, 1945

Class of Drugs Extent and Conditions of Exemptions

(xxviii) Plantago Major

(xxix) Rhus Toxicodendron
(xxx) Ruta Graveolens
(xxxi) Symphytum Officinalis (xxxii) Veratrum Album 1[32. 2[33. First Aid Kit supplied along wit h motor vehicle by the manufacturer or its distributor at the time of first sale of vehicle. Nicotine gum containing up to 2 mg. of nicotine. The provisions of Chapter IV of the Act and rules made thereunder which require them to be covered by a sale licence, subject to the condition that the drug items are procured from a manufacturer or dealer licensed under the rules.] The provisions of Chapter IV of the Act and the rules made thereunder which require them to covered by a sale licence subject to the condition that such a product has been manufactured under a valid drug manufacturing licence.] __________________________________________________________________ _____________________________________________________________________ 1 Ins. by G.S.R. 648 (E) , dt. 16.9.2002. 2 Ins. by G.S.R. 549(E), dt. 16.67.2005. Drugs and Cosmetics Rules, 1945 386

(Omitted)

GOOD MANUFACTURING PRACTICES AND REQUIREMENTS OF PREMISES,

PLANT AND EQUIPMENT FOR PHARMACEUTICAL PRODUCTS

Note: To achieve the objectives listed below, each licensee shall evolve appropriate methodology, systems and procedures which shall be documented and maintained for inspection and reference; and the manufacturing premises shall be used exclusively for production of drugs

3[and no other manufacturing activity shall be undertaken therein except

in respect of units licensed prior to 11th December, 2001].

PART 1

GOOD MANUFACTURING PRACTICES FOR PREMISES AND MATERIALS

1 GENERAL REQUIREMENTS:

1.1. Location and surroundings.- The factory building(s) for manufacture of drugs shall be so situated and shall have such measures as to avoid risk of contamination from external environment including open sewage, drain, public lavatory or any factory which produce disagreeable or obnoxious odour or fumes, excessive soot, dust, smoke, chemical or biological emissions.

1.2. Buildings and premises.- The building(s) used for the factory shall be designed, constructed, adapted and maintained to suit the manufacturing operations so as to permit production of drugs under hygienic conditions. They shall conform to the conditions laid down in the Factories Act, 1948 (63 of 1948).

The premises used for manufacturing, processing, warehousing, packaging, labelling and testing purposes shall be –

(i) compatible with other drug manufacturing operations that may be carried out in the same or adjacent area / section;
(ii) adequately provided with working space to allow orderly and logical placement of equipment, materials and movement of personnel so as to:

(a) avoid the risk of mix-up between different categories of drugs or with raw materials, intermediates and in-process material;
(b) avoid the possibilities of contamination and cross- contamination by providing suitable mechanism;
- (iii) designed / constructed / maintained to prevent entry of insects, pests, birds, vermins and rodents. Interior surface (walls, floors and ceilings) shall be smooth and free from cracks, and permit easy cleaning, painting and disinfection; _________________________________________________________________________ period up to 31.12.2003. Drugs and Cosmetics Rules, 1945 387
- (iv) air-conditioned, where prescribed for the operations and dosage forms under production. The production and dispensing areas shall be well lighted, effectively ventilated, with air control facilities and may have proper Air Handling Units (wherever applicable) to maintain conditions including temperature and, wherever necessary, humidity, as defined for the relevant product. These conditions shall be appropriate to the category of drugs and nature of the operation. These shall also be suitable to the comforts of the personnel working with protective clothing, products handled, operations undertaken within them in relation to the external environment. These areas shall be regularly monitored for compliance with required specifications;
- (v) provided with drainage system, as specified for the various categories of

¹ Omitted by G.S.R.462(E) , dt. 22.06.1982.

² Ins. by G.S.R. 894(E) , dt. 11.12.2001.- applicable to manufacturers licensed to manufacture drugs, for the

³ Subs. by Act 431(E), dt. 30.6.2005.

products, which shall be of adequate size and so designed as to prevent back-

flow and/or prevent insects and rodents entering the premises. Open channels shall be avoided in manufacturing areas and, where provided, these shall be shallow to facilitate cleaning and disinfection;

(vi) the walls and floors of the areas where manufacture of drugs is carried out shall be free from cracks and open joints to avoid accumulation of dust. These shall be smooth, washable, coved and shall permit easy and effective cleaning and disinfection. The interior surfaces shall not shed particles. A periodical record of cleaning and painting of the premises shall be maintained. 1.3 Water System. - There shall be validt. system for treatment of water drawn from own or any other source to render it potable in accordance with standards specified by the Bureau of Indian Standards or Local Municipality, as the case may be, so as to produce Purified Water conforming to Pharmacopoeial specification. Purified Water so produced shall only be used for all the operations except washing and cleaning operations where potable

water may be used. Water shall be stored in tanks, which do not adversely affect quality of

water and ensure freedom from microbiological growth. The tank shall be cleaned periodically and records maintained by the licensee in this behalf.

1.4. Disposal of waste. -

(i) The disposal of sewage and effluents (solid, liquid and gas) from the manufactory shall be in conformity with the requirements of Environment Pollution Control Board.
(ii) All bio-medical waste shall be destroyed as per the provisions of the Bio- Medical Waste (Management and Handling) Rules, 1996.
(iii) Additional precautions shall be taken for the storage and disposal of rejected drugs. Records shall be maintained for all disposal of waste.
(iv) Provisions shall be made for the proper and safe storage of waste materials awaiting disposal. Hazardous, toxic substances and flammable materials shall be stored in suitably designed and segregated, enclosed areas in conformity with Central and State Legislations.

2. Warehousing Area:

2.1 Adequate areas shall be designed to allow sufficient and orderly warehousing of various categories of materials and products like starting and packaging materials, intermediates, bulk and finished products, products in quarantine, released, rejected, returned or recalled, machine and equipment spare parts and change items.

Drugs and Cosmetics Rules, 1945 388

2.2 Warehousing areas shall be designed and adapted to ensure good storage

conditions. They shall be clean, dry and maintained with acceptable temperature limits. Where special storage conditions are required (e.g. temperature, humidity), these shall be provided, monitored and recorded. Storage areas shall have appropriate house-keeping and rodent, pests and vermin control procedures and records maintained. Proper racks, bins and platforms shall be provided for the storage of materials.

2.3 Receiving and dispatch bays shall protect materials and products from adverse weather conditions.

2.4. Where quarantine status is ensured by warehousing in separate earmarked areas in the same warehouse or store, these areas shall be clearly demarcated. Any system replacing the physical quarantine, shall give equivalent assurance of segregation. Access to these areas shall be restricted to authorized persons.

2.5. There shall be a separate sampling area in the warehousing area for active raw materials and excipients. If sampling is performed in any other area, it shall be conducted in such a way as to prevent contamination, cross-contamination and mix-up.

2.6. Segregation shall be provided for the storage of rejected, recalled or returned materials or products. Such areas, materials or products shall be suitably marked and secured. Access to these areas and materials shall be restricted.

2.7. Highly hazardous, poisonous and explosive materials such as narcotics, psychotropic drugs and substances presenting potential risks of abuse, fire or explosion shall be stored in safe and secure areas. Adequate fire protection measures shall be provided in conformity with the rules of the concerned civic authority.

2.8. Printed packaging materials shall be stored in safe, separate and secure areas.

2.9. Separate dispensing areas for β (Beta) lactum, Sex Hormones and

Cytotoxic substances or any such special categories of product shall be provided with proper supply of filtered air and suitable measures for dust control to avoid contamination. Such areas shall be under differential pressure.

2.10. Sampling and dispensing of sterile materials shall be conducted under aseptic conditions conforming to Grade A, which can also be performed in a dedicated area within the manufacturing facility.

2.11. Regular checks shall be made to ensure adequate steps are taken against

spillage, breakage and leakage of containers.

2.12. Rodent treatments (Pest control) should be done regularly and at least once in a year and record maintained.

3. Production area:

3.1. The production area shall be designed to allow the production preferably in uni-flow and with logical sequence of operations.

3.2. In order to avoid the risk of corss-contamination, separate dedicated and self- contained facilities shall be made available for the production of sensitive pharmaceutical products like penicillin or biological preparations with live micro-organisms. Separate

Drugs and Cosmetics Rules, 1945 389 dedicated facilities shall be provided for the manufacture of contamination causing and potent products such as Beta-Lactum, Sex Hormones and Cytotoxic substances.

3.3. Working and in-process space shall be adequate to permit orderly and logical positioning of equipment and materials and movement of personnel to avoid cross- contamination and to minimize risk of omission or wrong application of any manufacturing and control measures.

3.4. Pipe-work, electrical fittings, ventilation openings and similar service lines shall be designed, fixed and constructed to avoid

1[accumulation of dust]. Service lines shall preferably be identified by colours and the nature of the supply and direction of the flow shall be marked/indicated.

4. Ancillary Areas:

4.1 Rest and refreshment rooms shall be separate from other areas. These areas shall not lead directly to the manufacturing and storage areas.

4.2 Facilities for changing, storing clothes and for washing and toilet purposes shall be easily accessible and adequate for the number of users. Toilets, separate for males and females, shall not be directly connected with production or storage areas. There shall be written instructions for cleaning and disinfection of such areas.

4.3 Maintenance workshops shall be separate and away from production areas. Whenever spares, changed parts and tools are stored in the production area, these shall be kept in dedicated rooms or lockers. Tools and spare parts for use in sterile areas shall be disinfected before these are carried inside the production areas.

4.4. Areas housing animals shall be isolated from other areas. The other requirements regarding animal houses shall be those as prescribed in rule 150-C(3) of the Drugs and Cosmetics Rules, 1945 which shall be adopted for production purposes.

5. Quality Control Area.

5.1. Quality Control Laboratories shall be independent of the production areas. Separate areas shall be provided each for physico-chemical, biological, microbiological or radio-isotope analysis. Separate instrument room with adequate area shall be provided for sensitive and sophisticated instruments employed for analysis.

5.2 Quality Control Laboratories shall be designed appropriately for the operations to be carried out in them. Adequate space shall be provided to avoid mix-ups and cross-contamination. Sufficient and suitable storage space shall be provided for test samples, retained samples, reference standards, reagents and records.

5.3. The design of the laboratory shall take into account the suitability of construction materials and ventilation. Separate air handling units and other requirements shall be provided for biological, microbiological and radioisotopes testing areas. The laboratory shall be provided with regular supply of water of appropriate quality for cleaning and testing purposes.

¹ Subs. by G.S.R. 431(E), dt. 30.6.2005.

5.4. Quality Control Laboratory shall be divided into separate sections i.e. for chemical, microbiological and wherever required, biological testing. These shall have adequate area for basic installation and for ancillary purposes. The microbiology section shall have arrangements such as airlocks and laminar air flow work station, wherever considered necessary. ___________________________________________________________________________

Drugs and Cosmetics Rules, 1945 390 6. Personnel:

6.1. The manufacture shall be conducted under the direct supervision of competent technical staff with prescribed qualifications and practical experience in the relevant dosage form and / or active pharmaceutical products.

6.2 The head of the Quality Control Laboratory shall be independent of the manufacturing unit. The testing shall be conducted under the direct supervision of competent technical staff who shall be whole time employees of the licensee.

6.3. Personnel for Quality Assurance and Quality Control operations shall be suitably qualified and experienced.

6.4. Written duties of technical and Quality Control personnel shall be laid and followed strictly.

6.5. Number of personnel employed shall be adequate and in direct proportion to the workload.

6.6. The licensee shall ensure in accordance with a written instruction that all personnel in production area or into Quality Control Laboratories shall receive training appropriate to the duties and responsibility assigned to them. They shall be provided with regular in-service training.

7. Health, clothing and sanitation of workers:

7.1 The personnel handling Beta-lactum antibiotics shall be tested for Penicillin sensitivity before employment and those handling sex hormones, cytotoxic substances and other potent drugs shall be periodically examined for adverse effects. These personnel should be moved out of these sections (except in dedicated facilities), by rotation, as a health safeguard.

7.2 Prior to employment, all personnel, shall undergo medical examination including eye examination, and shall be free from Tuberculosis, skin and other communicable or contagious diseases. Thereafter, they should be medically examined periodically, at least once a year. Records shall be maintained thereof. The licensee shall provide the services of a qualified physician for assessing the health status of personnel involved in different activities.

7.3 All persons prior to and during employment shall be trained in practices which ensure personnel hygiene. A high level of personal hygiene shall be observed by all those engaged in the manufacturing processes. Instructions to this effect shall be displayed in change- rooms and other strategic locations. 7.4 No person showing, at any time, apparent illness or open lesions which may adversely affect the quality of products, shall be allowed to handle starting materials, packaging materials, in-process materials, and drug products until his condition is no longer judged to be a risk.

7.5 All employees shall be instructed to report about their illness or abnormal health condition to their immediate supervisor so that appropriate action can be taken.

7.6 Direct contact shall be avoided between the unprotected hands of personnel and raw materials, intermediate or finished, unpacked products.

7.7 All personnel shall wear clean body coverings appropriate to their duties. Before entry into the manufacturing area, there shall be change rooms separate for each sex

Drugs and Cosmetics Rules, 1945 391 with adequate facilities for personal cleanliness such as wash basin with running water,

1[clean towels or hand dryers], soaps, disinfectants, etc. The change rooms shall be provided with cabinets for the storage of personal belongings of the personnel.

7.8 Smoking, eating, drinking, chewing or keeping plants, food, drink and personal medicines shall not be permitted in production, laboratory, storage and other areas where they might adversely influence the product quality.

8. Manufacturing Operations and Control:

8.1 All manufacturing operations shall be carried out under the supervision of

technical staff approved by the Licensing Authority. Each critical step in the process relating

to the selection, weighing and measuring of raw material addition during various stages shall be performed by trained personnel under the direct personal supervision of approved technical staff.

The contents of all vessels and containers used in manufacture and storage during the various manufacturing stages shall be conspicuously labelled with the name of the product, batch number, batch size and stage of manufacture. Each label should be initialled and dt. by the auhorised technical staff.

Products not prepared under aseptic conditions are required to be free from pathogens like Salmonella, Escherichia coli, Pyocyanea, etc.

8.2. Precautions against mix-up and cross-contamination:

8.2.1. The licensee shall prevent mix-up and cross-contamination of drug material and drug product (from environmental dust) by proper air-handling system, pressure differential, segregation, status labelling and cleaning. Proper records and Standard Operating Procedures thereof shall be maintained.

8.2.2 The licensee shall ensure processing of sensitive drugs like Beta-Lactum antibiotics, sex hormones and cytotoxic substances in segregated areas or isolated production areas within the building with independent air-handling unit and proper pressure differentials.

1[The effective segregation of these areas shall be validated with adequate records of maintenance and services].

8.2.3 To prevent mix-ups during production stages, material under process shall be

conspicuously labelled to demonstrate their status. All equipment used for production shall be labelled with their current status.

8.2.4 Packaging lines shall be independent and adequately segregated. It shall be ensured that all left-overs of the previous packaging operations, including labels, cartons and caps are cleared before the closing hour.

8.2.5 Before packaging operations are begun, steps shall be taken to ensure that the work area, packaging lines, printing machines, and other equipment are clean and free from any products, materials and spillages. The line clearance shall be performed according to an approximate check list and recorded.

¹ Subs. by G.S.R. 431(E), dt. 30.6.2005.

8.2.6 The correct details of any printing (for example of batch numbers or expiry dates) done separately or in the course of the packaging shall be rechecked at regular intervals. All printing and overprinting shall be authorized in writing. ___________________________________________________________________________

Drugs and Cosmetics Rules, 1945 392

8.2.7 The manufacturing environment shall be maintained at the required levels of

temperature, humidity and cleanliness.

8.2.8 Authorised persons shall ensure change-over into specific uniforms before undertaking any manufacturing operations including packaging.

8.2.9

1[There shall be segregated secured areas for recalled or rejected material

and for such material which are to be reprocessed or recovered.]

9. Sanitation in the Manufacturing Premises:

9.1 The manufacturing premises shall be cleaned and maintained in an orderly manner, so that it is free from accumulated waste, dust, debris and other similar material. A validt. cleaning procedure shall be maintained.

9.2 The manufacturing areas shall not be used for storage of materials, except for the material being processed. It shall not be used as a general thoroughfare.

9.3 A routine sanitation program shall be drawn up and observed, which shall be properly recorded and which shall indicate–

(a) specific areas to be cleaned and cleaning intervals;
(b) cleaning procedure to be followed, including equipment and materials to be used for cleaning; and
(c) personnel assigned to and responsible for the cleaning operation. 9.4 The adequacy of the working and in-process storage space shall permit the orderly and logical positioning of equipment and materials so as to minimize the risk of mix- up between different pharmaceutical products or their components to avoid cross contamination, and to minimise the risk of omission or wrong application of any of the manufacturing or control steps. 9.5 Production areas shall be well lit, particularly where visual on-line controls are carried out.

10. Raw Materials:

10.1 The licensee shall keep an inventory of all raw materials to be used at any stage of manufacture of drugs and maintain records as per Schedule U.

10.2 All incoming materials shall be quarantined immediately after receipt or processing. All materials shall be stored under appropriate conditions and in an orderly fashion to permit batch segregation and stock rotation by a ‘first in/first expiry’ – ‘first-out’ principle. All incoming materials shall be checked to ensure that the consignment corresponds to the order placed.

10.3 All incoming materials shall be purchased from approved sources under valid purchase vouchers. Wherever possible, raw materials should be purchased directly from the producers.

¹ Subs. by G.S.R. 431(E), dt. 30.6.2005.

10.4 Authorized staff appointed by the licensee in this behalf, which may include personnel from the Quality Control Department, shall examine each consignment on receipt and shall check each container for integrity of package and seal. Damaged containers shall be identified, recorded and segregated. ___________________________________________________________________________

Drugs and Cosmetics Rules, 1945 393 10.5 If a single delivery of material is made up of different batches, each batch shall be considered as a separate batch for sampling, testing and release.

10.6 Raw materials in the storage area shall be appropriately labelled. Labels shall be clearly marked with the following information:

(a) designated name of the product and the internal code reference, where applicable, and analytical reference number;
(b) manufacturer’s name, address and batch number;
(c) the status of the contents (e.g. quarantine, under test, released, approved, rejected); and
(d) the manufacturing date, expiry date and re-test date. 10.7 There shall be adequate separate areas for materials “under test”, “approved” and “rejected” with arrangements and equipment to allow dry, clean and orderly placement of stored materials and products, wherever necessary, under controlled temperature and humidity. 10.8 Containers from which samples have been drawn shall be identified. 10.9 Only raw materials which have been released by the Quality Control Department and which are within their shelf-life shall be used. It shall be ensured that shelf life of formulation product shall not exceed with that of active raw materials used. 10.10 It shall be ensured that all the containers of raw materials are placed on the raised platforms/racks and not placed directly on the floor. 11. Equipment: 11.1 Equipment shall be located, designed, constructed, adapted and maintained to suit the operations to be carried out. The layout and design of the equipment shall aim to minimise the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build-up of dust or dirt and, in general, any adverse effect on the quality of products. Each equipment shall be provided with a logbook, wherever necessary. 11.2 Balances and other measuring equipment of an appropriate range, accuracy and precision shall be available in the raw material stores, production and in-process control operations and these shall be calibrated and checked on a scheduled basis in accordance with Standard Operating Procedures and records maintained. 11.3 The parts of the production equipment that come into contact with the product shall not be reactive, additive or adsorptive to an extent that would affect the quality of the product. 11.4 To avoid accidental contamination, wherever possible, non-toxic/edible grade lubricants shall be used and the equipment shall be maintained in a way that lubricants do not contaminate the products being produced. 11.5 Defective equipment shall be removed from production and Quality Control areas or appropriately labelled. Drugs and Cosmetics Rules, 1945 394 12. Documentation and Records:– Documentation is an essential part of the Quality assurance system and, as such, shall be related to all aspects of Good Manufacturing Practices (GMP). Its aim is to define the specifications for all materials, method of manufacture and control, to ensure that all personnel concerned with manufacture know the information necessary to decide whether or not to release a batch of a drug for sale and to provide an audit trail that shall permit investigation of the history of any suspected defective batch. 12.1 Documents designed, prepared, reviewed and controlled, wherever applicable, shall comply with these rules. 12.2 Documents shall be approved, signed and dt. by appropriate and authorized persons. 12.3 Documents shall specify the title, nature and purpose. They shall be laid out in an orderly fashion and be easy to check. Reproduced documents shall be clear and legible. Documents shall be regularly reviewed and kept up to date. Any alteration made in the entry of a document shall be signed and dt.. 12.4 The records shall be made or completed at the time of each operation in such a way that all significant activities concerning the manufacture of pharmaceutical products are traceable. Records and associated Standard Operating Procedures (SOP) shall be retained for at least one year after the expiry date of the finished product. 12.5 Data may be recorded by electronic data processing systems or other reliable means, but Master Formulae and detailed operating procedures relating to the system in use shall also be available in a hard copy to facilitate checking of the accuracy of the records. Wherever documentation is handled by electronic data processing methods, authorized persons shall enter or modify data in the computer. There shall be record of changes and deletions. Access shall be restricted by ‘passwords’ or other means and the result of entry of critical data shall be independently checked. Batch records electronically stored shall be protected by a suitable back-up. During the period of retention, all relevant data shall be readily available. 13. Labels and other Printed Materials:– Labels are absolutely necessary for identification of the drugs and their use. The printing shall be done in bright colours and in a legible manner. The label shall carry all the prescribed details about the product. 13.1 All containers and equipment shall bear appropriate labels. Different colour coded labels shall be used to indicate the status of a product (for example under test, approved, passed, rejected). 13.2 To avoid chance mix-up of printed packaging materials, product leaflets, relating to different products, shall be stored separately. 13.3 Prior to release, all labels for containers, cartons and boxes and all circulars, inserts and leaflets shall be examined by the Quality Control Department of the licensee. 13.4 Prior to packaging and labelling of a given batch of a drug, it shall be ensured by the licensee that samples are drawn from the bulk and duly tested, approved and released by the quality control personnel. 13.5 Records of receipt of all labelling and packaging materials shall be maintained for each shipment received indicating receipt, control reference numbers and whether accepted or rejected. Unused coded and damaged labels and packaging materials shall be destroyed and recorded. Drugs and Cosmetics Rules, 1945 395 13.6 The label or accompanying document of reference standards and reference culture shall indicate concentration, lot number, potency, date on which containers was first opened and storage conditions, where appropriate. 14. Quality Assuranc:–This is a wide-ranging concept concerning all matters that individually or collectively influence the quality of a product. It is the totality of the arrangements made with the object of ensuring that products are of the quality required for their intended use. 14.1 The system of quality assurance appropriate to the manufacture of pharmaceutical products shall ensure that: –
(a) the pharmaceutical products are designed and developed in a way that takes account of the requirements of Good Manufacturing Practices (hereinafter referred as GMP) and other associated codes such as those of Good Laboratory Practices (hereinafter referred as GLP) and Good Clinical Practices (hereinafter referred as GCP);
(b) adequate arrangements are made for manufacture, supply and use of the correct starting and packaging materials.
(c) adequate controls on starting materials, intermediate products and bulk products and other in-process controls, calibrations, and validations are carried out.
(d) the finished product is correctly processed and checked in accordance with established procedures;
(e) the pharmaceutical products are not released for sale or supplied before authorized persons have certified that each production batch has been produced and controlled in accordance with the requirements of the label claim and any other provisions relevant to production, control and release of pharmaceutical products.

15. Self Inspection and Quality audit:– It may be useful to constitute a self-inspection

team supplemented with a quality audit procedure for assessment of all or part of a system with the specific purpose of improving it.

15.1 To evaluate the manufacturer’s compliance with GMP in all aspects of production and quality control, concept of self-inspection shall be followed. The manufacturer shall constitute a team of independent, experienced, qualified persons from within or outside the company, who can audit objectively the implementation of methodology and procedures evolved. The procedure for self-inspection shall be documented indicating self-inspection results, evaluation, conclusions and recommended corrective actions with effective follow up program. The recommendations for corrective action shall be adopted.

15.2 The program shall be designed to detect shortcomings in the implementation of Good Manufacturing Practice and to recommend the necessary corrective actions. Self- inspections shall be performed routinely and on specific occasions, like when product recalls or repeated rejections occur or when an inspection by the licensing authorities is announced. The team responsible for self-inspection shall consist of personnel who can evaluate the implementation of Good Manufacturing Practice objectively; all recommendations for corrective action shall be implemented.

Drugs and Cosmetics Rules, 1945 396 15.3 Written instructions for self-inspection shall be drawn up which shall include the following: -

(a) Personnel.
(b) Premises including personnel facilities.
(c) Maintenance of buildings and equipment
(d) Storage of starting materials and finished products.
(e) Equipment.
(f) Production and in-process controls.
(g) Quality control.
(h) Documentation.
- (i) Sanitation and hygiene.
(j) Validation and revalidation programmes.
(k) Calibration of instruments or measurement systems.
(l) Recall procedures.
(m) Complaints management.
(n) Labels control.
(o) Results of previous self-inspections and any corrective steps taken. 16. Quality Control System. - Quality control shall be concerned with sampling, specifications, testing, documentation, release procedures which ensure that the necessary and relevant tests are actually carried and that the materials are not released for use, nor products released for sale or supply until their quality has been judged to be satisfactory. It is not confined to laboratory operations but shall be involved in all decisions concerning the quality of the product. It shall be ensured that all quality control arrangements are effectively and reliably carried out.The department as a whole shall have other duties such as to establish, evaluate, validate and implement all Quality Control Procedures and methods. 16.1 Every manufacturing establishment shall establish its own quality control

laboratory manned by qualified and experienced staff.

16.2 The area of the quality control laboratory may be divided into Chemical, Instrumentation, Microbiological and Biological testing.

16.3 Adequate area having the required storage conditions shall be provided for keeping reference samples. The quality control department shall evaluate, maintain and store reference samples.

16.4 Standard operating procedures shall be available for sampling, inspecting and testing of raw materials, intermediate bulk finished products and packing materials and, wherever necessary, for monitoring environmental conditions.

16.5 There shall be authorized and dt. specifications for all materials, products, reagents and solvents including test of identity, content, purity and quality. These shall include specifications for water, solvents and reagents used in analysis.

16.6 No batch of the product shall be released for sale or supply until it has been certified by the authorized person(s) that it is in accordance with the requirements of the standards laid down.

16.7 Reference/retained samples from each batch of the products manufactured shall be maintained in quantity which is at least twice the quantity of the drug required to conduct all the tests, except sterility and pyrogen/Bacterial Endotoxin Test performed on the active material and the product manufactured. The retained product shall be kept in its final pack or simulated pack for a period of three months after the date of expiry.

Drugs and Cosmetics Rules, 1945 397 16.8 Assessment of records pertaining to finished products shall include all relevant factors, including the production conditions, the results of in-process testing, the manufacturing (including packaging) documentation, compliance with the specification for the finished product, and an examination of the finished pack. Assessment records should be signed by the in-charge of production and countersigned by the authorised quality control personnel before a product is released for sale or distribution.

16.9 Quality control personnel shall have access to production areas for sampling and investigation, as appropriate.

16.10 The quality control department shall conduct stability studies of the products

to ensure and assign their shell life at the prescribed conditions of storage. All records of such studies shall be maintained.

16.11 The in-charge of Quality Assurance shall investigate all product complaints and records thereof shall be maintained.

16.12 All instruments shall be calibrated and testing procedures validt. before these

are adopted for routine testing. Periodical calibration of instrument and validation of procedures shall be carried out.

16.13 Each specification for raw materials, intermediates, final products, and packing materials shall be approved and maintained by the Quality Control Department. Periodic revisions of the specifications shall be carried out whenever changes are necessary.

16.14 Pharmacopoeia, reference standards, working standards, references, spectra, other reference materials and technical books, as required, shall be available in the Quality Control Laboratory of the licensee.

17. Specification

17.1 For raw materials and packaging materials. - They shall include-

(a) the designated name and internal code reference;
(b) reference, if any, to a pharmacopoeial monograph;
(c) qualitative and quantitative requirements with acceptance limits;
(d) name and address of manufacturer or supplier and original manufacturer of the material;
(e) specimen of printed material;
(f) directions for sampling and testing or reference to procedures;
(g) storage conditions; and
(h) maximum period of storage before re-testing. 17.2 For product containers and closures:– 17.2.1 All containers and closures intended for use shall comply with the pharmacopoeial requirements. Suitable validt. test methods, sample sizes, specifications, cleaning procedure and sterilization procedure, wherever indicated, shall be strictly followed to ensure that these are not reactive, additive, absorptive, or leach to an extent that significantly affects the quality or purity of the drug. No second hand or used containers and closures shall be used. 17.2.2 Whenever bottles are being used, the written schedule of cleaning shall be laid down and followed. Where bottles are not dried after washing, they should be rinsed with de-ionised water or distilled water, as the case may be. Drugs and Cosmetics Rules, 1945 398 17.3. For in-process and bulk products. - Specifications for in-process material, intermediate and bulk products shall be available. The specifications should be authenticated. 17.4 For finished products. - Appropriate specifications for finished products shall include: -
(a) the designated name of the product and the code reference;
(b) the formula or a reference to the formula and the pharmacopoeial reference;
(c) directions for sampling and testing or a reference to procedures;
(d) a description of the dosage form and package details;
(e) the qualitative and quantitative requirements, with the acceptance limits for release;
(f) the storage conditions and precautions, where applicable, and
(g) the shelf-life. 17.5 For preparation of containers and closures. - The requirements mentioned in the Schedule do not include requirements of machinery, equipments and premises required for preparation of containers and closures for different dosage forms and categories of drugs. The suitability and adequacy of the machinery, equipment and premises shall be examined taking into consideration the requirements of each licensee in this respect. 18. Master Formula Records: There shall be Master Formula records relating to all manufacturing procedures for each product and batch size to be manufactured. These shall be prepared and endorsed by the competent technical staff i.e. head of production and quality control. The Master Formula shall include: -
(a) the name of the product together with product reference code relating to its specifications;
(b) the patent or proprietary name of the product along with the generic name, a description of the dosage form, strength, composition of the product and batch size;
(c) name, quantity, and reference number of all the starting materials to be used. Mention shall be made of any substance that may ‘disappear’ in the course of processing.
(d) a statement of the expected final yield with the acceptable limits, and of relevant intermediate yields, where applicable.
(e) a statement of the processing location and the principal equipment to be used.
(f) the methods, or reference to the methods, to be used for preparing the critical equipments including cleaning, assembling, calibrating, sterilizing;
(g) detailed stepwise processing instructions and the time taken for each step;
(h) the instructions for in-process control with their limits;
- (i) the requirements for storage conditions of the products, including the container, labelling and special storage conditions where applicable;
(j) any special precautions to be observed;
(k) packing details and specimen labels. 19. Packing Records: There shall be authorised packaging instructions for each product, pack size and type. These shall include or have a reference to the following: -
(a) name of the product; Drugs and Cosmetics Rules, 1945 399
(b) description of the dosage form, strength and composition;
(c) the pack size expressed in terms of the number of doses, weight or volume of the product in the final container;
(d) complete list of all the packaging materials required for a standard batch size, including quantities, sizes and types with the code or reference number relating to the specifications of each packaging material.;
(e) reproduction of the relevant printed packaging materials and specimens indicating where batch number and expiry date of the product have been applied;
(f) special precautions to be observed, including a careful examination of the area and equipment in order to ascertain the line clearance before the operations begin.
(g) description of the packaging operation, including any significant subsidiary operations and equipment to be used;
(h) details of in-process controls with instructions for sampling and acceptance; and
- (i) upon completion of the packing and labelling operation, a reconciliation shall be made between number of labelling and packaging units issued, number of units labelled, packed and excess returned or destroyed. Any significant or unusual discrepancy in the numbers shall be carefully investigated before releasing the final batch. 20. Batch Packaging Records: 20.1 A batch packaging record shall be kept for each batch or part batch processed. It shall be based on the relevant parts of the packaging instructions, and the method of preparation of such records shall be designed to avoid transcription errors. 20.2 Before any packaging operation begins, check shall be made and recorded that the equipment and the work stations are clear of the previous products, documents or materials not required for the planned packaging operations, and that the equipment is clean and suitable for use. 21. Batch Processing Records 21.1 There shall be Batch Processing Record for each product. It shall be based on the relevant parts of the currently approved Master Formula. The method of preparation of such records included in the Master Formula shall be designed to avoid transcription errors. 21.2 Before any processing begins, check shall be performed and recorded to ensure that the equipment and work station are clear of previous products, documents or materials not required for the planned process are removed and the equipment is clean and suitable for use. 21.3 During processing, the following information shall be recorded at the time each action is taken and the record shall be dt. and signed by the person responsible for the processing operations: -
(a) the name of the product,
(b) the number of the batch being manufactured,
(c) dates and time of commencement, of significant intermediate stages and of completion of production,
(d) initials of the operator of different significant steps of production and where appropriate, of the person who checked each of these operations,
(e) the batch number and/or analytical control number as well as the quantities of each starting material actually weighed,
(f) any relevant processing operation or event and major equipment used,
(g) a record of the in-process controls and the initials of the person(s) carrying them out, and the results obtained, Drugs and Cosmetics Rules, 1945 400
(h) the amount of product obtained after different and critical stages of manufacture (yield),
- (i) comments or explanations for significant deviations from the expected yield limits shall be given,
(j) notes on special problems including details, with signed authorization, for any deviation from the Master Formula,
(k) addition of any recovered or reprocessed material with reference to recovery or reprocessing stages. 22. Standard Operating Procedures (SOPs) and Records, regarding:

22.1 Receipt of materials:

22.1.1 There shall be written Standard Operating Procedures and records for the receipt of each delivery of raw, primary and printed packaging material.

22.1.2 The records of the receipts shall include;

(a) the name of the material on the delivery note and the number of containers;
(b) the date of receipt;
(c) the manufacturer’s and/ or supplier’s name;
(d) the manufacturer’s batch or reference number;
(e) the total quantity, and number of containers, quantity in each container received;
(f) the control reference number assigned after receipt;
(g) any other relevant comment or information. 22.1.3 There shall be written standard operating procedures for the internal labelling, quarantine and storage of starting materials, packaging materials and other materials, as appropriate. 22.1.4 There shall be Standard Operating Procedures available for each instrument and equipment and these shall be placed in close proximity to the related instrument and equipment. 22.2 Sampling: 22.2.1 There shall be written Standard Operating Procedures for sampling which include the person(s) authorized to take the samples. 22.2.2 The sampling instructions shall include:
(a) the method of sampling and the sampling plan,
(b) the equipment to be used,
(c) any precautions to be observed to avoid contamination of the material or any deterioration in its quality,
(d) the quantity of samples to be taken,
(e) instructions for any required sub-division or pooling of the samples,
(f) the types of sample container to be used,
(g) any specific precautions to be observed, especially in regard to sampling of sterile and hazardous materials. 22.3. Batch Numbering: 22.3.1 There shall be Standard Operating Procedures describing the details of the batch Drugs and Cosmetics Rules, 1945 401
(lot) numbering set up with the objective of ensuring that each batch of intermediate, bulk or finished product is identified with a specific batch number. 22.3.2 Batch numbering Standard Operating Procedures applied to a processing stage and to the respective packaging stage shall be same or traceable to demonstrate that they belong to one homogenous mix. 22.3.3 Batch number allocation shall be immediately recorded in a logbook or by electronic data processing system. The record shall include date of allocation, product identity and size of batch.

22.4. Testing:

22.4.1 There shall be written procedures for testing materials and products at different stages of manufacture, describing the methods and equipment to be used. The tests performed shall be recorded.

22.5 Records of analysis:

22.5.1 The records shall include the following data:

(a) name of the material or product and the dosage form,
(b) batch number and, where appropriate the manufacturer and/ or supplier,
(c) references to the relevant specifications and testing procedures,
(d) test results, including observations and calculations, and reference to any specifications (limits),
(e) dates of testing,
(f) initials of the persons who performed the testing,
(g) initials of the persons who verified the testing and the detailed calculations,
(h) a statement of release or rejection, and
- (i) signature and date of the designated responsible person. 22.5.2 There shall be written standard operating procedures and the associated records of actions taken for:
(a) equipment assembly and validation
(b) analytical apparatus and calibration,
(c) maintenance, cleaning and sanitation;
(d) personnel matters including qualification, training, clothing, hygiene;
(e) environmental monitoring;
(f) pest control;
(g) complaints;
(h) recalls made; and
- (i) returns received.

23. Reference Samples:-

23.1 Each lot of every active ingredient, in a quantity sufficient to carry out all the tests,

except sterility and pyrogens/Bacterial Endotoxin Test, shall be retained for a

period of 3 months after the date of expiry of the last batch produced from that active ingredient.

23.2. Samples of finished formulations shall be stored in the same or simulated containers in which the drug has been actually marketed.

Drugs and Cosmetics Rules, 1945 402

24. Reprocessing and Recoveries:

24.1. Where reprocessing is necessary, written procedures shall be established and approved by the Quality Assurance Department that shall specify the conditions and limitations of repeating chemical reactions. Such reprocessing shall be validt..

24.2. If the product batch has to be reprocessed, the procedure shall be authorized and recorded. An investigation shall be carried out into the causes necessitating re- processing and appropriate corrective measures shall be taken for prevention of recurrence. Re-processed batch shall be subjected to stability evaluation.

24.3. Recovery of the product residue may be carried out, if permitted, in the master production and control records by incorporating it in subsequent batches of the product.

25. Distribution records:

25.1. Prior to distribution or dispatch of given batch of a drug, it shall be ensured that the

batch has been duly tested, approved and released by the quality control personnel. Pre-dispatch inspection shall be performed on each consignment on a random basis to ensure that only the correct goods are dispatched. Detailed instructions for warehousing and stocking of Large Volume Parenterals, if stocked, shall be in existence and shall be complied with after the batch is released for distribution. Periodic audits of warehousing practices followed at distribution centers shall be carried out and records thereof shall be maintained. Standard Operating Procedures shall be developed for warehousing of products.

25.2. Records for distribution shall be maintained in a manner

1[so as] to facilitate

prompt and complete recall of the batch, if and when necessary.

26. Validation and process validation:

26.1.

Validation studies shall be an essential part of Good Manufacturing Practices and shall be conducted as per the pre-defined protocols. These shall include validation of processing, testing and cleaning procedures. 26.2. A written report summarizing recorded results and conclusions shall be prepared, documented and maintained.

26.3. Processes and procedures shall be established on the basis of validation study and

undergo periodic revalidation to ensure that they remain capable of achieving the intended results. Critical processes shall be validt., prospectively or retrospectively.

26.4. When any new Master Formula or method of preparation is adopted, steps shall be taken to demonstrate its suitability for routine processing. The defined process, using the materials and equipment specified shall be demonstrated to yield a product consistently of the required quality.

26.5. Significant changes to the manufacturing process, including any change in equipment or materials that may affect product quality and/or the reproducibility of the process, shall be validt..

27. Product Recalls:

27.1 A prompt and effective product recall system of defective products shall be

Drugs and Cosmetics Rules, 1945 403 devised for timely information of all concerned stockists, wholesalers, suppliers, upto the retail level within the shortest period. The licensee may make use of both print and electronic media in this regard.

27.2. There shall be an established written procedure in the form of Standard Operating Procedure for effective recall of products distributed by the licensee. Recall operations shall be capable of being initiated promptly so as to effectively reach at the level of each distribution channel.

27.3 The distribution records shall be readily made available to the persons designated for recalls.

27.4 The designated person shall record a final report issued, including reconciliation between the delivered and the recovered quantities of the products.

27.5 The effectiveness of the arrangements for recalls shall be evaluated from time to time.

27.6 The recalled products shall be stored separately in a secured segregated area pending final decision on them.

28. Complaints and Adverse Reactions:.

28.2. Reports of serious adverse drug reactions resulting from the use of a drug along with comments and documents shall be forthwith reported to the concerned licensing authority.

28.3 There shall be written procedures describing the action to be taken, recall to be made of the defective product.

29.1 General information:

(a) brief information of the firm;
(b) pharmaceutical manufacturing activities as permitted by the licensing authority;
(c) other manufacturing activities, if any, carried out on the premises;
(d) type of products licensed for manufacture with flow charts mentioning procedure and process flow;
(e) number of employees engaged in the production, quality control, storage and distribution;
(f) use of outside scientific, analytical or other technical assistance in relation to manufacture and analysis;
(g) short description of the Quality Management System of the firm; and
(h) products details registered with foreign countries. Drugs and Cosmetics Rules, 1945 404 29.2 Personnel:
(a) organisational chart showing the arrangement for quality assurance including production and quality control;
(b) qualification, experience and responsibilities of key personnel;
(c) outline for arrangements for basic and in-service training and how the records are maintained;
(d) health requirements for personnel engaged in production; and
(e) personnel hygiene requirements, including clothing. 29.3 Premises:
(a) simple plan or description of manufacturing areas drawn to scale;
(b) nature of construction and fixtures/fittings;
(c) brief description of ventilation systems. More details should be given for critical areas with potential risk of airborne contamination (schematic drawing of systems). Classification of the rooms used for the manufacture of sterile products should be mentioned;
(d) special areas for the handling of the highly toxic, hazardous and sensitizing materials;
(e) brief description of water system (schematic drawings of systems), including sanitation;
(f) description of planned preventive maintenance programs for premises and of the recording system. 29.4 Equipment:
(a) brief description of major equipment used in production and Quality Control Laboratories (a list of equipment required);
(b) description of planned preventive maintenance programs for equipment and of the recording system; and
(c) qualification and calibration including the recording systems and arrangements for computerized systems validation. 29.5 Sanitation:
(a) availability of written specifications and procedures for cleaning manufacturing areas and equipment. 29.6 Documentation. -
(a) arrangements for the preparation, revision and distribution of;
(b) necessary documentation for the manufacture;
(c) any other documentation related to product quality that is not mentioned elsewhere (e.g. microbiological controls about air and water). 29.7 Production:.
(a) brief description of production operations using, wherever possible, flow sheets and charts specifying important parameters;
(b) arrangements for the handling of starting materials, packaging materials, bulk and Drugs and Cosmetics Rules, 1945 405 finished products, including sampling, quarantine, release and storage;
(c) arrangements for the handling of rejected materials and products;
(d) brief description of general policy for process validation. 29.8 Quality Control:
(a) description of the quality control system and of the activities of the Quality Control Department. Procedures for the release of the finished products. 29.9 Loan licence manufacture and licensee:
(a) description of the way in which compliance of Good Manufacturing Practices by the loan licensee shall be assessed. 29.10 Distribution, complaints and product recall:
(a) arrangements and recording system for distribution;
(b) arrangements for the handling of complaints and product recalls. 29.11 Self inspection. -
(a) short description of the self-inspection system indicating whether an outside, independent and experienced external expert was involved in evaluating the manufacturer’s compliance with Good manufacturing Practices in all aspects of production. 29.12 Export of drugs. -
(a) products exported to different countries;
(b) complaints and product recall, if any.

PART IA

SPECIFIC REQUIREMENTS FOR MANUFACTURE OF STERILE PRODUCTS, PARENTERAL PREPARATIONS (SMALL VOLUME INJECTABLES AND LARGE VOLUME PARENTERALS) AND STERILE OPHTHALMIC PREPARATIONS.

Note. - The general requirements as given in Part 1 of this Schedule relating to Requirements of Good Manufacturing Practices for Premises and Materials for pharmaceutical products shall be complied with, mutatis mutandis, for the manufacture of sterile products, Parenteral preparations (Small Volume Injectables and Large Volume Parenterals) and Sterile Ophthalmic Preparations. In addition to these requirements, the following specific requirements shall also be followed, namely: -

1. General : Sterile products, being very critical and sensitive in nature, a very high degree of precautions, prevention and preparations are needed. Dampness, dirt and darkness are to be avoided to ensure aseptic conditions in all areas. There shall be strict compliance in the prescribed standards especially in the matter of supply of water, air, active materials and in the maintenance of hygienic environment.

Drugs and Cosmetics Rules, 1945 406

2. Buildings and Civil Works:

2.1 The buildings shall be built on proper foundation with standardized materials to avoid cracks in critical areas like aseptic solution preparation, filling and sealing rooms.

2.2 Location of services like water, steam, gases etc. shall be such that their servicing or repair shall not pose any threat to the integrity of the facility. Water lines shall not pose any threat of leakage to aseptic area.

2.3. The manufacturing areas shall be clearly separated into support areas (e.g. washing and component preparation areas, storage areas etc.), preparation areas (e.g. bulk manufacturing area, non-aseptic blending areas etc.) change areas and aseptic areas. Operations like removal of outer cardboard wrappings of primary packaging materials shall be done in the de-cartoning areas which are segregated from the washing areas. Wooden pallets, fiber board drums, cardboard and other particle shedding materials shall not be taken inside the preparation areas.

2.4. In aseptic areas –

(a) walls, floors and ceiling should be impervious, non-shedding, non-flaking and non-cracking. Flooring should be unbroken and provided with a cove both at the junction between the wall and the floor as well as the wall and the ceiling.
(b) walls shall be flat, and ledges and recesses shall be avoided. Wherever other surfaces join the wall (e,g, sterilizers, electric sockets, gas points etc.) these shall flush the walls. Walls shall be provided with a cove at the joint between the ceiling and the floor;
(c) ceiling shall be solid and joints shall be sealed. Light-fittings and air-grills shall flush with the walls and not hanging from the ceiling, so as to prevent contamination;
(d) there shall be no sinks and drains in Grade A and Grade B areas;
(e) doors shall be made of non-shedding material. These may be made preferably of Aluminium or Steel material. Wooden doors shall not be used. Doors shall open towards the higher-pressure area so that they close automatically due to air pressure;
(f) Windows shall be made of similar material as the doors, preferably with double panel and shall be flush with the walls. If fire escapes are to be provided, these shall be suitably fastened to the walls without any gaps;
(g) The furniture used shall be smooth, washable and made of stainless steel or any other appropriate material other than wood. 2.5. The manufacturing and support areas shall have the same quality of civil structure described above for aseptic areas, except the environmental standards which may vary in the critical areas. 2.6 Change rooms with entrance in the form of air-locks shall be provided before entry into the sterile product manufacturing areas and then to the aseptic area. Separate exit space from the aseptic areas is advisable. Change rooms to the aseptic areas shall be clearly demarcated into ‘black’. ‘grey’, and ‘white rooms’ with different levels of activity and air cleanliness. The ‘black’ change room shall be provided with a hand-washing sink. The sink Drugs and Cosmetics Rules, 1945 407 and its drain in the un-classified (first) change rooms may be kept clean all the time. The specially designed drain shall be periodically monitored to avoid presence of pathogenic micro-organisms. Change room doors shall not be opened simultaneously. An appropriate inter-locking system and a visual and/or audible warning system may be installed to prevent the opening of more than one door at a time. 2.7. For communication between aseptic areas and non-aseptic areas, intercom telephones or speak-phones shall be used. These shall be minimum in number. 2.8 Material transfer between aseptic areas and outside shall be through suitable airlocks or pass-boxes. Doors of such airlocks and pass-boxes shall have suitable interlocking arrangements. 2.9. Personal welfare areas like rest rooms, tea room, canteen and toilets shall be outside and separated from the sterile product manufacturing area. 2.10 Animal houses shall be away from the sterile product manufacturing area and shall not share a common entrance or air handling system with the manufacturing area. 3. Air Handling System (Central Air-Conditioning): 3.1 Air Handling Units for sterile product manufacturing areas shall be different from those for other areas. Critical areas, such as the aseptic filling area, sterilized components unloading area and change room conforming to Grades B, C and D respectively shall have separate air handling units. The filter configuration in the air handling system shall be suitably designed to achieve the Grade of air as given in Table1. Typical operational activities for clean areas are highlighted in Table II and Table III. 3.2 For products which are filled aseptically, the filling room shall meet Grade B conditions at rest unmanned. This condition shall also be obtained within a period of about 30 minutes of the personnel leaving the room after completion of operations. 3.3. The filling operations shall take place under Grade A conditions which shall be demonstrated under working of simulated conditions which shall be achieved by providing laminar air flow work stations with suitable HEPA filters or isolator technology. 3.4. For products, which are terminally sterilized, the filling room shall meet Grade C conditions at rest. This condition shall be obtainable within a period of about 30 minutes of the personnel leaving the room after completion of operations. 3.5. Manufacturing and component preparation areas shall meet Grade C conditions. 3.6. After completion of preparation, washed components and vessels shall be protected with 1[Grade D background and should be handled in such a way that they are not recontaminated]. 3.7. The minimum air changes for Grade B and Grade C areas shall not be less than 20 air changes per hour in a room with good air flow pattern and appropriate HEPA filters. For Grade A laminar air flow work stations, the air flow rate shall be 0.3 meter per

second ± 20% (for vertical flows) and 0.45 meter per second ± 20% (for horizontal flows).

3.8. Differential pressure between areas of different environmental standards shall be at least 15 Pascal (0.06 inches or 1.5 mm water gauge). Suitable manometers or gauges shall be installed to measure and verify pressure differential.

Drugs and Cosmetics Rules, 1945 408 3.9 The final change room shall have the same class of air as specified for the aseptic area. The pressure differentials in the change rooms shall be in the descending order from ‘white’ to ‘black’. 3.10 Unless there are product specific requirements, temperature and humidity in the aseptic areas

1[shall be 27 ± 2 degree centigrade and relative humidity 55% ± 5, respectively].

1[TABLE I AIR BORNE PARTICULATE CLASSIFICATION FOR MANUFACTURE OF STERILE PRODUCTS

Grade Maximum number of permitted particles per cubic metre equal

tto or above

At rest (b)

In operation (a)

0.5μm 5μm 0.5μm 5μm

A 3500 0 3500 0 B (a) 3500 0 3,50,000 2,000 C (a) 350,000 2,000 35,00,000 20,000

D (a) 35,00,000 20,000 Not defined (c) Not defined (c)]

Notes :

(a) In order to reach the B, C and D air grades, the number of air changes shall be related to the size of the room and the equipment and personnel present in the room. The air system shall be provided with the appropriate filters such as HEPA for Grades A, B and C. The maximum permitted number of particles in the “at rest” condition shall approximately be as under:

1[Grade A and B corresponds with class 100 or M 3.5 or class 5]; Grade C with Class 10,000 or M 5.5 or ISO Class 7; Grade D with Class 1,00,000 or M 6.5 or ISO Class 8.

(b) The requirement and limit for the area shall depend on the nature of the operation carried out.

TABLE II

TYPES OF OPERATIONS TO BE CARRIED OUT IN THE VARIOUS GRADES FOR ASEPTIC PREPARATIONS

Grade Types of operations for aseptic preparations A Aseptic preparation and filling B Background room conditions for activities requiring Grade A C Preparation of solution to be filtered D Handling of components after washing

¹ Subs. by G.S.R. 431(E), dt. 30.6.2005.

__________________________________________________________________________

Drugs and Cosmetics Rules, 1945 409 TABLE III

TYPES OF OPERATIONS TO BE CARRIED OUT IN THE VARIOUS GRADES FOR TERMINALLY STERILIZED PRODUCTS

Grade Types of operations for terminally sterilized products. A Filling of products, which are usually at risk. C Placement of filling and sealing machines, preparation of solutions when

1[unusually at risk]. Filling of product when unusually at risk. D Moulding, blowing (pre-forming) operations of plastic containers, preparations of solutions and components for subsequent filling.

4. Environmental Monitoring:

4.1 All environmental parameters listed under para 3.1 to 3.10 shall be verified and established at the time of installation and thereafter monitored at periodic intervals. The

recommended frequencies of periodic monitoring shall be as follows :-

(a) Particulate monitoring in air – 6 Monthly.
(b) HEPA filter integrity testing (smoke testing) – Yearly
(c) Air change rates – 6 Monthly.
(d) Air pressure differentials – Daily.
(e) Temperature and humidity – Daily
(f) Microbiological monitoring by settle plates and/or swabs in aseptic areas– Daily, and at decreased frequency in other areas. `Note: The above frequencies of monitoring shall be changed as per the requirements and load in individual cases. 4.2 There shall be a written environmental monitoring program and microbiological results shall be recorded. Recommended limits for microbiological monitoring of clean areas “in operation” are as given in the table below: TABLE RECOMMENDED LIMITS FOR MICROBIOLOGICAL MONITORING OF CLEAN AREAS “ IN OPERATION” Grade Air sample Cfu/m Settle plates (dia. 90mm. Cfu/2 hrs. Contact plates (dia. 55mm) cfu per plate Glove points (five fingers) cfu per glove A < 1 < 1 < 1 < 1 B 10 5 5 5 C 100 50 25 -- D 500 100 50 -- Notes:
(a) These are average values.
(b) Individual settle plates may be exposed for not less than two hours in Grade B, C and D areas and for not less than thirty minutes in Grade A area. __________________________________________________________________________ Drugs and Cosmetics Rules, 1945 410 4.3 Appropriate action shall be taken immediately if the result of particulate and microbiological monitoring indicates that the counts exceed the limits. The Standard Operating Procedures shall contain corrective action. After major engineering modification to the HVAC system of any area, all monitoring shall be re-performed before production commences. 5. Garments. 5.1 This section covers garments required for use by personnel working only in

¹ Subs. by G.S.R. 431(E), dt. 30.6.2005.

aseptic area. Outdoor clothing shall not be brought into the sterile areas.

5,2 The garments shall be made of non-shedding and tight weave material. Cotton garments shall not be used. The garments shall shed virtually no fibres or particulate matter.

5.3 The clothing and its quality shall be adopted to the process and the work place and worn in such a way as to protect the product from contamination. Garments shall be single piece with fastenings at cuffs, neck and at legs to ensure close fit. Trouser legs shall be tucked inside the cover boots. Suitable design of garments shall either include a hood (head- cover) or a separate hood which can be tucked inside the over-all. Pockets, pleats and belts shall be avoided in garments. Zips (if any) shall be of plastic material. Garments with damaged zips shall not be used.

5.4. Only clean, sterilized and protective garments shall be used at each work session where aseptic filtration and filling operations are undertaken and at each work shift for products intended to be sterilized, post-filling. The mask and gloves shall be changed at every work session in both instances. 5.5 Gloves shall be made of latex or other suitable plastic materials and shall be powder-free. These shall be long enough to cover wrists completely and allow the over-all cuff to be tucked in. 5.6. The footwear shall be of suitable plastic or rubber material and shall be daily cleaned with a bactericide. 5.7. Safety goggles or numbered glasses with side extension shall be used inside aseptic areas. These shall be sanitized by a suitable method. 5.8. Garment changing procedures shall be documented and operators trained in this respect. A full size mirror shall be provided in the final change room for the operator to verify that he is appropriately attired in the garments. Periodic inspection of the garments shall be done by responsible staff. 6. Sanitation: 6.1. There shall be written procedures for the sanitation of sterile processing facilities. Employees carrying out sanitation of aseptic areas shall be trained specifically for this purpose. 6.2. Different sanitizing agent shall be used in rotation and the concentrations of the same shall be as per the recommendations of the manufacturer. Records of rotational use of sanitizing agents shall be maintained. 6.3. Distilled water freshly collected directly from the distilled water plant or water maintained above 70 degree centigrade from the re-circulation loop shall be used for dilution of disinfectants. Alternatively, distilled water sterilized by autoclaving or membrane filtration shall be used. The dilution shall be carried out in the ‘white’ change room.

Drugs and Cosmetics Rules, 1945 411 6.4.

1[Where alcohol or isopropyl alcohol is used for dilution of disinfectants for use as hand sprays, the preparation of the same shall be done in the bulk preparation area in grade C.] 6.5. Diluted disinfectants shall bear the label ‘use before’, based on microbiological establishment of the germicidal properties. The solutions shall be adequately labelled and documents maintained. 6.6. Formaldehyde or any other equally effective fumigant is recommended for the fumigation of aseptic areas or after major civil modifications. There shall be Standard Operating Procedures for this purpose. Its use for routine purpose shall be discouraged and an equally effective surface cleaning regime shall be followed. 6.7. Cleaning of sterile processing facilities shall be undertaken with air suction devices or with non-linting sponges or clothes. 6.8. Air particulate quality shall be evaluated on a regular basis and record maintained. 7. Equipment: 7.1 The special equipment required for manufacturing sterile products includes component washing machines, steam sterilizers, dry heat sterilizers, membrane filter assemblies, manufacturing vessels, blenders, liquid filling machines, powder filling machines, sealing and labelling machines, vacuum testing chambers, inspection machines, lyophilisers, pressure vessels etc. Suitable and fully integrated washing sterilizing filling lines may be provided, depending upon the type and volume of activity.

7.2. Unit-sterilizers shall be double-ended with suitable inter-locking arrangements between the doors. The effectiveness of the sterilization process shall be established initially by biological inactivation studies using microbial spore indicators and then at least once a year by carrying out thermal mapping of the chamber. Various sterilization parameters shall be established based on these studies and documented. For membrane filters used for filtration, appropriate filter integrity tests that ensure sterilization shall be carried out before and after filtration.

7.3. Filling machines shall be challenged initially and then at periodic intervals by simulation trials including sterile media fill. Standard Operating Procedures and acceptance criteria for media fills shall be established, justified and documented. Special simulation trial procedures shall be developed, validt. and documented for special products like ophthalmic ointments.

7.4. The construction material used for the parts which are in direct contact with products and the manufacturing vessels may be stainless steel 316 or Boro-silicate glass (if glass containers) and the tubing shall be capable of being washed and autoclaved.

7.5 On procurement, installation qualification of each of the equipment shall be done by engineers with the support of production and quality assurance personnel. Equipment for critical processes like aseptic filling and sterilizers shall be suitably validt. according to a written program before putting them to use.

¹ Subs. by G.S.R. 431(E), dt. 30.6.2005.

7.6. Standard Operating Procedures shall be available for each equipment for its calibration and operation and cleaning. Gauges and other measuring devices attached to equipment shall be calibrated at suitable intervals against a written program. Calibration status of equipment gauges shall be adequately documented and displayed. ____________________________________________________________________________

Drugs and Cosmetics Rules, 1945 412 8. Water and Steam Systems:

8.1. Potable water meeting microbiological specification of not more than 500 cfu/ml and indicating absence of individual pathogenic micro-organisms. Escherichia coli, Salmonella, Staphylococcus aureus and Pseudomonas aeruginosa per 100 ml sample shall be used for the preparation of purified water.

8.2 Purified water prepared by de-mineralization shall meet the microbiological specification of not more than 100 cfu per ml and indicate absence of pathogenic micro- organisms in 100 ml. Purified water shall also meet IP specification for chemical quality. Purified water shall be used for hand washing in change rooms. Containers, closures and machine parts may be washed with potable water followed by suitably filtered purified water. Purified water shall be stored in stainless steel tanks or plastic tanks.

8.3. Water for Injection (hereinafter as WFI) shall be prepared from potable water or purified water meeting the above specifications by distillation. Water for Injection shall meet microbiological specification of not more than 10 cfu per 100 ml. WFI shall also meet IP specification for Water for Injection and shall have an endotoxin level of not more than 0.25 EU/Ml. Bulk solutions of liquid parenterals shall be made in WFI. Final rinse of product containers and machine parts shall be done with WFI. Disinfectant solutions for use in aseptic areas shall be prepared in WFI.

8.4. Water for Injection for the manufacture of liquid injectables shall be freshly collected from the distillation plant or from a storage or circulation loop where the water has been kept at above 70 degree centigrade. At the point of collection, water may be cooled using suitable heat exchanger.

8.5 Water for non-injectable sterile products like eye drops shall meet IP specifications for purified water. In addition, microbiologial specification of not more than 10 cfu per 100 ml and absence of Pseudomonas aeruginosa and Enterobacter coli in 100 ml shall also be met.

8.6. Water for Injection shall be stored in steam jacketed stainless steel tanks of suitable size and the tanks shall have hydrophobic bacterial retention with 0.22 μ vent filters. The filters shall be suitably sterilized at periodic intervals. The distribution lines for purified water and distilled water shall be of stainless steel 316 construction and shall not shed particles.

8.7. There shall be a written procedure and program for the sanitation of different water systems including storage tanks, distribution lines, pumps and other related equipment. Records of sanitation shall be maintained.

8.8. There shall be written microbiological monitoring program for different types of water. The results shall justify the frequency of sampling and testing. Investigation shall be carried out and corrective action taken in case of deviation from prescribed limits.

8.9 Steam coming in contact with the product, primary containers and other product contact surfaces shall be sterile and pyrogen free.

• * *. 9. Manufacturing Process: 9.1. Manufacture of sterile products shall be carried out only in areas under defined conditions. ___________________________________________________________________________ Drugs and Cosmetics Rules, 1945 413 9.2. Bulk raw materials shall be monitored for bio-burden periodically. Bio- burden of bulk solution prior to membrane filtration shall be monitored periodically and a limit of not more than 100 cfu per ml is recommended. 9.3 The time between the start of the preparation of the solution and its sterilization or filtration through a micro-organism retaining filter shall be minimized. There shall be a set maximum permissible time for each product that takes into account its composition and method of storage mentioned in the Master formula record. 9.4. Gases coming in contact with the sterile product shall be filtered through two 0.22 μ hydrophobic filters connected in-series. These filters shall be tested for integrity. Gas cylinders shall not be taken inside aseptic areas. 9.5. Washed containers shall be sterilized immediately before use. Sterilized containers, if not used within an established time, shall be rinsed with distilled or filtered purified water and re-sterilized. 9.6. Each lot of finished product shall be filled in one continuous operation. In each case, where one batch is filled in using more than one operation, each lot shall be tested separately for sterility and held separately till sterility test results are known. 9.7. Special care shall be exercised while filling products in powder form so as not to contaminate the environment during transfer of powder to filling machine-hopper. 10. Form-Fill-Seal Technology or Blow, Fill-Seal Technology: 10.1 Form-Fill-Seal units are specially built automated machines in which through one continuous operation, containers are formed from thermoplastic granules, filled and then sealed. Blow, fill-seal units are machines in which containers are moulded / blown (pre- formed) in separate clean rooms, by non-continuous operations. Note:

¹ Omitted by G.S.R. 431(E), dt. 30.6.2005.

(i) These shall be installed in at least Grade C environment.
(ii) These shall comply with the limits as recommended in Table at Item 4.2. 10.2. Form-Fill-Seal/Blow, Fill-Seal machines used for the manufacture of products for terminal sterilization shall be installed in at least Grade C environment and the filling zone within the machine shall fulfil Grade A requirements. 10.3. Terminally sterilized products.– 10.3.1. Preparation of primary packaging material such as glass bottles, ampoules and rubber stoppers shall be done in at least Grade D environment. Where there is unusual risk to the product from microbial contamination, the above operation shall be done in Grade

C environment. All the processes used for component preparation shall be validt..

10.3.2. Filling of products requiring terminal sterilization shall be done under Grade

A environment with a Grade C background.

10.4 Preparation of solutions, which are to be sterilized by filtration, shall be done in Grade C environment, and if not to be filtered, the preparation of materials and products shall be in a Grade A environment with Grade B in background.

Drugs and Cosmetics Rules, 1945 414 10.5 Filtration (Membrane).-

(i) Solutions for Large Volume Parenterals shall be filtered through a non-fibre releasing,

sterilizing grade cartridge/membrane filter of nominal pore size of 0.22 μ for aseptic

filling whereas 0.45 μ porosity shall be used for terminally sterilized products.

(ii) A second filtration using another 0.22 μ sterilizing grade cartridge / membrane filter shall be performed immediately prior to filling. Process specifications shall indicate the maximum time during which a filtration system may be used with a view to precluding microbial build-up to levels that may affect the microbiological quality of the Large Volume Parenterals.
(iii) The integrity of the sterilized filter shall be verified and confirmed immediately after use by an appropriate method such as Bubble Point, Diffusive Flow or Pressure Hold Test.

10.6 Sterilization (Autoclaving).–

10.6.1. Before any sterilization process is adopted, its suitability for the product and

its efficacy in achieving the desired sterilizing conditions in all parts of each type of load pattern to be processed, shall be demonstrated by physical measurements and by biological indicators, where appropriate.

10.6.2 All the sterilization process shall be appropriately validt.. The validity of the

process shall be verified at regular intervals, but at least annually. Whenever significant modifications have been made to the equipment and product, records shall be maintained thereof.

10.6.3 The sterilizer shall be double ended to prevent mix-ups.

10.6.4 Periodic bio-burden monitoring of products before terminal sterilization shall

be carried out and controlled to limits specified for the product in the Master Formula.

10.6.5 The use of biological indicators shall be considered as an additional method of monitoring the sterilization. These shall be stored and used according to the manufacturer’s instructions. Their quality shall be checked by positive controls. If biological indicators used, strict precautions shall be taken to avoid transferring microbial contamination from them.

10.6.6 There shall be clear means of differentiating ‘ sterilized’ and ‘un-sterilized’ products. Each basket, tray or other carrier of products or components shall be clearly labelled with the name of the material, its batch number, and sterilization status. Indicators shall be used, where appropriate, to indicate whether a batch (or sub-batch) has passed through the sterilization process.

10.6.7 Sterilization records shall be available for each sterilization-run and may also

include thermographs and sterilization monitoring strips. They shall be maintained as part of the batch release procedure.

10.7. Sterilization (By dry heat).–

10.7.1 Each heat sterilization cycle shall be recorded on a time/temperature chart of a suitable size by appropriate equipment of the required accuracy and precision. The position of temperature probes used for controlling and/or recording shall be determined during the validation and, where applicable, shall also be checked against a second independent temperature probe located in the same position. The chart shall form a part of the

Drugs and Cosmetics Rules, 1945 415 batch record. Container mapping may also be carried out in the case of Large Volume Parenterals.

10.7.2 Chemical or biological indicators may also be used, but shall not take the place of physical validation.

10.7.3. Sufficient time shall be allowed for the load to reach the required temperature before measurement of sterilization time commences. This time shall be separately determined for each type of load to be processed.

10.7.4. After the high temperature phase of a heat sterilization cycle, precautions shall be taken against contamination of sterilized load during cooling. Any cooling fluid or gas in contact with the product shall be sterilized unless it can be shown that any leaking container would not be approved for use. Air inlet and outlets shall be provided with bacterial retaining filters.

10.7.5. The process used for sterilization by dry heat shall include air-circulation within the chamber and the maintenance of a positive pressure to prevent the entry of non- sterile air. Air inlets and outlets should be provided with micro-organism retaining filters. Where this process of sterilization by dry heat is also intended to remove pyrogens, challenge tests using endotoxins would be required as part of the validation process.

10.8. Sterilization (By Moist Heat).-

10.8.1 Both the temperature and pressure shall be used to monitor the process. Control instrumentation shall normally be independent of monitoring instrumentation and recording charts. Where automated control and monitoring systems are used for these applications, these shall be validt. to ensure that critical process requirements are met. System and cycle faults shall be registered by the system and observed by the operator. The reading of the independent temperature indicator shall be routinely checked against the chart-recorder during the sterilization period. For sterilizers fitted with a drain at the bottom of the chamber, it may also be necessary to record the temperature at this position throughout the sterilization period. There shall be frequent leak tests done on the chamber during the vacuum phase of the cycle.

10.8.2 The items to be sterilized, other than products in sealed containers, shall be wrapped in a material which allows removal of air and penetration of steam but which prevents re-contamination after sterilization. All parts of the load shall be in contact with the sterilizing agent at the required temperature for the required time.

10.8.3. No Large Volume Parenteral shall be subjected to steam sterilization cycle until it has been filled and sealed.

10.8.4 Care shall be taken to ensure that the steam used for sterilization is of a suitable quality and does not contain additives at a level which could cause contamination of the product or equipment.

10.9. Completion/finalisation of sterile products–

10.9.1. All unit operations and processes in the manufacture of a batch shall have a minimum time specified and the shortest validt. time shall be used from the start of a batch to its ultimate release for distribution.

Drugs and Cosmetics Rules, 1945 416 10.9.2. Containers shall be closed by appropriately validt. methods. Containers closed by fusion e.g. glass or plastic ampoules shall be subjected to 100% integrity testing. Samples of other containers shall be checked for integrity according to appropriate procedures.

10.9.3 Containers sealed under vacuum shall be tested for required vacuum conditions.

10.9.4 Filled containers of parenteral products shall be inspected individually for extraneous contamination or other defects. When inspection is done visually, it shall be done under suitably controlled conditions of illumination and background. Operators doing the inspection shall pass regular eye-sight checks with spectacles, if worn, and be allowed frequent rest from inspection. Where other methods of inspection are used, the process shall be validt. and the performance of the equipment checked at suitable intervals. Results shall be recorded.

11. Product Containers and Closures. –

11.1 All containers and closures intended for use shall comply with the

pharmacopoeial and other specified requirements. Suitable samples sizes, specifications, test

methods, cleaning procedures and sterilization procedures, shall be used to assure that containers, closures and other component parts of drug packages are suitable and are not reactive, additive, adsorptive or leachable or presents the risk of toxicity to an extent that significantly affects the quality or purity of the drug. No second hand or used containers and closures shall be used.

11.2 Plastic granules shall also comply with the pharmacopoeial requirements including physio-chemical and biological tests.

11.3. All containers and closures shall be rinsed prior to sterilization with Water for Injection according to written procedure.

11.4. The design of closures, containers and stoppers shall be such as to make cleaning, easy and also to make airtight seal when fitted to the bottles.

11.8 Glass Bottles. –

11.8.1 Shape and design of the glass bottle shall be rational and standardized. Glass bottles made of USP Type-I and USP Type-II glass shall only be used. Glass bottles shall not be reused. Before use, USP Type-II bottles shall be validt. for the absence of particulate matter generated over a period of the shelf -life of the product and shall be

Drugs and Cosmetics Rules, 1945 417 regularly monitored after the production, following statistical sampling methods. USP Type- III glass containers may be used for non-parenteral sterile products such as Otic Solutions.

11.9. Plastic Containers. –

11.9.1 Pre-formed plastic containers intended to be used for packing of Large Volume Parenteral shall be moulded in-house by one-continuous operation through an automatic machine.

11.9.2. Blowing, filling and sealing (plugging) operation shall be conducted in room(s) conforming to requirements as mentioned in Table III of Item 3.10. Entry to the area where such operations are undertaken, shall be through a series of airlocks. Blowers shall have an air supply which is filtered through 0.22μ filters. Removal of runners and plugging operations shall be conducted under a laminar airflow workstation.

11.10 Rubber Stoppers. –

11.10.1 The rubber stoppers used for Large Volume Parenterals shall comply with specifications prescribed in the current edition of the Indian Pharmacopoeia.

12. Documentation:

12.1 The manufacturing records relating to manufacture of sterile products shall indicate the following details:-

(1) Serial number of the Batch Manufacturing Record.
(2) Name of the product
(3) Reference to Master Formula Record.
(4) Batch/Lot number
(5) Batch/Lot size.
(6) Date of commencement of manufacture and date of completion of manufacture.
(7) Date of manufacture and assigned date of expiry.
(8) Date of each step in manufacturing.
(9) Names of all ingredients with the grade given by the quality control department.
(10) Quality of all ingredients.
(11) Control reference numbers for all ingredients.
(12) Time and duration of blending, mixing, etc. whenever applicable.
(13) pH of solution whenever applicable.
(14) Filter integrity testing records
(15) Temperature and humidity records whenever applicable
(16) Records of plate-counts whenever applicable.
(17) Results of pyrogen and/or bacterial endotoxin & toxicity.
(18) Records of weight or volume of drug filled in containers.
(19) Bulk sterility in case of aseptically filled products.
(20) Leak test records.
(21) Inspection records.
(22) Sterilization records including autoclave leakage test records, load details, date, duration, temperature, pressure, etc.
(23) Container washing records.
(24) Total number of containers filled.
(25) Total numbers of containers rejected at each stage
(26) Theoretical yield, permissible yield, actual yield and variation thereof.
(27) Clarification for variation in yield beyond permissible yield.
(28) Reference numbers of relevant analytical reports.
(29) Details of reprocessing, if any. Drugs and Cosmetics Rules, 1945 418
(30) Name of all operators carrying out different activities.
(31) Environmental monitoring records.
(32) Specimens of printed packaging materials.
(33) Records of destruction of rejected containers and printed packaging materials.
(34) Signature of competent technical staff responsible for manufacture and testing.

Note: (1) Products shall be released only after complete filling and testing.

(2) Result of the tests relating to sterility, pyrogens, and Bacterial endotoxins shall be maintained in the analytical records.
(3) Validation details and simulation trial records shall be maintained separately,
(4) Records of environmental monitoring like temperature, humidity, microbilogical data, etc. shall be maintained. Records of periodic servicing of HEPA filters, sterilizers and other periodic maintenance of facilities and equipment carried out also be maintained.
(5) Separate facilities shall be provided for filling-cum-sealing of Small

Volume Injectables and Large Volume Parenterals.

(6) It is advisable to provide separate facilities for manufacture of Large Volume Parenterals in glass containers and / or plastic containers.
(7) For manufacture of Large Volume Parenterals in plastic containers, it is advisable to instal automatic (with all operations) Form–Fill- Seal machines having one continuous operation.

PART IB

SPECIFIC REQUIREMENTS FOR MANUFACTURE OF ORAL SOLID DOSAGE FORMS (TABLETS AND CAPSULES)

Note: - The General Requirements as given in Part 1 of this Schedule relating to requirements of Good Manufacturing Practices for Premises and materials for pharmaceutical products shall be complied with, mutatis mutandis, for the manufacture of oral Solid Dosage Forms (Tablets and Capsules). In addition to these requirements, the following Specific Requirement shall also be followed, namely :-

1. General:

1.1 The processing of dry materials and products creates problems of dust control and cross-contamination. Special attention is therefore, needed in the design, maintenance and use of premises and equipment in order to overcome these problems. Wherever required, enclosed dust control manufacturing systems shall be employed.

1.2. Suitable environmental conditions for the products handled shall be maintained by installation of air-conditioning wherever necessary. Effective air-extraction systems, with discharge points situated to avoid contamination of other products and processes shall be provided. Filters shall be installed to retain dust and protect the factory and local environment.

Drugs and Cosmetics Rules, 1945 419 1.3. Special care shall be taken to protect against subsequent contamination of the product by particles of metal or wood. The use of metal detector is recommended. Wooden equipment should be avoided. Screens, sieves, punches and dies shall be examined for wear and tear or for breakage before and after each use.

1.4. All ingredients for a dry product shall be sifted before use unless the quality of the input material can be assured. Such sifting shall normally be carried out at dedicated areas.

1.5.

1[Where the facilities are designed to provide special environmental conditions of pressure differentials between rooms, these conditions shall be regularly monitored and any deviation shall be brought to the immediate attention of the production and quality assurance departments].

1.6. Care shall be taken to guard against any material lodging and remaining undetected in any processing or packaging equipment. Particular care shall be taken to ensure that any vacuum, compressed air or air-extraction nozzles are kept clean and that there is no

evidence of lubricants leaking into the product from any part of the equipments.

2. Sifting, Mixing and Granulation:

2.1. Unless operated as a closed system, mixing, sifting and blending equipments shall be fitted with dust extractors

1[or in a dedicated area for each operation].

2.2. Residues from sieving operations shall be examined periodically for evidence of the presence of unwanted materials.

2.3. Critical operating parameters like time and temperature for each mixing, blending and drying operation shall be specified in a Master Formula, monitored during processing, and recorded in the batch records.

2.4. Filter bags fitted to fluid-bed dryer shall not be used for different products, without being washed in-between use. With certain highly potent or sensitizing products, bags specific to one product only shall be used. Air entering the dryer shall be filtered. Steps shall be taken to prevent contamination of the site and local environment by dust in the air leaving the dryer due to close positioning of the air-inlets and exhaust.

2.5. Granulation and coating solutions shall be made, stored and used in a manner which minimizes the risk of contamination or microbial growth. 3. Compressions (Tablets):

3.1. Each tablet compressing machine shall be provided with effective dust control

facilities to avoid cross-contamination. Unless the same product is being made on each machine, or unless the compression machine itself provides its own enclosed air controlled environment, the machine shall be installed in separate cubicles. 3.2. Suitable physical, procedural and labelling arrangements shall be made to prevent mix up of materials, granules and tablets on compression machinery.

3.3. Accurate and calibrated weighing equipment shall be readily available and used for in-process monitoring of tablet weight variation. Procedures used shall be capable of detecting out-of-limits tablets.

Drugs and Cosmetics Rules, 1945 420 3.4. At the commencement of each compression run and in case of multiple compression points in a compression machine, sufficient individual tablets shall be examined at fixed intervals to ensure that a tablet from each compression station or from each compression point has been inspected for suitable pharmacopoeial parameters like ‘appearance’, ‘weight variation’, ‘disintegration’, ‘hardness’, ‘friability’ and ‘thickness’. The results shall be recorded as part of the batch documentation.

3.5. Tablets shall be de-dusted, preferably by automatic device and shall be monitored for the presence of foreign materials besides any other defects.

3.6. Tablets shall be collected into clean, labelled containers.

3.7. Rejected or discarded tablets shall be isolated in identified containers and their quantity recorded in the Batch Manufacturing Record. 3.8 In-process control shall be employed to ensure that the products remain within specification. During compression, samples of tablets shall be taken at regular intervals of not greater than 30 minutes to ensure that they are being produced in compliance with specified in-process specification. The tablets shall also be periodically checked for additional parameters such as ‘appearance’, ‘weight variation’, ‘disintegration’, ‘hardness’, ‘friability’ and ‘thickness’ and contamination by lubricating oil. 4. Coating (Tablets): 4.1. Air supplied to coating pans for drying purposes shall be filtered air and of suitable quality. The area shall be provided with suitable exhaust system and environmental control (temperature, humidity) measures. 4.2 Coating solutions and suspensions shall be made afresh and used in a manner, which shall minimize the risk of microbial growth. Their preparation and use shall be documented and recorded. 5. Filling of Hard Gelatin Capsule: Empty capsules shells shall be regarded as ‘drug component’ and treated accordingly. They shall be stored under conditions which shall ensure their safety from the effects of excessive heat and moisture. 6. Printing (Tablets and Capsules) 6.1. Special care shall be taken to avoid product mix-up during any printing of tablets and capsules. Where different products, or different batches of the same product, are printed simultaneously, the operations shall adequately be segregated. Edible grade colours and suitable printing ink shall be used for such printing. 6.2. After printing, tablets and capsules shall be approved by Quality Control before release for packaging or sale. 7. Packaging (Strip and Blister): 7.1. Care shall be taken when using automatic tablet and capsule counting, strip and blister packaging equipment to ensure that all ‘rogue’ tablets, capsules or foils from packaging operation are removed before a new packaging operation is commenced. There shall be an independent recorded check of the equipment before a new batch of tablets or capsules is handled. 7.2. Uncoated tablets shall be packed on equipment designed to minimize the risk of cross-contamination. Such packaging shall be carried out in an isolated area when potent tablets or Beta-Iactum containing tablets are being packed.

¹ Ins. by G.S.R. 431(E), dt. 30.6.2005.

___________________________________________________________________________

Drugs and Cosmetics Rules, 1945 421 7.3. The strips coming out of the machine shall be inspected for defects such as misprint, cuts on the foil, missing tablets and improper sealing. 7.4. Integrity of individual packaging strips and blisters shall be subjected to vacuum test periodically to ensure leak proofness of each pocket strip and blister and records maintained. PART IC

SPECIFIC REQUIREMENTS FOR MANUFACTURE OF ORAL LIQUIDS (SYRUPS, ELIXIRS, EMULSIONS AND SUSPENSIONS)

Note: The General Requirements as given in Part I of this Schedule relating to Requirements of Good Manufacturing Practices for Premises and Materials for pharmaceutical products shall be complied with, mutatis mutandis, for the manufacture of (Syrups, Elixirs, Emulsions and Suspensions). In addition to these requirements, the following Specific Requirements shall also be followed, namely:-

1. Building and Equipment:.

1.1. The premises and equipment shall be designed, constructed and maintained to suit the manufacturing of Oral Liquids. The layout and design of the manufacturing area shall strive to minimize the risk of cross-contamination and mix-ups.

1.2. Manufacturing area shall have entry through double door airlock facility. It shall be made fly proof by use of ‘fly catcher’ and/or ‘air curtain’.

1.3. Drainage shall be of adequate size and have adequate traps, without open channels and the design shall be such as to prevent back flow. Drains shall be shallow to facilitate cleaning and disinfecting.

1.4. The production area shall be cleaned and sanitized at the end of every production process.

1.5. Tanks, containers, pipe work and pumps shall be designed and installed so that they can be easily cleaned and sanitized. Equipment design shall be such as to prevent accumulation of residual microbial growth or cross-contamination.

1.6. Stainless steel or any other appropriate material shall be used for parts of equipments coming in direct contact with the products. The use of glass apparatus shall be minimum.

1.7. Arrangements for cleaning of containers, closures and droppers shall be made with the help of suitable machines/devices equipped with the high pressure air, water and steam jets.

1.8. The furniture used shall be smooth, washable and made of stainless steel

1[or any other appropriate material which is scratch proof, washable and smooth].

2. Purified Water. 2.1. The chemical and microbiological quality of purified water used shall be specified and monitored routinely. The microbiological evaluation shall include testing for absence of pathogens and shall not exceed 100 cfu/ml (as per Appendix 12.5 of IP 1996.) ___________________________________________________________________________

1. Added by G.S.R. 431(E), dt. 30.6.2005.

Drugs and Cosmetics Rules, 1945 422 2.2. There shall be a written procedure for operation and maintenance of the purified water system. Care shall be taken to avoid the risk of microbial proliferation with appropriate methods like re-circulation, use of UV treatment, treatment with heat and sanitizing agent. After any chemical sanitisation of the water system, a flushing shall be done to ensure that the sanitizing agent has been effectively removed. 3. Manufacturing: 3.1.

1[Manufacturing personnel shall wear wherever required, non-fiber shedding clothing to prevent contamination of the products]. 3.2. Materials likely to shed fibre like gunny bags, or wooden pallets shall not be carried into the area where products or cleaned-containers are exposed. 3.3. Care shall be taken to maintain the homogenecity of emulsion by use of appropriate emulsifier and suspensions by use of appropriate stirrer during filling. Mixing and filling processes shall be specified and monitored. Special care shall be taken at the beginning of the filling process, after stoppage due to any interruption and at the end of the process to ensure that the product is uniformly homogenous during the filling process. 3.4. The primary packaging area shall have an air supply which is filtered through 5 micron filters. The temperature of the area shall not exceed 30 degrees centigrade. 3.5. When the bulk product is not immediately packed, the maximum period of storage and storage conditions shall be specified in the Master Formula. The maximum period of storage time of a product in the bulk stage shall be validt.. PART ID SPECIFIC REQUIREMENTS FOR MANUFACTURE OF TOPICAL PRODUCTS ,

i.e. EXTERNAL PREPARATIONS (CREAMS, OINTMENTS, PASTES,

EMULSIONS, LOTIONS, SOLUTIONS, DUSTING POWDERS AND IDENTICAL PRODUCTS) Note: The General Requirements as given in Part I of this Schedule relating to Requirements of Good Manufacturing Practices for Premises and Materials for pharmaceutical products shall be complied with, mutatis mutandis, for the manufacture of Topical Products i.e. External preparations (Creams, Ointments, Pastes, Emulsions, Lotions, Solutions, Dusting powders and identical products used for external applications). In

addition to these requirements, the following Specific Requirements shall also be followed,

namely: - 1. The entrance to the area where topical products are manufactured shall be through a suitable airlock. Outside the airlock, insectocutors shall be installed. 2. The air to this manufacturing area shall be filtered through at least 20μ air filters and shall be air-conditioned.

• * *. 3. The area shall be fitted with an exhaust system of suitable capacity to effectively remove vapours, fumes, smoke, floating dust particles. 4. The equipment used shall be designed and maintained to prevent the product from being accidentally contaminated with any foreign matter or lubricant. 5. 3[Suitable cleaning equipment and material] shall be used in the process of cleaning or drying the process equipment or accessories used. _____________________________________________________________________

¹ Subs. by G.S.R. 431(E), dt. 30.6.2005.

³ Subs. by G.S.R. 431(E), dt. 30.6.2005.

2. The words “The air shall be ventilated.” omitted by G.S.R. 431(E), dt. 30.6.2005.

Drugs and Cosmetics Rules, 1945 423 6. Water used in compounding shall be Purified Water IP. 7. Powders, wherever used, shall be suitably sieved before use. 8. Heating vehicles and a base like petroleum jelly shall be done in separate mixing area in suitable stainless steel vessels, using steam, gas, electricity, solar energy, etc. 9. A separate packing section may be provided for primary packaging of the products. PART 1E

SPECIFIC REQUIREMENTS FOR MANUFACTURE OF METERED-DOSE-INHALERS (MDI) Note: The General Requirements as given in Part I of this Schedule relating to Requirements of Good Manufacturing Practices for Premises and Materials for pharmaceutical products shall be complied with, mutatis mutandis, for the manufacture of Metered-Dose-Inhalers (MDI). In addition to these requirements, the following Specific Requirements shall also be followed, namely: -

1. General:

Manufacture of Metered-Dose-Inhalers shall be done under conditions which shall ensure minimum microbial and particulate contamination. Assurance of the quality of components and the bulk product is very important. Where medicaments are in suspended state, uniformity of suspension shall be established.

2. Building and Civil Works:

2.1. The building shall be located on a solid foundation to reduce risk of cracking walls and floor due to the movement of equipment and machinery.

2.2 All building surfaces shall be impervious, smooth and non-shedding. Flooring shall be continuous and provided with a cove between the floor and the wall as well as the wall to the ceiling. Ceiling shall be solid, continuous and covered to walls. Light fittings and air-grills shall be flush with the ceiling. All service lines requiring maintenance shall be erected in such a manner that these are accessible from outside the production area.

2.3. The manufacturing area shall be segregated into change rooms for personnel, container preparation area, bulk preparation and filling area, quarantine area and spray testing and packing areas.

2.4. Secondary change rooms shall be provided for operators to change from factory clothing to special departmental clothing before entering the manufacturing and filling area.

2.5. Separate area shall be provided for de-cartoning of components before they are air washed.

2.6. The propellants used for manufacture shall be delivered to the manufacturing area distribution system by filtering them through 2μ filters. The bulk containers of propellants shall be stored, suitably identified, away from the manufacturing facilities.

Drugs and Cosmetics Rules, 1945 424 3. Environmental Conditions:

3.1. Where products or clean components are exposed, the area shall be supplied with filtered air of Grade C.

3.2. The requirements of temperature and humidity in the manufacturing area shall be decided depending on the type of product and propellants handled in the facility. Other support areas shall have comfort levels of temperature and humidity.

3.3. There shall be a difference in room pressure between the manufacturing area and the support areas and the differential pressure shall be not less than 15 Pascals (0.06 inches or 1.5 mm water gauge).

3.4. There shall be a written schedule for the monitoring of environmental

conditions. Temperature and humidity shall be monitored daily.

4. Garments:

4.1. Personnel in the manufacturing and filling section shall wear suitable single- piece-garment made out of non-shedding, tight weave material. Personnel in support areas shall wear clean factory uniforms.

4.2. Gloves made of suitable material having no interaction with the propellants shall be used by the operators in the manufacturing and filling areas. Preferably, disposable gloves shall be used.

4.3. Suitable department-specific personnel protective equipment like footwear and safety glasses shall be used wherever hazard exists.

5. Sanitation:

5.1. There shall be written procedures for the sanitation of the MDI manufacturing facility. Special care should be taken to handle residues and rinses of propellants.

5.2. Use of water for cleaning shall be restricted and controlled. Routinely used disinfectants are suitable for sanitizing the different areas. Records of sanitation shall be maintained.

6. Equipmen:

6.1. Manufacturing equipment shall be of closed system. The vessels and supply lines shall be of stainless steel.

6.2. Suitable check weights, spray testing machines and labelling machines shall be provided in the department.

6.3. All the equipment shall be suitably calibrated and their performance validt. on receipt and thereafter periodically.

7. Manufacture:

7.1. There shall be an approved Master Formula Records for the manufacture of metered dose inhalers. All propellants, liquids and gases shall be filtered through 2μ filters to remove particles.

Drugs and Cosmetics Rules, 1945 425

7.2. The primary packing material shall be appropriately cleaned by compressed air suitably filtered through 0.2μ filter. The humidity of compressed air shall be controlled as applicable.

7.3. The valves shall be carefully handled and after de-cartoning, these shall be kept in clean, closed containers in the filling room.

7.4. For suspensions, the bulk shall be kept stirred continuously.

7.5. In-process controls shall include periodical checking of weight of bulk formulation filled in the containers. In a two-shot-filling process (liquid filling followed by gaseous filling), it shall be ensured that 100% check on weight is carried out.

7.6. Filled containers shall be quarantined for a suitable period established by the manufacturer to detect leaking containers prior to testing, labelling and packing.

8. Documentation-

8.1. In addition to the routine good manufacturing practices documentation, manufacturing records shall show the following additional information:-

(1) Temperature and humidity in the manufacturing area.
(2) Periodic filled weights of the formulation.
(3) Records of rejections during on-line check weighing.
(4) Records of rejection during spray testing. PART 1F SPECIFIC REQUIREMENTS OF PREMISES, PLANT AND MATERIALS FOR MANUFACTURE OF ACTIVE PHARMACEUTIAL INGREDIENTS (BULK DRUGS) Note : The General Requirements as given in Part I of this Schedule relating to Requirements of Good Manufacturing Practices for premises and Materials for pharmaceutical products shall be complied with, mutatis mutandis, for the manufacture of active pharmaceutical ingredients (Bulk Drugs). In addition to these requirements, the following Specific Requirements shall also be followed, namely: - 1. Building and Civil Works: 1.1. Apart from the building requirements contained in Part I, General ante, the active pharmaceutical ingredients facilities for manufacture of hazardous reactions, Beta- Lactum antibiotics. Steroids and Steroidal Hormones / Cytotoxic substances shall be provided in confined areas to prevent contamination of the other drugs manufactured. 1.2. The final stage of preparation of a drug, like isolation/filtration/drying/ milling / sieving and packing operations shall be provided with air filtration systems including pre-filters and finally with a 5 micron filter. Air handling systems with adequate number of air changes per hour or any other suitable system to control the air borne contamination shall be Drugs and Cosmetics Rules, 1945 426 provided. Humidity / Temperature shall also be controlled for all the operations wherever required. 1.3. Air filtration systems including pre-filters and particulate matter retention air filters shall be used, where appropriate, for air supplies to production areas. If air is re- circulated to production areas, measures shall be taken to control re-circulation of floating dust particles from production. In areas where air contamination occurs during production, there shall be adequate exhaust system to control contaminants. 1.4. Ancillary area shall be provided for Boiler-house. Utility areas like heat exchangers, chilling workshop, store and supply of gases shall also be provided. 1.5. For specified preparation like manufacture of sterile products and for certain antibiotics, sex hormones, cytotoxic and oncology products, separate enclosed areas shall be designed. The requirements for the sterile active pharmaceutical ingredient shall be in line with the facilities required for formulation to be filled aseptically. 2. Sterile Products: Sterile active pharmaceutical ingredient filled aseptically shall be treated as formulation from the stage wherever the process demands like crystallization, lyophilisation, filtration etc. All conditions applicable to formulations that are required to be filled aseptically shall apply mutatis mutandis for the manufacture of sterile active pharmaceutical ingredients involving stages like filtration, crystallization and lyophilisation. 3. Utilities / Services: Equipment like chilling plant, boiler, heat exchangers, vacuum and gas storage vessels shall be serviced, cleaned, sanitized and maintained at appropriate intervals to prevent mal-functions or contamination that may interfere with safety, identity, strength, quality or purity of the drug product. 4. Equipment Design, Size and Location: 4.1. Equipment used in the manufacture, processing, packing or holding of an active pharmaceutical ingredient shall be of appropriate design, adequate size and suitably located to facilitate operations for its intended use and for its cleaning and maintenance. 4.2. If equipment is used for different intermediates and active pharmaceutical ingredients, proper cleaning before switching from one product to another becomes particularly important. If cleaning of a specific type of equipment is difficult, the equipment may need to be dedicated to a particular intermediate or active pharmaceutical ingredient. 4.3. The choice of cleaning methods, detergents and levels of cleaning shall be defined and justified. Selection of cleaning agents (e.g. solvents) should depend on :
- (a) the suitability of the cleaning agent to remove residues of raw materials; intermediates, precursors, degradation products and isomers, as appropriate.
- (b) whether the cleaning agent leaves a residue itself;
- (c) compatibility with equipment construction materials like centrifuge/ filtration, dryer/fluid bed dryer, rotocone proton dryer, vacuum dryer, frit mill, multi-mill/jet mills/sewetters cut sizing;
- (d) test for absence of intermediate or active pharmaceutical ingredient in the final rinse. Drugs and Cosmetics Rules, 1945 427 4.4. Written procedures shall be established and followed for cleaning and maintenance of equipment, including utensils used in the manufacture, processing, packing or holding of active pharmaceutical ingredients. These procedures shall include but should not be limited to the following :
- (a) assignment of responsibility for cleaning and maintaining equipment;
- (b) maintenance and cleaning program schedules, including where appropriate, sanitizing schedules;
- (c) a complete description of the methods and materials used to clean and maintain equipment, including instructions for de-assembling and re- assembling each article of equipment to ensure proper cleaning and maintenance.;
- (d) removal or obliteration of previous batch identification;
- (e) protection of clean equipment from contamination prior to use;
- (f) inspection of equipment for cleanliness immediately before use;
- (g) establishing the maximum time that may elapse between completion of processing and equipment cleaning as well as between cleaning and equipment reuse. 4.5. Equipment shall be cleaned between successive batches to prevent contamination and carry-over of degraded material or contaminants unless otherwise established by validation. 4.6. As processing approaches the final purified active pharmaceutical ingredient, it is important to ensure that incidental carry over between batches does not have adverse impact on the established impurity profile. However, this does not generally hold good for any biological, active pharmaceutical ingredient where many of the processing steps are accomplished aseptically and where it is necessary to clean and sterilize equipment between batches. 5. In-Process Controls: 5.1. In-process control for chemical reactions may include the following:
- (a) reaction time or reaction completion;
- (b) reaction mass appearance, clarity, completeness or pH solutions;
- (c) reaction temperature;
- (d) concentration of a reactant;
- (e) assay or purity of the product;
- (f) process completion check by TLC / any other means. 5.2. In-process control for physical operations may include the following:
- (a) appearance and colour;
- (b) uniformity of the blend;
- (c) temperature of a process;
- (d) concentration of a solution;
- (e) processing rate or time;
- (f) particle size analysis;
- (g) bulk/tap density;
- (h) pH determination;
  - (i) moisture content. Drugs and Cosmetics Rules, 1945 428 6. Product Containers and Closures: 6.1. All containers and closures shall comply with the pharmacopoeial or any other requirement, suitable sampling methods, sample sizes, specifications, test methods, cleaning procedures and sterilization procedures, when indicated, shall be used to assure that containers, closures and other component parts of drug packages are suitable and are not reactive, additive, adsorptive or leachable to an extent that significantly affects the quality or purity of the drug. 6.2. The drug product container shall be tested or re-examined as appropriate and approved or rejected and shall be identified and controlled under a quarantine system designed to prevent their use in manufacturing or processing operations for which these are unsuitable. 6.3 Container closure system shall provide adequate protection against foreseeable external factors in storage / transportation and use that may cause deterioration or contamination of the active pharmaceutical ingredient. 6.4. Bulk containers and closures shall be cleaned and, where indicated by the nature of the active pharmaceutical ingredient, sterilized to ensure that they are suitable for their intended use. 6.5. The container shall be conspicuously marked with the name of the product and the following additional information concerning :
- (a) quality and standards, if specified;
- (b) manufacturing licence number/drug master file number (whichever applicable), batch number;
- (c) date of manufacture and date of expiry;
- (d) method for container disposal (label shall give the methodology, if required);
- (e) storage conditions, if specified and name and address of the manufacturer, if available. 6.6. Areas for different operation of active pharmaceutical ingredients (bulk drugs) section shall have appropriate area which may be suitably partitioned for different operations. PART II REQUIREMENTS OF PLANT AND EQUIPMENT . External Preparations: The following equipment is recommended for the manufacture of ‘External preparations’ i.e. Ointments, Emulsion, Lotions, Solutions, Pastes, Creams, Dusting powders and such identical products used for external applications, whichever is applicable, namely :- (1)

1[Mixing and storage tanks preferably of stainless steel or any other appropriate

material].

(2) Jacketted Kettle 2[Stainless steel container] (steam, gas or electrically heated).
(3) Mixer (electrically operated).
(4) Planetary mixer.
(5) A colloid mill or a suitable emulsifier.
(6) A triple roller mill or an ointment mill. _________________________________________________________________ Drugs and Cosmetics Rules, 1945 429
(7) Liquid filling equipment (electrically operated).
(8) Jar or tube filling equipment
- • * * Area. - (1) A minmum area of thirty square meters for basic installation and ten square meters for Ancillary area is recommended.
(2) Areas for formulations meant for external use and internal use shall be separately provided to avoid mix-up. 2[Note: The requirement for ancillary area in this part shall not apply to units registered before 1st January, 2002.] 2. Oral Liquid Preparations: The following equipments are recommended for the manufacture of oral/internal use preparations i.e. Syrups, Elixirs, Emulsions and Suspensions, whichever is applicable, namely: - (1) 3[Mixing and storage tanks preferably of Stainless steel or any other appropriate material].
(2) Jacketted Kettle / Stainless steel tank (steam, gas or electrically heated).
(3) Portable stirrer (electrically operated).
(4) A colloid mill or suitable emulsifier (electrically operated).
(5) Suitable filtration equipment (electrically operated).
(6) Semi-automatic/automatic bottle filling machine.
(7) Pilfer proof cap sealing machine.
(8) Water distillation unit or deionizer.
(9) Clarity testing inspection units. Area. - A minimum area of thirty square meters for basic installation and ten square meters for Ancillary area is recommended. 2[Note: The requirement for ancillary area in this part shall not apply to units registered before 1st January, 2002.] 3. Tablets: The Tableting section shall be free from dust and floating particles and may be air- conditioned. For this purpose, each 3[tablet compression machine] shall be isolated into cubicles and connected to a vacuum dust collector or an exhaust system. For effective operations, the tablet production department shall be divided into four distinct and separate sections as follows: -
- (a) Mixing, Granulation and Drying section.
- (b) Tablet compression section.
- (c) Packaging section (strip/blister machine wherever required).
- (d) Coating section (wherever required). 3.1. The following electrically operated equipments are recommended for the manufacture of compressed tablets and hypodermic tablets, in each of the above sections, namely: -
- (a) Granulation-cum-Drying section:
(1) Disintegrator and sifter.
(2) Powder mixer.
(3) Mass mixer/Planetary mixer/Rapid mixer granulator. _______________________________________________________________ 2.

¹ Subs. by G.S.R. 431(E), dt. 30.6.2005.

² Ins. by G.S.R. 431(E), dt. 30.6.2005.

¹ Omitted by G.S.R. 431(E), dt. 30.6.2005.

Drugs and Cosmetics Rules, 1945 430 (4)

1[Granulator wherever required].

(5) Thermostatically controlled hot air oven with trays (preferably mounted on a trolley)/Fluid bed dryer.
(6) Weighing machines.
- (b) Compression section:
(1) Tablet compression machine, single/multi punch/rotatory.
(2) Punch and dies storage cabinets. (3) Tablet de-duster
(4) Tablet inspection unit/belt. (5)

1[Dissolution test apparatus wherever required].

(6) In-process testing equipment like single pan electronic balance, hardness tester, friability and disintegration test apparatus.
(7) Air-conditioning and dehumidification arrangement (wherever necessary)
- (c) Packaging section:
(1) Strip/blister packaging machine.
(2) Leak test apparatus (vacuum system).
(3) Tablet counters (wherever applicable).
(4) Air-conditioning and dehumidification arrangement (wherever applicable). Area. – A minimum area of sixty square meters for basic installation and twenty square meters for Ancillary area is recommended for un-coated tablets.
- (d) Coating section:
(1) Jacketted kettle 2[stainless steel container or any other appropriate material] (steam, gas or electrically heated for preparing coating suspension).
(2) Coating pan (Stainless steel).
(3) Polishing pan (where applicable).
(4) Exhaust system (including vacuum dust collector).
(5) Air-conditioning and Dehumidification Arrangement.
(6) Weighing balance. 2[Note: The requirement for ancillary area in this part shall not apply to units registered before 1st January, 2002.] 3.2. The coating section shall be made dust free with suitable exhaust system to remove excess powder and fumes resulting from solvent evaporation. It shall be air- conditioned and dehumidified wherever considered necessary. Area. – A minimum additional area of thirty square meters for coating section for basic installation and ten square meters for Ancillary area is recommended. Separate area and equipment for mixing, granulation, drying, tablet compression, coating and packing shall be provided for Penicillin group of drugs on the lines indicated above. In case of operations involving dust and floating particles, care shall be exercised to avoid cross-contamination. 2[Note: The requirement for ancillary area in this part shall not apply to units registered before 1st January, 2002.] 3.3. The manufacture of Hypodermic tablets shall be conducted under aseptic conditions in a separate air-conditioned room, the walls of which shall be smooth and washable. The granulation, tableting and packing shall be done in this room. _______________________________________________________________ Drugs and Cosmetics Rules, 1945 431 3.4. The manufacture of effervescent and soluble
- • * * tablets shall be carried out in air- conditioned and dehumidified areas.

¹ Subs. by G.S.R. 431(E), dt. 30.6.2005.

² Ins. by G.S.R. 431(E), dt. 30.6.2005.

4. Powders:

The following equipment is recommended for the manufacture of powders, namely:-

(1) Disintegrator.
(2) Mixer (electrically operated).
(3) Sifter.
(4) Stainless steel vessels and scoops of suitable sizes.
(5) Filling equipment
- • * *.
(6) Weighing balance. In the case of operation involving floating particles of fine powder, suitable exhaust system shall be provided. Workers should be provided with suitable masks during operation. Area. – A minimum area of thirty square meters is recommended to allow for the basic installations. Where the actual blending is to be done on the premises, an additional room shall be provided for the purpose. 2[Note: The requirement for additional room in this part shall not apply to units registered before 1st January, 2002.]

5. Capsules:

For the manufacture of capsules, separate enclosed area suitably air-conditioned and dehumidified with an airlock arrangement shall be provided. The following equipment is recommended for filling Hard Gelatin Capsules, namely: -

(1) Mixing and blending equipment (electrically or power driven).
(2) Capsules filling units
- • * *.
(3) Capsules counters (wherever applicable).
(4) Weighing balance.
(5) Disintegration test apparatus.
(6) Capsule polishing equipment. Separate equipment and, filling and packaging areas shall be provided in penicillin and non-penicillin sections. In case of operations involving floating particles of fine powder, a suitable exhaust system shall be provided. Manufacture and filling shall be carried out in air- conditioned area. The room shall be dehumidified. Area. –A minimum area of twenty-five square meters for basic installation and ten square meters for Ancillary area each for penicillin and non-penicillin sections is recommended. 2[Note: The requirement for ancillary area in this part shall not apply to units registered before 1st January, 2002.]

6. Surgical Dressing:

The following equipment is recommended for the manufacture of Surgical Dressings other than Absorbent Cotton Wool, namely:-

(1) Rolling machine. ______________________________________________________________________ 1.

² Ins. by G.S.R. 431(E), dt. 30.6.2005.

Omitted by G.S.R. 431(E), dt. 30.6.2005.

Drugs and Cosmetics Rules, 1945 432

(2) Trimming machine.
(3) Cutting equipment.
(4) Folding and pressing machine for gauze.
(5) Mixing tanks for processing medicated dressing.
(6) Hot air dry oven.
(7) Steam sterilizer or dry heat sterilizer or other suitable equipment.
(8) Work tables/benches for different operations. Area. – A minimum area of thirty square meters is recommended to allow for the basic installations. In case medicated dressings are to be manufactured, another room with a minimum area of thirty square meters shall be provided.

7. Ophthalmic Preparations:.

For the manufacture of Ophthalmic preparations, separate enclosed areas with airlock arrangement shall be provided. The following equipment is recommended for the manufacture under aseptic conditions of Eye-Ointment, Eye-Lotions and other preparations for external use, namely:-

(1) Thermostatically controlled hot air ovens (preferably double ended).
(2) Jacketted kettle/stainless steel tanks (steam, gas or electrically heated).
(3) Mixing and storage tanks of stainless steel/Planetary mixer.
(4) Colloid mill or ointment mill.
(5) Tube filling and crimping equipment (semi-automatic or automatic filling machines).
(6) Tube cleaning equipment (air jet type).
(7) Tube washing and drying equipment, if required.
(8) Automatic vial washing machine.
(9) Vial drying oven.
(10) Rubber bung washing machine.
(11) Sintered glass funnel, Seitz filter and filter candle (preferably cartridge and membrane filters).
(12) Liquid filling equipment (semi-automatic or automatic filling machines).
(13) Autoclave (preferably ventilator autoclave).
(14) Air conditioning and dehumidification arrangement (preferably centrally air- conditioned and dehumidification system).
(15) Laminar airflow units. Area. – (1) A minimum area of twenty-five square meters for basic installation and ten square meters for Ancillary area is recommended. Manufacture and filling shall be carried out in air-conditioned areas under aseptic conditions. The rooms shall be further dehumidified as considered necessary if preparations containing antibiotics are manufactured.
(2) Areas for formulations meant for external use and internal use shall be separately provided to avoid mix up. 1[Note: The requirement for ancillary area in this Part shall not apply to units registered before 1st January, 2002.] 8. Pessaries and Suppositories:
- (i) The following equipment is recommended for manufacture of Pessaries and Suppositories, namely: -
(1) Mixing and pouring equipment
(2) Moulding equipment.
(3) Weighing devices. ___________________________________________________________________________ Drugs and Cosmetics Rules, 1945 433 Area. – A minimum area of twenty square meters is recommended to allow for the basic installation.
- (ii) In the case of pessaries manufactured by granulation and compression, the requirements as indicated under “Item 3 of Tablet”, shall be provided. 9. Inhalers and Vitrallae: The following equipment is recommended for manufacture of inhalers and vitrallae, namely: -
(1) Mixing equipment.
(2) Graduated delivery equipment for measurement of the medicament during filling.
(3) Sealing equipment. Area. – An area of minimum twenty square meters is recommended for the basic installations.

¹ Ins. by G.S.R. 431(E), dt. 30.6.2005.

10. Repacking of drugs and pharmaceutical chemicals:

The following equipment is recommended for repacking of drugs and pharmaceuticals chemicals, namely:-

(1) Powder disintegrator.
(2) Powder sifter (electrically operated).
(3) Stainless steel scoops and vessels of suitable sizes.
(4) Weighing and measuring equipment.
(5) Filling equipment (semi-automatic / automatic machines).
(6) Electric sealing machine. Area. – An area of minimum thirty square metres is recommended for the basic installation. In case of operations involving floating particles of fine powder, a suitable exhaust system shall be provided. 11. Parenteral Preparations The whole operation of manufacture of parenteral preparations (small volume injectables and large volume parenterals) in glass and plastic containers may be divided into the following separate areas/rooms, namely: -

11.1 Parenteral preparations in glass containers: –

(1) Water management area: This includes water treatment and storage.
(2) Containers and closures preparation area: This includes washing and drying of ampoules, vials, bottles and closures.
(3) Solution preparation area: This includes preparation and filtration of solution.
(4) Filling, capping and sealing area: This includes filling and sealing of ampoules and/or filling, capping and sealing of vials and bottles.
(5) Sterilization area
(6) Quarantine area
(7) Visual inspection area.
(8) Packaging area Drugs and Cosmetics Rules, 1945 434 The following equipment is recommended for different above-mentioned areas, namely: -
- (a) Water management area:
(1) De-ionised water treatment unit.
(2) Distillation (multi-column with heat exchangers) unit.
(3) Thermostatically controlled water storage tank.
(4) Transfer pumps.
(5) Stainless steel service lines for carrying water into user areas.
- (b) Containers and closures preparation area:
(1) Automatic rotary ampoule/vial/bottle washing machine having separate air, water distilled water jets.
(2) Automatic closures washing machine,
(3) Storage equipment for ampoules, vials, bottles and closures.
(4) Dryer/sterilizer (double ended)
(5) Dust proof storage cabinets.
(6) Stainless steel benches/stools.
- (c) Solution preparation area:
(1) Solution preparation and mixing stainless steel tanks and other containers.
(2) Portable stirrer.
(3) Filtration equipment with cartridge and membrane filters/bacteriological filters.
(4) Transfer pumps.
(5) Stainless steel benches/stools
- (d) Filling, capping and sealing area:
(1) Automatic ampoule/vial/bottle filling, sealing and capping machine under laminar air flow workstation.
(2) Gas lines (Nitrogen, Oxygen, Carbon dioxide) wherever required.
(3) Stainless steel benches / stools.
- (e) Sterilization area:
(1) Steam sterilizer (preferably with computer control for sterilization cycle along with trolley sets for loading/unloading containers before and after sterilization).
(2) Hot air sterilizer (preferably double ended).
(3) Pressure leak test apparatus.
- (f) Quarantine area. –
(1) Storage cabinets.
(2) Raised platforms/steel racks.
- (g) Visual inspection area:
(1) Visual inspection units (preferably conveyor belt type and composite white and black assembly supported with illumination).
(2) Stainless steel benches/stools.
- (h) Packaging area. -
(1) Batch coding machine (preferably automatic). Drugs and Cosmetics Rules, 1945 435
(2) Labelling unit (preferably conveyor belt type).
(3) Benches/stools. Area. – (1) A minimum area of one hundred and fifty square meters for the basic installation and an Ancillary area of one hundred square meters for Small Volume Injectables is recommended. For Large Volume Parenterals, an area of one hundred and fifty square meters each for the basic installation and for Ancillary area is recommended. These areas shall be partitioned into suitable enclosures with airlock arrangements.
(2) Areas for formulations meant for external use and internal use shall be separately provided to avoid mix up.
(3) Packaging materials for large volume parenteral shall have a minimum area of 100 square meters. 1[Note: The requirement for ancillary area in this part shall not apply to units registered before 1st January, 2002.] 11.2 Parenteral preparations in plastic containers by Form-Fill-Seal/Blow, Fill- Seal Technology.-The whole operation of manufacture of large volume parenteral preparations in plastic containers including plastic pouches by automatic (all operations in one station) Form-Fill-Seal machine or by semi-automatic blow moulding, filling-cum-sealing machine may be divided into following separate areas/rooms, namely: -
(1) Water management area.
(2) Solution preparation area.
(3) Containers moulding-cum-filling and sealing area.
(4) Sterilization area.
(5) Quarantine area .
(6) Visual inspection area.
(7) Packaging area. The following equipment is recommended for different above mentioned areas namely: -
- (a) Water management area:
(1) De-ionised water treatment unit.
(2) Distillation unit (multi column with heat exchangers).
(3) Thermostatically controlled water storage tank.
(4) Transfer pumps.
(5) Stainless steel service lines for carrying water into user areas.
- (b) Solution preparation area:
(1) Solution preparation and storage tanks.
(2) Transfer pumps.
(3) Cartridge and membrane filters.
- (c) Container moulding-cum-filling and sealing area:
(1) Sterile Form-Fill-Seal machine (all operations in one station with built-in laminar air flow workstation having integrated container output conveyor belt through pass box). (2) Arrangement for feeding plastic granules through feeding-cum-filling tank into the machine. ________________________________________________________________________ Drugs and Cosmetics Rules, 1945 436
- (d) Sterilization area: Super heated steam sterilizer (with computer control for sterilization cycle along with trolley sets for loading/unloading containers for sterilization).
- (e) Quarantine area:- Adequate number of platforms/racks with storage system.
- (f) Visual inspection area. - Visual inspection unit (with conveyor belt and composite white and black assembly supported with illumination).
- (g) Packaging area:
(1) Pressure leak test apparatus (pressure belt or rotating disc type).
(2) Batch coding machine (preferably automatic).
(3) Labelling unit (preferably conveyor belt type). Area. – (1) A minimum area of two hundred and fifty square meters for the basic installation and an Ancillary area of one hundred and fifty square metres for large volume parenteral preparations in plastic containers by Form-Fill-Seal technology is recommended. These areas shall be partitioned into suitable enclosures with airlock arrangements.
(2) Areas for formulations meant for external use and internal use shall be separately provided to avoid mix up.
(3) Packaging materials for large volume parenteral shall have a minimum area of 100 square meters.] 1[Note: The requirement for ancillary area in this part shall not apply to units registered before 1st January, 2002.] 1[Note I: There are certain categories of drugs such as chemicals and pharmaceutical aids, gauzes and bandages, medicinal gases, empty gelatin capsules, non- chemical/mechanical contraceptives, diagnostic kits and reagents, medical devices, new dosage forms and their delivery systems, disinfectant fluids, antacids, raw-materials manufactured from sea bittern, veterinary biologicals including poultry vaccines, re-packing of drugs, etc. for which this Schedule does not prescribe specific requirements of space and equipments. The Licensing Authority, as the case may be, in respect of such categories of drugs, have the discretion to modify the requirements of this Schedule, if he is of the opinion that having regard to the nature off the products and extent of manufacturing operations and for reasons to be recorded in writing, it is necessary to relax or alter them in the circumstances of a particular case and direct the manufacturer to carry out necessary modifications in them and the modifications having been made, approve the manufacturer of such categories of the drugs.

¹ Ins. by 431(E), dt. 30.6.2005.

¹ Ins. by G.S.R. 431(E), dt. 30.6.2005.

___________________________________________________________________________

Drugs and Cosmetics Rules, 1945 437

1[SCHEDUE M-I

[See Rule 85-E (2)]

1. Requirements of factory premises for manufacture of Homoeopathic preparations:

(a) Location and surroundings. - The factory shall be situated in a place which shall not be adjacent to an open sewage drain, public lavatory or any factory which produces a disagreeable or obnoxious odour or fumes or large quantities of soot, dust or smoke. The factory shall be located in a sanitary place, remove from filthy surroundings.
(b) Buildings. - The part of the building used for manufacturing shall not be used for a sleeping place and no sleeping place adjoining to it shall communicate therewith except through open air or through an intervening open space. The walls of the room in which manufacturing operations are carried out shall, upto a height of six feet from the floor, be smooth, waterproof and shall be capable of being kept clean. The flooring shall be smooth, even and washable and shall be such as not to permit retention or accumulation of dust. There shall be no chinks or crevices in the walls or floor.
(c) The building used for the factory shall be constructed so as to permit production under hygienic conditions laid down in the Factories Act, 1948 (63 of 1948).
(d) Water Supply. - The water used in manufacture shall be pure and drinkable quality, free from pathogenic microorganisms.
(e) Disposal of waste. - There should be adequate arrangement for disposal of waste-water and other residues from the laboratory.
(f) The rooms should be airy and clean and the temperature of the room should be moderately comfortable.
(g) Health, Clothing and Sanitary requirement of the Staff. - All workers shall be free from contagious or obnoxious disease. Their clothing shall consist of a white or coloured uniform suitable to the nature of the work and the climate, and shall be clean. Adequate facilities for personal cleanliness, such as clean towels, soap and hand scrubbing brushes, shall be provided separately for each sex. The workers shall be required to wash and change into clean footwear before entering the rooms where the manufacturing operations are carried on. Workers shall be required to wear either a clean cap or a suitable headgear so as to avoid any possibility of contamination by air or perspiration. (h) Medical services. - The manufacturer shall provide adequate facilities for First Aid, Medical inspection of workers at the time of employment and periodically check-up thereafter at least once a year.
- (i) Working benches. - Working benches shall be provided for carrying out operations such as filling, labelling, packing etc. Such benches shall be fitted with smooth, impervious tops capable of being washed.
(j) Container management. - Where operations involving use of containers such as bottles, phials and jars are conducted, there shall be adequate arrangements separated from potentisation chamber for washing, cleaning and drying such containers, with _____________________________________________________________________ Drugs and Cosmetics Rules, 1945 438 suitable equipment for the purpose. Wherever these are attended manually adequate precaution of perfection in respect of cleanliness and avoidance of pollutants shall be taken.

¹ Ins. by G.S.R. No. 507(E) , dt. 12-6-1987 (w.e.f. 12.6.1987).

2. Requirements of Plant and Equipment:

(a) Mother tinctures. External tinctures and Mother solution section. - The following plant and equipment shall be provided namely: -
- (i) Disintegrator.
- (ii) Sieved Separator.
- (iii) Balances and fluid measures.
- (iv) Chopping boards and knives.
- (v) Macerators with lids.
- (vi) Percolators with lids and regulated discharge.
- (vii) Moisture determination apparatus or other suitable arrangement.
- (viii) Filtering arrangement.
- (ix) Mixing vessels and suitable non-metallic storage containers.
- (x) Portable stirrers.
- (xi) Water still.

Note: (1) As far as possible metal contacts may be avoided once the drug is processed.

(2) An area of 55 sq. meters is recommended for basic installations.
(3) Adequate separate storage facility should be provided for raw material quarantine, storage and bonded room for alcohol where applicable.
(4) Separate and suitable storage facility should be provided for fresh herbs and odorous raw materials.
(5) Adequate laboratory facility shall be provided for testing of raw materials and finished products,
- (b) Potentisation Section. - (1) The following arrangements are recommended for container for closure preparation section namely:
  - (i) Washing tanks with suitable brushing arrangement manual or mechanical.
  - (ii) Purified Water rinsing tank
  - (iii) Closure macerating or washing tanks.
  - (iv) Drying chambers. An area of 20 sq. meters is recommended for basic installations.
(2) The following arrangements are recommended for potency preparation section, namely: –
- (i) Working tables with washable top.
- (ii) Facilities for separate storage of different grades of back potencies.
- (iii) Suitable measuring devices for discharge of drug and diluent in potentisation vial,
- (iv) Potentiser with counter or suitable manual arrangement. Drugs and Cosmetics Rules, 1945 439 Note: - (1) Different droppers shall be used for different drugs potencies.
(2) All measuring devices shall be of metric system and be made of glass and shall be free from metallic contents.
(3) It is desired that glass droppers etc. intended for re-use after cleaning should be sterilized by autoclave or heating in a hot air oven.
(4) Plastics, rubber tubes, bulks etc. coming in contact with tinctures or back potencies should not be re-used for other tincture and potencies.
(5) Method of potentisation will be adopted as specified in Homoeopathic Pharmacopoeia of India Vol. I. 3. Triturating, Tableting and Pill/Globules section -
(3) The following arrangements are recommended:
- (i) Triturating machine for suitable device.
- (ii) Disintegrator.
- (iii) Mass Mixer.
- (iv) Granulator.
- (v) Oven.
- (vi) Tableting punches or machines.
- (vii) Kettle (Steam/gas/electrically heated) for preparation solution.
- (viii) Dryers.
- (ix) Sieved separator, tablet counters and balances. Note: Tablet section shall be free from dust and floating particles. An area of 55 sq. meters is recommended for basic installations.
(4) Ointments and lotion section: The following arrangements are recommended namely: -
- (i) Mixing tank
- (ii) Kettle (Steam, gas or electrically heated).
- (iii) Suitable powder mixer
- (iv) Ointment mill
- (v) Filling equipment or arrangement. An area of 20 sq. meters is recommended for basic installations.
(5) Syrups and tonics: The following arrangements are recommended namely:-
- (i) Mixing and storage tank.
- (ii) Potable mixer.
- (iii) Filtering equipment.
- (iv) Water still / Deioniser. Drugs and Cosmetics Rules, 1945 440
- (v) Filling and sealing equipment. An area of 20 sq. meters is recommended for basic installations.
(6) Ophthalmic Preparations: The following equipment is recommended for manufacture under aseptic conditions of Eye-Ointments, Eye-Drops, Eye-lotions and other preparations for external use, namely: -
- (i) Hot air even electrically heated with thermostatic control.
- (ii) Colloid mill or ointment mill.
- (iii) Kettle (gas or electrically heated) with suitable mixing arrangement.
- (iv) Tube filling equipment.
- (v) Mixing and storage tanks of stainless steel or of other suitable material.
- (vi) Sintered glass funnel, Seitz filter or filter candle.
- (vii) Liquid filling equipment.
- (viii) Autoclaves. Adequate precaution should be taken to ensure that the finished product is sterile. An area of 20 sq. meters is recommended for basic installations.
(7) Adequate arrangements for space and equipment should be made for labelling and packing. Drugs and Cosmetics Rules, 1945 441

REQUIREMENTS OF FACTORY PREMISES FOR MANUFACTURE

OF COSMETICS

I. GENERAL REQUIREMENTS

(A) Location and surroundings.–The factory shall be located in a sanitary place and hygienic conditions shall be maintained in the premises. Premises shall not be used for residence or be interconnected with residential area. It shall be well ventilated and clean.
(B) Buildings.– The buildings used for the factory shall be constructed so as to permit production under hygienic conditions and not to permit entry of insects, rodents, files, etc. The walls of the room in which manufacturing operations are carried out, shall be up to a height of six feet from the floor, be smooth, waterproof and capable of being kept clean. The flooring shall be smooth, even and washable and shall be such as not to permit retention or accumulation of dust.
(C) Water supply: - The water used in manufacture shall be of potable quality.
(D) Disposal of water. –- Suitable arrangements shall be made for disposal of waste-water.
(E) Health, clothing and sanitary requirements of the staff.– All workers shall be free from contagious or infectious diseases. They shall be provided with clean uniforms, masks, headgears, and gloves wherever required. Washing facilities shall also be provided.
(F) Medical Services. - Adequate facilities for first aid shall be provided.
(G) Work benches shall be provided for carrying out operations such as filling, labelling, packing, etc. Such benches shall be fitted with smooth, impervious tops capable of being washed.
(H) Adequate facilities shall be provided for washing and drying of glass containers if the same are to be used for packing the product. II. REQUIREMENTS OF PLANT AND EQUIPMENT The following equipment, area and other requirements are recommended for the manufacture of: −

A. Powders:− Face powder, cake make-up, compacts, face packs, masks and

rouges, etc.

1. Equipment:

(a) Powder mixer of suitable type provided with a dust collector.
(b) Perfume and colour blender.
(c) Sifter with sieves of suitable mesh size.
(d) Ball mill or suitable grinder. _______________________________________ Drugs and Cosmetics Rules, 1945 442
(e) Trays and scoops (stainless steel).
(f) Filling and sealing equipment provided with dust extractor.
(g) For compacts: -
- (i) a separate mixer, (ii) compact pressing machine.
(h) Weighing and measuring devices
- (i) Storage tanks. An area of 15 square meters is recommended. The section is to be provided with adequate exhaust fans. B. Creams, lotions, emulsions, pastes, cleansing milks, shampoos, pomade, brilliantine, shaving creams and hair-oils etc.
(a) Mixing and storage tanks of suitable materials.
(b) Heating kettle – steam, gas or electrically heated.
(c) Suitable agitator.
(d) Colloidal mill or homogeniser (wherever necessary).
(e) Triple roller mill (wherever necessary).
(f) Filling and sealing equipment.
(g) Weighing and measuring devices. An area of 25 square meters is recommended. C. Nail Polishes and Nail lacquers.

¹ Ins. by G.S.R 723(E) , dt. 11-8-1992.

1. Equipment:

(a) A suitable mixer.
(b) Storage tanks.
(c) Filling machine – hand operated or power driven. (d) Weighing and Measuring devices. An area of 15 square meters is recommended. The section shall be provided with flameproof exhaust system. 2. Premises:–The following are the special requirements related to Nail Polishes and Nail Lacquers: -
(a) It shall be situated in an industrial area.
(b) It shall be separate from other cosmetic-manufacturing areas by metal/brick partition up to ceiling.
(c) Floors, walls, ceiling and doors shall be fireproof.
(d) Smoking, cooking and dwelling shall not be permitted and no naked flame shall be brought in the premises.
(e) All electrical wiring and connections shall be concealed and main electric switch shall be outside the manufacturing area.
(f) All equipment, furniture and light fittings in the section shall be flameproof.
(g) Fire extinguisher like foam and dry powder and sufficient number of buckets containing sand shall be provided.
(h) All doors of the section shall open outwards. 3. Storage: All explosive solvents and ingredients shall be stored in metal cupboards or in a separate enclosed area. Drugs and Cosmetics Rules, 1945 443 4. Manufacture:
(a) Manufacture of lacquer shall not be undertaken unless the above conditions are complied with.
(b) Workers shall be asked to wear shoes with rubber soles in the section. 5. Other requirements: No objection certificate from the local Fire Brigade Authorities shall be furnished. D. Lipsticks and Lip-gloss, etc. 1. Equipment
(a) Vertical mixer.
(b) Jacketted kettle – steam, gas or electrically heated.
(c) Mixing vessel (stainless steel).
(d) Triple roller mill/Ball mill.
(e) Moulds with refrigeration facility.
(f) Weighing and measuring devices. An area of 15 square meters is recommended.

(a) Mixing tanks.
(b) Mixer
(c) Triple roller mill or homogeniser (where necessary).
(d) Filling and sealing equipment.
(e) Weighing and measuring devices.
(f) Moulds (where necessary). An area of 10 square meters is recommended. F. Preparations used for Eyes: - Such preparations shall be manufactured under strict hygienic conditions to ensure that these are safe for use.

(a) Mixing tanks.
(b) A suitable mixer.
(c) Homogeniser (where necessary)
(d) Filling and sealing equipment.
(e) Weighing and measuring devices. An area of 10 square meters is recommended.

(a) Base sterilizer.
(b) Powder sterilizer (dry heat oven).
(c) Stainless steel tanks.
(d) A suitable Mixer. Drugs and Cosmetics Rules, 1945 444
(e) Stainless steel sieves.
(f) Filling and sealing arrangements.
(g) Weighing and measuring devices.
(h) Homogeniser (where necessary).
- (i) Pestle and Mortar (for Surma). An area of 10 square meters with a separate area of 5 square meters for base sterilization is recommended. Other requirements for 1 and 2:
(a) False ceiling shall be provided wherever required.
(b) Manufacturing area shall be made fly proof. An airlock or an aircurtain shall be provided.
(c) Base used for Kajal shall be sterilized by heating the base at 150 degree C for required time in a separate enclosed area.
(d) The vegetable carbon black powder shall be sterilized in a drying oven at 120 degree C for required time.
(e) All utensils used for manufacture shall be of stainless steel and shall be washed with detergent water, antiseptic liquid and again with distilled water.
(f) Containers employed for ‘Kajal’ shall be cleaned properly with bactericidal solution and dried.
(g) Workers shall put on clean overalls and use hand gloves wherever necessary.

(a) Air-compressor (wherever necessary).
(b) Mixing tanks.
(c) Suitable propellant filling and crimping equipments.
(d) Liquid filling unit.
(e) Leak testing equipment.
(f) Fire extinguisher (wherever necessary)
(g) Suitable filtration equipment.
(h) Weighing and measuring devices. An area of 15 square meters is recommended. 2. Other requirements: - No objection certificate from the Local Fire Brigade Authorities shall be furnished. H. Alcoholic Fragrance Solutions. Equipment: -
(a) Mixing tanks with stirrer
(b) Filtering equipment.
(c) Filling and sealing equipment.
(d) Weighing and measuring devices. An area of 15 square meters is recommended.

I. Hair Dyes.

Equipment:

(a) Stainless steel tanks.
(b) Mixer. Drugs and Cosmetics Rules, 1945 445
(c) Filling Unit.
(d) Weighing and measuring devices.
(e) Masks, gloves and goggles. An area of 15 square meters with proper exhaust is recommended. J. Tooth powders and toothpastes, etc.:

1. Tooth-powder in General.

Equipment:

(a) Weighing and measuring devices.
(b) Dry mixer (powder blender).
(c) Stainless steel sieves.
(d) Powder filling and sealing equipments. An area of 15 square meters with proper exhaust is recommended.

2. Toothpastes.

Equipment:

(a) Weighing and measuring devices.
(b) Kettle – steam, gas or electrically heated (where necessary).
(c) Planetary mixer with de-aerator system.
(d) Stainless steel tanks.
(e) Tube filling equipment. (f) Crimping machine. An additional area of 15 square meters with proper exhaust is recommended.

3. Tooth-powder (Black)

Equipment:

(a) Weighing and measuring devices.
(b) Dry mixer powder blender.
(c) Stainless steel sieves. (d) Powder filling arrangements. An area of 15 square meters with proper exhaust is recommended. Areas for manufacturing “Black” and “White” tooth powders should be separate.

K. Toilet Soaps:

Equipment: -

(a) Kettles/pans for saponification.
(b) Boiler or any other suitable heating arrangement.
(c) Suitable stirring arrangement.
(d) Storage tanks or trays.
(e) Driers.
(f) Amalgamator/chipping machine.
(g) Mixer.
(h) Triple roller mill.
- (i) Granulator.
(j) Plodder.
(k) Cutter.
(l) Pressing, stamping and embossing machine. (m) Weighing and measuring devices. Drugs and Cosmetics Rules, 1945 446 A minimum area of 100 square meters is recommended for the small-scale manufacture of toilet soaps. The areas recommended above are for basic manufacturing of different categories of cosmetics. In addition to that separate adequate space for storage of raw materials, finished products, packing materials shall be provided in factory premises.
- • * * Note No. I−The above requirements of the Schedule are made subject to modification at the discretion of the Licensing Authority, if he is of the opinion that having regard to the nature and extent of the manufacturing operations it is necessary to relax or alter them in the circumstances of a particular case. Note No. II.−The above requirements do not include requirements of machinery, equipments and premises required for preparation of containers and clousers of different categories of cosmetics. The Licensing Authority shall have the discretion to examine the suitability and adequacy of the machinery, equipments and premises for the purpose of taking into consideration of the requirements of the licensee. Note No. III.−Schedule M-II specifies equipments and space required for certain categories of cosmetics only. There are other cosmetics items, viz. Attars, perfumes, etc., which are not covered in the above categories. The Licensing Authority shall, in respect of such items or categories of cosmetics have the discretion to examine the adequacy of factory premises, space, plant and machinery and other requisites having regard to the nature and extent of the manufacturing operations involved and direct the licensee to carry on necessary modification in them. Note No. IV. −**[Areas for formulations meant for external use and areas for formulations meant for internal use shall be separately provided to avoid mix-up even though they are from the same category of formulations]. ___________________________________________________________________________ 1. The words “A testing laboratory shall also be provided” omitted by G.S.R.285 (E) , dt. 16.7.1996. Drugs and Cosmetics Rules, 1945 447

REQUIREMENTS OF FACTORY PREMISES FOR MANUFACTURE OF

MEDICAL DEVICES

1. GENERAL REQUIREMENTS:

1.1.1. Location and surroundings. - The factory building(s) shall be located in a

sanitary place and hygienic conditions shall be maintained in the premises. Premises shall not

be used for residence or be interconnected with residence. It shall be well ventilated and clean.

1.1.2. Buildings. - The buildings used for the factory shall be constructed so as to

permit production under hygienic conditions and not to permit entry of insects, rodents, flies etc.

The walls of the rooms in which manufacturing operations are carried out, shall be up to a height of six feet from the floor, be smooth, water proof and capable of being kept clean. The flooring shall be smooth, even and washable and shall be such as not to permit retention or accumulation of dust.

1.1.3. Water supply. - The water used in manufacture shall be of potable quality.

1.1.4. Disposal of waste. - Suitable arrangements shall be made for disposal of wastewater.

1.1.5. Health, Clothing and Sanitation of workers. - All workers shall be free from contagious or infectious diseases. They shall be provided with clean uniforms, masks, headgears and gloves wherever required. Washing facilities shall also be provided.

1.1.6. Medical Services. - Adequate facilities for first-aid shall be provided.

1.1.7. Work-benches shall be provided for carrying out operations such as moulding,

assembling, labelling, packing etc. Such benches shall be fitted with smooth impervious tops capable of being washed.

1.1.8. Adequate facilities shall be provided wherever required for cleaning, washing, drying of different containers of devices is required.

1.1.9. The premises shall be kept under controlled conditions of temperature and humidity so as to prevent any deterioration in the properties of materials and products due to storage and process conditions.

2. Requirements for Manufacture of Medical Devices.- The process of manufacture of medical devices shall be conducted at the licensed premises, wherever required, and shall be divided into the following separate operations/Sections:-

(1) Moulding (wherever manufacture of medical devices is to start from granules).
(2) Assembling (include cutting, washing and drying, sealing, packing, labelling, etc.)
(3) Raw Materials.
(4) Storage Area. _______________________________________________________________________ Drugs and Cosmetics Rules, 1945 448
(5) Washing, drying and sealing area (wherever required).
(6) Sterilization.
(7) Testing facilities. The following equipments and space are recommended for the basic manufacture of different categories of medical devices:

¹ Ins. by G.S.R. 109(E), dt. 22.2.1994.

A. STERILE DISPOSABLE PERFUSION AND BLOOD COLLECTION SETS.

(1) Moulding:
- (a) Injection Moulding Machine.
- (b) Extruder Machine.
- (c) PVC Resin compounding Machine.
(2) Assembling:
- (a) Hand Pressing Machine for filter fixing a Drip Chamber.
- (b) Bag Sealing Machine.
- (c) Compressor Machine.
- (d) Leak Testing Bench
- (e) PVC Tube Cutting Machine.
- (f) Tube Winding Machine (wherever necessary).
- (g) Welding Machine (wherever necessary) An area of 30 square meters for moulding and 15 square meters for Assembling are recommended for basic installation. The assembling area shall be air-conditioned provided with HEPA filters. The moulding section shall, if necessary, have proper exhaust system. Note: - An additional area of 20 square meters is recommended for any extra category.

B. STERILE DISPOSABLE HYPODERMIC SYRINGES.

(1) Moulding: -
- (a) Granulator.
- (b) Injection Moulding Machine. (c) Weighing devices.
(2) Assembling:
- (a) Blister Pack Machine.
- (b) Vacuum Dust Cleaner.
- (c) Rubber-tip Washing Machine. (d) Foil stamping or screen printing equipment. An area of 30 square meters for moulding and 15 square metres for assembling are recommended for basic installation. The assembling area shall be air-conditioned provided with HEPA filters. The moulding section shall, if necessary, have proper exhaust system. Note: - An additional area of 20 square meters is recommended for any extra category. Drugs and Cosmetics Rules, 1945 449

C. STERILE DISPOSABLE HYPRODERMIC NEEDLES.

(1) Moulding:
- (a) Needle grinding and levelling machine.
- (b) Electro Polishing Machine. (c) Cutting Machine
- (d) Injection Moulding Machine.
- (e) Needle Pointing Deburrine Machine (f) Air-compressor.
(2) Assembling:
- (a) Needle cleaning Machine with Magnetic Separator.
- (b) Blister Packing Machine. (c) Needle Inspection Unit. An area of 30 square meters for Moulding and 15 square meters for Assembling are recommended for basic installation. The assembling area shall be air-conditioned provided with HEPA filters. The molding section shall, if necessary, have proper exhaust system. Note: - An additional area of 20 square meters is recommended for any extra category.

3. Raw Materials. - The licensee shall keep an inventory of all raw materials to be

used at any stage of manufacture of devices and shall maintain records as per Schedule U. All such raw materials shall be identified and assigned control reference numbers. They shall be conspicuously labelled indicating the name of the material, control reference number, name of the manufacturer and be specially labelled “Under Test” or “ Approved” or “Rejected”. The under test, approved or rejected materials shall appropriately be segregated. These shall be tested for compliance with required standards of quality.

A minimum area of 10 square meters shall be provided for storage of raw materials.

4. Storage Area. - The licensee shall provide separate storage facilities for quarantine and sterilized products.

An area not less than 10 square metre shall be provided for each of them.

5. Washing, drying and sealing area. - The licensee shall provide wherever required adequate equipments like water distillation still, deionizer, washing machine. Drying Oven with trays for washing, drying and sealing of medical device.

An area not less than 10 square metre shall be provided.

6. Sterilization. - The licensee shall provide requisite equipments with required controls and recording device for sterilization of medical devices by Ethylene Oxide Gas in his own premises or may make arrangements with some Institution approved by the Licensing Authority for sterilization. The products sterilized in this manner shall be monitored to assure acceptable levels of residual gas and its degradation products. An area of 10 square meters is recommended for basic installation of such facility:

Provided that the above equipment may not be required in case the licensee opts for sterilization of medical devices by Ionising Radiation.

Drugs and Cosmetics Rules, 1945 450

7. Testing Facilities. - The licensee shall provide testing laboratory for carrying

out Chemical and Physico-Chemical testing of medical devices and of raw materials used in its own premises:

Provided that the Licensing Authority shall permit the licensee in the initial stage to carry out testing of Sterility, Pyrogens, Toxicity

1[wherever applicable] on their products from the approved testing institutions but after one renewal period the licensee shall provide testing facilities of all such tests in their own premises.

8. Records. - The licensee shall maintain records of different manufacturing activities with regard to each stage of manufacture in-process controls, assembling, packing, batch records for the quantity of devices manufactured from each lot of blended granules, duration of work, hourly quantum of production in respect of each item as well as record of each sterilizing cycle of the gaseous method employed.

Note: - The above requirements of machinery, equipments, space, qualifications are made subject to the modification at the discretion of the Licensing Authority, if he is of the opinion that having regard to the nature and extent of the manufacturing operations it is necessary to relax or alter them in the circumstances of a particular case.]

¹ Ins. by G.S.R. 548(E), dt. 16.11.2003.

___________________________________________________________________________

Drugs and Cosmetics Rules, 1945 451

N

[See Rule 64(1)] LIST OF MINIMUM EQUIPMENT FOR THE EFFICIENT RUNNING OF A PHARMACY

1. Entrance. - The front of a pharmacy shall bear an inscription “Pharmacy” in front.

2. Premises. - The premises of a pharmacy shall be separated from rooms for private

use. The premises shall be well built, dry, well lit and ventilated and, of sufficient dimensions to allow the goods in stock, especially medicaments and poisons to be kept in a clearly visible and appropriate manner. The areas of the section to be used as dispensing department shall be not less than 6 square meters for one pharmacist working therein with additional 2 square meters for each additional pharmacist. The height of the premises shall be at least 2.5 meters.

The floor of the pharmacy shall be smooth and washable. The walls shall be plastered or tiled or oil painted so as to maintain smooth, durable and washable surface devoid of holes, cracks and crevices.

A pharmacy shall be provided with ample supply of good quality water.

The dispensing department shall be separated by a barrier to prevent the admission of the public.

3. Furniture and apparatus. - The furniture and apparatus of a pharmacy shall be adopted to the uses for which they are intended and correspond to the size and requirements of the establishment.

Drugs, chemicals, and medicaments shall be kept in a room appropriate to their properties and in such special containers as will prevent any deterioration of the contents or of contents of containers kept near them. Drawers, glasses and other containers used for keeping medicaments shall be of suitable size and capable of being closed tightly to prevent the entry of dust.

Every container shall bear a label of appropriate size, easily readable with names of medicaments as given in the Pharmacopoeias.

A pharmacy shall be provided with a dispensing bench, the top of which shall be covered with washable and impervious material like stainless steel, laminated or plastic, etc.

A pharmacy shall be provided with a cupboard with lock and key for the storage of poisons and shall be clearly marked with the work ‘POISON’ in red letters on a white background.

Containers of all concentrated solution shall bear special label or marked with the words “To be diluted”.

A Pharmacy shall be provided with the following minimum apparatus and books necessary for making of official preparations and prescriptions:-

¹ Subs. by S.O.2139 , dt. 12.8.1972.

_______________________________________________________________________

Drugs and Cosmetics Rules, 1945 452

Apparatus: -

Balance, dispensing, sensitivity 30 mg. Balance, counter, capacity 3 Kgm., sensitivity 1 gm. Beakers, lipped, assorted sizes. Bottles, prescription, ungraduated assorted sizes. Corks assorted sizes and tapers.

Litmas paper, blue and red. Measure glasses cylindrical 10 ml, 25 ml, 100 ml and 500 ml. Mortars and pestles, glass. Mortars and pestles, wedgwood. Ointment pots with bakelite or suitable caps. Ointment slab, porcelain

Pipette graduated, 2 ml, 5 ml and 10 ml.

Ring, stand (retort) iron, complete with rings. Rubber stamps and pad Scissors Spatulas, rubber or vulcanite Spatulas, stainless steel.

o C to 200 o C.

Water distillation still in case Eye drops and Eye lotions are prepared. Weights, Metric, 1 mg. to 100 gm. Wire Gauze. *Pill finisher, boxwood.

• Pill Machine.
• Pill Boxes.
• Suppository mould. Books : The Indian Pharmacopoeia (Current Edition). National Formulary of Indian (Current Edition). The Drugs and Cosmetics Act, 1940. The Drugs and Cosmetics Rules, 1945. The Pharmacy Act, 1948. The Dangerous Drugs Act, 1930. Drugs and Cosmetics Rules, 1945 453 4. General provisions. - A pharmacy shall be conducted under the continuous personal supervision of a Registered Pharmacist whose name shall be displayed conspicuously in the premises. The Pharmacist shall always put on clean white overalls. The premises and fittings of the pharmacy shall be properly kept and everything shall be in good order and clean. All records and registers shall be maintained in accordance with the laws in force. Any container taken from the poison cupboard shall be replaced therein immediately after use and the cupboard locked. The keys of the poison cupboard shall be kept in the personal custody of the responsible person. Medicaments when supplied shall have labels conforming to the provisions of laws in force. Note: - The above requirements are subject to modifications at the discretion of the licensing authority, if he is of opinion that having regard to the nature of drugs dispensed, compounded or prepared by the licensee. It is necessary to relax the above requirements or to impose additional requirements in the circumstances of a particular case. The decision of the licensing authority in that regard shall be final.
• These items are to be provided only by those who intend to dispense pills or suppositories, as the case may be.] Drugs and Cosmetics Rules, 1945 454

O

[See Rule 126]

STANDARD FOR DISINFECTANT FLUIDS PART 1 Provision applicable to Black Fluids and White Fluids. 1. Classification. - The disinfectants shall be classified as follows: -

(a) Black fluids
(b) White fluids
(A) Black fluids.– These shall be homogeneous dark brown solution of coal tar acid or similar acids derived from petroleum with or without hydrocarbon, and/or other phenolic compounds, and their derivatives and a suitable emulsifier.
(B) White fluids.– These shall be finely dispersed homogeneous white to off- white emulsion consisting of coal tar acids or similar acids derived from petroleum, with or without hydrocarbons, and/or other phenolic compounds, and their derivatives. 2. Gradation .– Each of the above classes of disinfectant fluids shall be graded on the basis of the minimum requirements in respect of– Rideal Walker (RW) Coefficient as follows: -

3. Type. - Each of the above grades of disinfectant fluids shall be stable in the range of

temperature indicated against each type. -

Type Stable in the range of

(I) Normal 15 o C to 45 o C.
(II) Winter 5 o C to 30 o C 4. Requirements. - All classes and grades of disinfectant fluids shall comply with the following requirements, namely: -

(1) Stability after dilution. - When tested by the method described hereinafter the disinfectant fluid shall be miscible with artificial hard water (for Black fluids) or with artificial sea water (for White fluids) in all proportion from 1 per cent to 5 per cent by volume, to give emulsion which shall not break or show more than traces of separation of either top or bottom oil when kept for 6 hours at 15 o C to 45 o C for Type (I) (Normal) and 5 o C to 30 o C for Type (II) (Winter). ___________________________________________________________________________ Drugs and Cosmetics Rules, 1945 455
(2) Germicidal Value.– Rideal Walker Coefficient – Black fluids and White fluids shall be tested for determination of Rideal Walker Coefficient (R.W.Coefficient) by the method described hereinafter.
(3) Storage.– Disinfectant fluids of all classes shall be stored in mild steel, tinned mild steel or other suitable containers. These shall not be stored in containers made of galvanized iron.
(4) Labelling. -Subject to the other provisions in these rules, the label on the container shall state-
- (w) the name of the product,
  - (ii) the name and full address of the manufacturer,
  - (iii) grade, type, R.W. Coefficient of product,
  - (iv) date of manufacture,
  - (v) quantity present in the container,
  - (vi) indications and mode of use, and
  - (vii) date up to which the product can be used. 5. Method of testing -
(1) Preparation of sample. - The sample of disinfectant fluid to be tested should be mixed thoroughly taking care that no air is beaten into the fluid immediately before withdrawing any portion for testing. The rest portion should be withdrawn from the middle of the sample.
(2) Method of resting stability after dilution. -
- (a) Preparation of Artificial Hard Water: 40 ml of I N Hydrochloric Acid (Analytical Reagent Quality) is neutralized with a slight excess of Calcium Carbonate and filtered. The filtrate is diluted to 1000 ml with distilled water, 10 parts of this solution is further diluted to 100 parts with distilled water.
- (b) Preparation of Artificial Sea Water: 27G of Sodium Chloride (Analytical Reagent Quality) and 5 G of Magnesium Sulphate (Analytical Reagent Quality) are dissolved in distilled water and diluted to 1000 ml. The solution is filtered before use.
- (c) Procedure: Take 1 ml and 5 ml portions of the sample in duplicate in

¹ Subs. by G.S.R. 1243(E) , dt. 19.9.1979.

100 ml stoppered measuring cylinder (IS: 878 – 1956) by means of pipettes.

Dilute the sample with artificial Hard water or Artificial Sea water (as the case may be) upto 10 ml mark. Mix thoroughly by inverting the cylinders 5 times. Keep the cylinders containing the diluted fluids for 6 hours at the extremes of the temperature range specified for the particular type. The sample complies with the test if the solution shows not more than a trace of separation at its top and bottom.

(3) Method of determination of Rideal Walker Coefficient (R.W.C) Apparatus – A loop, 4 mm in internal diameter is made at the end of 28 swg (0.376 mm) wire of platinum or platinum iridium alloy, 38 mm long from the loop to the holder. The loop is bent at such an angle to the length of the wire as will facilitate in removal vertically from the surface of the liquid while keeping the place of the loop horizontal. Drugs and Cosmetics Rules, 1945 456 Incubator – Set and maintained at 37 o C ± 1 o C Pipettes – Standard graduated pipettes of capacity 10 ml; 5 ml and 1 ml Dropping Pipette – Made of delivery 0.2 ml Medication tubes – 5 sterile plugged rimless test tubes 125 mm x 22 mm (5 inch x ¾ inch) made of hard neutral glass. Both tubes – About 2 dozens of the same description as medication tubes. Standard measuring cylinders stopped and graduated—500 ml graduated in 10 ml–;one 100 ml graduated 1 ml– five. All apparatus must be scrupulously clean and sterile; immediately before use. Reagents.– (a) Broth.– Prepare a mixture of the following ingredients: Meat extract (Microbiological grade) 20 g Peptone (Micro biological grade) 20 g Sodium Chloride (Regent Quality) 10 g Distilled Water- 1000 ml. Dissolve the solids in distilled water. Add sufficient sodium hydroxide to neutralize the solution; then boil it to bring down phosphates and filter while hot. The broth thus prepared is then adjusted to pH 7.6 with normal Hydrochloric acid. The broth is then sterilized by autoclaving at 15 lbs pressure for 20 minutes. It is then filtered and placed in 5 ml quantities in sterilized broth tubes. The tubes of media thus prepared are sterilized by autoclaving at 15 lbs pressure for 10 minutes. The final pH of the medium should lie between

7.3 and 7.5. Further resterilization in bulk or in tubes is not permissible.

(b) Test Organism- Test organism used is Salmonella typhi (NCTC 786) of which suitable culture shall be obtained from the Director, Central Drugs Laboratory, Calcutta. This culture is maintained by weekly sub-culture on a nutrient agar slope (made by dissolving 2.5 per cent Agar Agar (Bacteriological grade) in broth prepared as above), incubating the sub- culture for 24 hours at 37 O C and then storing in refrigerator at a temperature below 22 o C. For the purpose of the test a little of the growth from the most recent sub-culture in nutrient agar slope is placed in tube of R.W. broth and incubated for 23 hours at 38 o

C. A standard loopful

is then transferred to a second tube and incubated as before. This is done at least three times before a test is carried out. Sub-culturing in broth is limited to 14 days.

(c) Standard phenol: 5 per cent W/V solution in sterile distilled water of chemically pure phenol having a crystallizing point of not less than 40.5 o C is prepared. Test dilutions are prepared from this stock solution containing 1 g of phenol in each 95, 100, 105, 115 ml of the solution made. These dilutions shall be used within a week of preparation.
(d) Test dilutions of Disinfectant (sample)- The sample is prepared as described under “Preparation of samples”. A test portion of 5 ml is withdrawn and discharged into about 480 ml of sterile distilled water in a 500 ml glass stoppered sterile measuring cylinder and the pipette is rinsed three times or more in the clear liquid. The whole is then made up to 500 ml with sterile distilled water, the cylinder is stoppered and the contents thoroughly mixed by inverting the cylinder several times. Suitable test dilutions in sterile distilled water are then immediately prepared from this stock solution. Procedure: 5 ml of 4 chosen dilutions of the disinfectant are placed in 4 medication tubes which are then placed in a rack provided with water bath maintained at a constant temperature between 17 o C and 19 o C, with the strongest dilution on the left. The fifth medication tube containing 5 ml of the particular phenol dilution is placed on the right. When the content on the medication tubes and broth culture of the test organism have reached the Drugs and Cosmetics Rules, 1945 457 temperature of the water bath, starting at Zero time, 0.2 ml of the culture is added to the left hand medication tube and the tube is shaken gently. After 30 seconds the next tube is inoculated similarly and the process is repeated with each successive tube at intervals of 30 seconds until the phenol control has been inoculated. Thirty seconds after this last addition (that is 2-1/2 minutes from zero) a loopful of the well-shaken content of the tube at the extreme left is withdrawn and placed in tube containing 5 ml of the broth medium. Thirty seconds after this similar operation is performed on the second medication tube. The procedure is repeated at an interval of 30 seconds with each of the 5 medication tubes working from left to right until 4 sets of cultures have been made i.e. at 2-1/2, 5, 7-1/2 and 10 minutes respectively after exposure. In each withdrawal care should be taken to ensure that the loop is removed vertically from the surface of the liquid with its plane horizontally and without touching the side of the test tubes. The loop shall be sterilized by flaming between each operation, care being taken that the loop is cooled before being again used. The inoculated broth tubes are incubated for not less than 48 hours and not more than 72 hours at o C when the tubes showing growth of the test organisms will be recognized by turbidity of the broth. Calculation of Coefficient.– The R.W. Coefficient is obtained by dividing that dilution of the disinfectant which shows life of test organism in 2-1/2 and 5 minutes but no life thereafter by that dilution of the phenol which gives the same response.A typical set of sample is given below: Sample disinfectant Time of exposures in minutes Dilutions 2½ 5 7½ 10 __________________________________________________________________________ _ R.W. Coefficient = = ___________________________________________________________________________ 1:1000 − − − − 1:1100 + − − − 1:1200 + + − . −

1:1300 + + +

− 1:100 Pheno control + + − −

Provisions applicable to other disinfectant fluids:

Disinfectant fluids which are made with chemicals other than those specified under Part I of this Schedule shall conform to the formula or list of ingredients shown on the label.

Labelling : Subject to the provisions of rules on labelling, the label of container shall state:

(i) the name of the product;
(ii) the name and full address of the manufacturer;
(iii) the full formula or list of ingredients of the preparation;
(iv) date of manufacture;
(v) date up to which the product can be used;
(vi) quantity present in the container; and
(vii) indications and mode of use. Cautionary note: Mercury compounds shall be strictly excluded from all grades.] Drugs and Cosmetics Rules, 1945

P

[See Rule 96]

LIFE PERIOD OF DRUGS

Sl. No.

potency period of the drug shall not exceed under the conditions of storage specified in Column No.4

Condition of storage 1 2 3 4

ANTIBIOTICS

o C.

15. Carbenicillin Sodium Powder 24 At temperature

not exceeding o C.

20. Chloramphenicol Palmitate Oral Suspension 36 21. Chloramphenicol Eye drops 24

25. Chlortetracycline Hydrochloride Capsules 60 26. Chlortetracycline Hydrochloride Tablets 24 27. Chlortetracycline Hydrochloride Ointment 24

¹ Subs. by G.S.R. 17(E) , dt. 7.1.1986 ( w.e.f. 7.1.1986 ).

___________________________________________________________________________________

Drugs and Cosmetics Rules, 1945

1 2

3 4

32. Dimethyl Chlortetracycline Hydrochloride 48 33. Dimethyl Chlortetracycline Hydrochloride Capsules 34. Daunoblastin Injection. 36

37. Doxycyline Monohydrate for Oral Suspension. 24 38. Doxycycline Monohydrate Capsules. 36

41. Erythromycin Oral Suspension 36 42. Erythromycin Estolate for Oral Suspension 36 43. Erythromycin Ethyl Succinate Tablet 24 44. Erythromycin Estolate Tablets 24

45. Erythromycin Stearate 36 In a cool place

46. Framycetin Sulphate 48 In a well closed container with temperature not exceeding 30 o C

47. Framycetin Sulphate Eye drops 24 In a well closed container with

temperature not exceeding 30 o C

o C.

49. Gentamycin Sulphate 60 In a cool place.

50. Gentamycin Sulphate Injection 36

53. Griseofulvin Tablets 36

54. Kanamycin Sulphate Injection. 24 55. Kanamycin Acid Sulphate Powder 48 In a cool place 56. Mitomycin C 48 In a cool place 57. Neomycin Sulphate. 48 In a cool place 58. Nystatin 36 At temperature not exceedin g o C. 59. Oleandomycin Phosphate sterile 24 In a cool place 60. Oleandomycin Phosphate non sterile 36 In a cool place

61. Oxytetracline Hydrochloride 36 In a cool place

62. Oxytetracycline Hydrochloride Capsules. 36 63. Oxytetracycline Hydrochloride Tablets 24 64. Oxytetracycline Hydrochloride Injection 24 65. Oxytetracycline Hydrochloride Ointment 36 66. Penicillin Crystalline 36 In a cool place 67. Penicillin Tablets 18 In a cool place 68. Procaine Penicillin G 36 In a cool place

Drugs and Cosmetics Rules, 1945

1 2 3 4

69. Benzathin Penicillin G 48 In a cool place 70. Potassium Phenoxy Methyl Penicillin 48 In a cool place 71. Potassium Phenoxy Methyl PenicillinTablets 24 72. Polymixin B Sulphate 48 In a cool place 73. Polymixin B Sulphate Ointment or Powder 24 In a cool place 74. Rifampicin 36 In a cool place

1[75 Rifampicin Capsules 36]

76. Spramycin Base 24 In a cool place 77. Strepromycin Injection. 36 78. Streptomycin Ointment 24 79. Streptomycin Tablets 24 80. Streptomycin Sulphate 48 At temperature not exceeding 20 o C 81. Tetracycline Base 24 In a cool place 82. Tetracycline Hydrochloride 36 In a cool place 83. Tetracycline Hydrochloride Capsules 36 84. Tetracycline Tablets 24 85. Tyrothricin 60 In a cool place.

VITAMINS 1. Vitamin A Injection 24 2. Vitamin B Injection 24 3. Thiamine Mononitrate Tablets 36

4. Thiamine Hydrochloride 48 In a well closed container, protected

from light, in a cool place.

5. Thiamine Mononitrate 48 In a well closed container, protected

from light, in a cool place.

6. Riboflavin 60 In a well closed container, protected

from light, in a cool place.

7. Riboflavin-5-Phosphate 24 In a well closed container, protected

from light, in a cool place. 8. Riboflavin Tablets 36 9. Vitamin B Injection 24 10. Vitamin B

60 In a well closed container, protected

from light, in a cool place.

11. Vitamin B

tablets 36

12. Cyanacobalamin 48 In a well closed container, protected

from light, in a cool place.

13. Hydroxycobalamin 48 In a well closed container, protected

from light, in a cool place.

14. Vitamin B

Injection 36

15. Calcium Pantothenate 36 In a well closed container, protected

from light, in a cool place. 16. Vitamin C Injection 24 17. Calcium Pantothenate Tablets 36

18. Vitamin C 48 In a well closed container, protected

from light, in a cool place.

¹ Subs. by G.S.R. 250(E), dt. 4.4.2002

___________________________________________________________________________________

Drugs and Cosmetics Rules, 1945 1 2 3 4

19. Vitamin D

36 In a well closed container, protected

from light, in a cool place.

20. Vitamin E or E-Acetate 60 In a well closed container, protected

from light, in a cool place.

21. Folic Acid 60 In a well closed container, protected

from light, in a cool place. 22. Folic Acid Tablets 36

23. Vitamin K 60 In a well closed container, protected

from light, in a cool place. 24. Vitamin K Injection 36

25. Niacinamide 60 In a well closed container, protected

from light, in a cool place.

from light, in a cool place. INSULIN PREPARATIONS

Globuline Zinc Insulin Injection

At temperature between 2 o C and 8 o C, must not be allowed to freeze.

2. Insulin Injection 24 At temperature between 2 o C and 8 o C, must not be allowed to freeze.

3. Insulin Zinc Suspension 24 At temperature between 2 o C and 8 o C, must not be allowed to freeze.

4. Isophane Insulin Injection. 24 At temperature between 2 o C and 8 o C, must not be allowed to freeze.

1[5. Human Insulin Injection 30 At temperature between 2 o C and 8 o C, must not be allowed to freeze.

NORMAL HUMAN PLASMA

Anti-Haemophillic Human Globulin

In a cool place 2. Dried Plasma 60 At a temperature not exceeding 25 o C 3. Dried Normal Human Serum Albumin 60 At a temperature not exceeding 25 o C 4. Frozen Plasma 60 In deep freeze 5. Liquid Plasma 24 In cold place 6. Liquid Normal Human Serum Albumin. 60 In cold place.

2[7. Whole Human Blood-

(a) Collected in ACD solution
(b) Collection in CPDA solution. 21days 35days At temperature between 4 o C and 6 o C At temperature between 4 o C and 6 o C] SERA TOXIN AND TOXOID

1. Alum Precipitated Diphtheria Toxoid 24 In cold place.

2. Alum Precipitated Diphtheria and Tetanus toxoid and Pertusis vaccine combined 18 In cold place

¹ Ins. by G.S.R. 215(E) , dt. 19.3.1999.

² Subs. by G.S.R. 626(E) , dt. 14.10.1991.

___________________________________________________________________________________

Drugs and Cosmetics Rules, 1945 1 2 3 4

3. Alum Precipitated Tetanus Toxoid 24 In a cold place

4. Aluminium Hydroxide Absorbed Diphtheria Toxoid

Diphtheria Tetanus Toxoid and Pertussis Vaccine combined.

Toxoid.

24 In a cold place.

7. Aluminium Phosphate absorbed Diphtheria and Tetanus Toxoid

24 In a cold place.

8. Aluminium phosphate absorbed diphtheria Toxoid Tetanus Toxoid and Pertussis vaccine combined.

o C and 5 o C protected from light.

o C and 10 o C preferable at the lower limit.

OTHER VACCINES

days In cold place

When stored at minus 20 o C When stored at Zero o C When stored at 4 o C

Tetanus Vaccine. 18 In cold place

Drugs and Cosmetics Rules, 1945 1 2 3 4

1[16. Anti-Rabies Vaccine (Cell Culture) 24 In cold place.]

ANTITOXIN

(For serum extracted preparations)

10% Excess potency 24 In cold place

15% Excess potency 36 In cold place

20% Excess Potency 48 In cold place

MISCELLANEOUS DRUGS

1. Andrenaline for Injection 12 In cold place.

2. Chorionic Gonadotrophin for Injection (Lyophilised) 36 At temperature not exceeding 20 o C.

Note : (1) The term “cool place” means place having a temperature between 10 o C and 25 o C.

(2) The term “cold place” means a place having a temperature not exceeding 8 o C.
(3) Capsules should be kept in a well-closed container at temperature not exceeding o C.
(4) Wherever condition of storage is not specified in Column 4, it may be stored under normal room temperature.] ___________________________________________________________________________________ Drugs and Cosmetics Rules, 1945

¹ Ins. by G.S.R. 215(E) , dt. 19. 3. 1999.

P1

Albendazole

Suspension

10ml Atenolol Tablets Anti-Haemmorhoidal Topicals Rectal Capsules Aspirin (Low-dose) Tablets Cholecalciferol or Ergocalciferol Granules 1 gm. Sachet Ciclopiroxolamine Vaginal Cream 30 gms.

Catalin Ophthalmic drops

15 ml Famotidine Tablets Glyceryl Trinitrate Spansules (Long Acting) Isosorbide Dinitrate Spansules (Long Acting) Isoniazide Syrup 200 ml Ipecacuanha Syrup 10 ml Oral Rehydration Salt (ORS) Powder Pouches to be reconstituted to one litre in one pack or in 5 unit dose sachets in one pack.

Piperazine Granules

5 gm. Syrup 30 ml Pyrantel Pamoate Syrup 8 ml or 10 ml Potassium Chloride. Syrup 60 ml and 200 ml. Progestogen Qestrogen (Combinations for Oral Contraception) Tablets 21 or 22 with or without 7 placebo.

Roxatidine Acetate Hydrochloride Tablets Vitamin A Oral Drops Drops 7.5 ml.]

1[Co-trimoxazole Suspension

50 ml.

Haloperidol Oral Solution

15 ml.

Loxapine Oral Liquid Concentrate

15 ml.]

________________________________________ 1.

² Ins. by G.S.R. 753(E), dt. 4.11.1999.

Ins. by G.S.R. 796(E) , dt. 1.10.1992 (w. e. f. 1.1.1993).

Drugs and Cosmetics Rules, 1945

Q

(See rules 134 and 144)

2[PART I]

3[List of Dyes, colours and Pigments permitted to be used in Cosmetics and Soaps as given under IS : 4707 (Part I)-1988 as amended by the Bureau of Indian Standards].]

Common name of the

colour Colour Index Number Chemical name of the colour 1 2 3

Guinea Green B 42085 Monosodium salt of 4-(N-ethyl-p-sulfobenzylamino)–

diphenylmethylone-(1-(N-ethyl-N-p-sulfoniumbenzyl)∆ 2,5-

cyclohexadienimine).

2,5-Cyclohexadienimine. Tartrazine 19140 Trisodium salt of 3-carboxy-5-hydroxy-1-p-sulfophenyl-4-p- sulfophenylazo-pyrazole. Sunset yellow FCF 15985 Disodium salt of 1-p-sulfophenylazo-2- naphthol-6-sulfonic acid. Ponceau 3R 16155 Disodium salts of a mixture of 1-alkyl- phenylazo-2-napthol 3, 6-disulfonic acids.

Amarnath. 16185

Trisodium salt of 1-(4-sulfo-1- napthylazo) 2-naphthol 3, 6- disulfonic acid.

Erythrosine. 45430

Disodium salt of 9-0-carboxyphenyl-6- hydroxy 2,4,5, 7- tetraiodo-3- isoxanthone. Ponceau SX. 14700 Disodium salt of 2-(5 sulfo-2, 4-xylyl- azo)-1-naphthol-4- sulfonic acid.

∆ 2, 5-cyclohexadienimine).

Indigocarmine. 73015 Disodium salt of 5,5’-indigotindisulfonic acid.

Wool Violet 5 BN (Acid- violet 6B) 42640 Monosodium salt of 4-(N-ethyl-p-sulfobenzylamino)-phenyl)-(4- (N-ethyl-p-(sulfonium-benzylamine)-phenyl) methylene)-(N, N- dimethyl-∆ 2,5-cyclohexadienimine)

Light Green SF Yellowish 42095Calcium salt of 4-(4-(N-ethyl-p-sulfobenzylamino)-phenyl) (4-

sulfonium-phenyl)methylene), (1-(N-ethyl-N-p-sulfobenzyl)-∆ 2,5-cyclohexadienimine).

¹ Inserted by Notification F.-1-36/64 D, dated 17.8.1964.

² Renumbered as Part I by G.S.R. 11(E) , dated 7.1.1991.

³ Substituted by G.S.R. 811(E) , dated 14.11.1994.

______________________________________

Drugs and Cosmetics Rules, 1945

2 3

Alizarin Cyanine Green F 61570 Disodium salt of 1,4-bis (O-sulfo-p-toluino) anthraquinone Quinazarine Green SS 61565 1,4-bis-(p-Toluino)-anthraquinone Fast Green FCF 42053 Disodium salt of 4-(4-(ethyl-p-sulfobenzylamino)-phenyl) (4- hydroxy-2 sulphoniumphenyl) methylene)-(1-N-ethyl-N-p-

sulfobenzyl) ∆ 2, 5, cyclohexadienimine).

Acid Fast Green 42100 Monosodium salt of 4-(4-N-ethyl-p-sulfobenzylomino) phenyl)- (o-chlorophenyl)-methylene)- 1-(N-ethyl-N- p-sulfonium- benzyl- ∆ 2,5, cyclohexadienimine).

Pyranine Concentrated 59040 Trisodium salt of 10-hydroxy-,3,5,8-pyrene-trisulfonic acid.

Quinoline Yellow WS 47005 Disodium salt of disulfonic acid of 2-(2-Quinolyl)-1, 3- indandione. Quinoline Yellow SS 47000 2-(2-quinolyl)-1, 3 indandiene. Poneceau 2 R 16150

Disodium salt of 1-xylylazo-2-naphthol-3, 6-disulfonic acid.

Lithol Rubin B. 15850

Monosodium salt of 4-(o-sulfo-p-tolylazo)3 hydroxy-2-naphthoic acid. Lithol Rubin BCA 15850 Calcium salt of 4-(o-sulfo-p-tolylazo)-3-hydroxy-2-naphthoic acid

Lake Red D. 15500 Monosodium salt of 1-0-carboxyphenylazo-2-naphthol. Lake Red DBA 15500 Barium salt of 1-o-carboxyphenylazo-2-naphthol. Lake Red DCA. 15500 Calcium salt of 1-o-carboxyphenylazo-2-naphthol.

Eosin TS 45380 Disodium salt of 2,4,5,7-tetrabromo-9-0 carboxyphenyl-6- hyroxy-3-isoxanthone. Eosin YSK. . 45380

Dipotassium salt of 2,4,5,7-tetrabromo-9-0 carboxyphenyl- 6-hyroxy-3-isoxanthone Tetrachlorofluorescein NA 45366 2,4,5,7- tetrachloro-S, 6-Fluorandiol Tetrachlorofluorescein K. 45366 Disodium salt of 9-0-carboxyphenyl-2,4,5,7-tetrachloro-6- hydroxy-3-isoxanthone. Tetrachloro Tetrabromo fluorescein 45410

2,4,5,7-Tetrabromo-12,13,14,15-tetrachloro-3, 6-fluorandiol. Phloxine B 45410 Disodium salt of 2,4,5,7-tetrabromo-9 (3,4,5,6-tetra chloro- o-carboxyphenyl)-6-hydroxy-3-isoxanthone Bluish Orange T.R. 45457 1,4,5,8, 15-Pentabromo-2, 7-dicarboxy-3, 6-fluoran diol.

Helindone Pink CN. 73360 5, 5-Dichloro-3, 3’ dimethyl-thioindigo

Drugs and Cosmetics Rules, 1945

2 3

Deep Maroon (Fanchon Maroon) 15880 Calcium salt of 4-(I-sulfo-2-naphthylazo 3- hydroxy-2- naphthoic acid.

Toluidine Red. . 12120 1-(o-Nitro-p-tolylazo)-2-naphthol.

Flaming Red. 12085 I- (o-Chloro-p-nitrophenylazo)-2-naphthol Deep Red (Maroon). 12350

3-Hydroxy-N- (m-nitrophenyl)-4-(o-nitro-p-tolylazo)-2-

naphthamide. Alba Red. 13058

o-(p,β,β-Dihydroxy-diethylamino)- phenylazo)-benzoic

acid. Orange G. 16230 Disodium salt of 1-phenylazo-2-naphthol-6-8-disulfonic acid.

Dichlorofluorescein. NA 45365 Disodium salt of 9-o-carboxyphenyl-1-4,5- dichloro-6- hydroxy-3-isoxanthone Diiodofluorescein. 45425 4,5 –Diiodo-3, 6-fluorandiol Erythrosine Yellowish NA. 45425 Disodium salt of 9-o-carboxyphenyl-6- hydroxy-4, 5- diiodo-3-isoxanthone.

Erythrosine Yellowish K. 45425

Dipotassium salt of 9-o-carboxyphenyl-6-hydroxy-4, 5- diiodo-3-isoxanthone. Erythrosine Yellowish NH 45425 Dipotassium salt of 9-o-carboxyphenyl-6-hydroxy-4, 5- diiodo-3-isoxanthone Orange TR 45456 4,5, 15-Tribromo 2, 7-dicarboxy-3, 6- fluorandiol.

Alizarin. 58000 1,2- Anthraquinonediol.

Dibromodiiodofluorescein. 45371 4 ,5- Dibromo-2, 7-diiodo-3, 6-fluorandiol. Resorcin Brown. 20170

Monosodium salt of 4-p-sulfophenylazo-2-2 4, xylylazo)- 1, 3-resorcinol. Alphazurine FG. 42090

Diammonium salt of 4-(N-ethyl-p- sulfobenzyl amino)- phenyl)-(2-sulfoniumphenyl)-Methytlene)-(-(1 (N-ethyl-N- p-sulfobenzyl) ∆ 2 ,5-cyclohexadienimine).

Allarin Astrol B. 61530 Monosodium salt of 1-methylamino-4-(o-sulfo-p-toluino)-

anthroquinone.

Indigo. 73000 Indigotin.

Patent Blue NA. . 42052

Monosodium salt of 4-(4- (N-ethyl- benzyl-amino)-phenyl – (5-hydroxy-4-sulfo-2-sulfoniumphenyl-methylene)(N-ethyl- Benzyl- ∆ 2, 5-cyclohexadienimine). Patent Blue CA. 42052

Calcium salt of 4-(4- (N-ethyl- benzyl-amino)-phenyl)-(5 hydroxy-4-sulfo-2-sulfoniumphenyl, methylene)- (N-ethyl- N-benzyl- ∆ 2- 5-cyclohexadienimine).

Curbrantherene Blue

69825

3, 3- Dichloroindanthrene.

Drugs and Cosmetics Rules, 1945

2 3

Napthol Blue Black

Alizurol purple SS

Acid Red 89

20470

60725

23910

Disodium salt of 8-amino-7-p- nitrophenylazo 3-phenylazo-1- naphthol-3, 6-disulfonic acid

I-hydroxy-4-p-toluino-anthraquinone.

----

Fanchon Yellow (Hansa Yellow G).

11680 (α) -(O-Nitro-p-tolylazo) accetoacetanilide

1[Part II – List of Colours permitted to be used in Soaps. ___________________________________________________________________________________

___________________________________________________________________________________

Phthalocyanine Blue 74160 (phthalocyninate (2--) copper.

Iragalite Red CVPB Paste or Pigment Orange 5 12075 1-(2,4-dinithro phenylazo)-2-Naphthalenol. Citrus Red No.2. 12156 1-2(2,5-dimethoxy phenylazo) 2-naphthol. Rhodamine B 500 45170 3-ethochloride of 9-0 carboxy-ethenyl-6-diethylamino- 3-ethylamine-3-isoxanthene. Aqueous Green Paste 74260 Polychloro copper Phthalocyanine. Pigment Yellow 3 11710 2-(4-Chloro-2-nitrophenyl)-azo-N-(-2-Chloro-phenyl)-3- Oxobutamide. Irgalite Carmine F-P Powder or Pigments Red 5.

12490 N-(5-Chloro-2, 4-dimethoxy-phenyl)-4-(CS-diathylamine)

Sulfonyl-2-methoxyphenyl)azo-3-hydroxy-2-naphthalene carboxamide. Monolite Red 4R HV Paste or Pigment Red 7.

12420 N-(4-Chloro-2-methylphenyl-4-(-4-Chloro-2-methylphenyl) azo

3-hydroxy-2-naphthalenol Carboxamide. Oil Red No.1 or Solvent Red 24 or Oil Red 3R.

26105 4-0-Tolylazo-Toluidine azo 2-naphthalenol.]

___________________________________________________________________________ *This list of colour for use in soaps is in addition to those colours already given in

Schedule Q and are used for soaps.]

_________________________________________________________ 1.

Ins. by G.S.R. 11(E) , dt. 7.1.1991.

Drugs and Cosmetics Rules, 1945

R

[See Rule 125]

Standards for condoms made of rubber latex intended for single use and other mechanical contraceptives

I-Condoms 1. Description. -Condoms consist of cylindrical rubber sheaths with one end open. The open end shall terminate with an integral rim. The closed end may have a receptacle. They may be supplied rolled and shall be free from tackiness and shall be capable of being unrolled readily. 2. Materials. -(1) Condoms shall be manufactured from good quality rubber latex and shall be free from embedded grit and shall be opaque or translucent prior to the application of dusting materials or lubricants.

(2) The rubber latex, colours used and any dusting materials or lubricants applied to the condoms shall neither contain nor liberate substances which are known to have toxic or other harmful effects under normal conditions of use. Any dusting material or lubricant or colour used shall not have deleterious effect on the condoms or be harmful to the users. 3. Procedure for sampling during production −(1) Specimens constituting the test samples shall be taken at random successively from each quantum of production that is, from the quantity produced from the same finished rubber latex and under the same processing and finishing conditions of manufacture and samples from each quantum shall be tested separately to ascertain conformity of quantum with the specified requirements in accordance with the tests described in this Schedule.
(2) (a) The number of samples drawn from each quantum shall be not less than 0.5 per cent of the number.
- (b) The number of samples drawn from each quantum shall be tested for Burst Volume and Pressure Test and Water Leakage Test in accordance with the method prescribed in paras 9 and 10 of this Schedule. 75 per cent of the samples drawn will be tested for Water Leakage Test and 25 per cent will be tested for Burst Volume and Pressure Test.
- (c) The number of test samples ‘N’ and the number of rejected samples ‘R’ from a sequence of

production quanta shall be recorded in a register. The cumulative total of test samples ‘N’ and the cumulative

total of rejects ‘R’ from the test shall be recorded and the condoms shall be deemed to comply with the requirements if the cumulative total of rejects ‘R’ is not more than

2[0.0025N+3 x √0.0025N] for Water Leakage Test, and

3[0.015N+3 x √0.015N] for Burst Volume and Pressure Test. Each unit of 100 test samples shall be distributed for the various tests as follows: - 25 for Burst Volume Pressure Test, and; 75 for Water Leakage Test.

________________________________________________________________________

² Subs. by G.S.R. 353(E), dt. 26.4.2000.

1 Subs. by G.S.R. 495(E) , dt. 9.6.1995.

Drugs and Cosmetics Rules, 1945

(4) Where the number of test samples is a multiple of 100 the distribution scale mentioned above shall be prorated.
(5) If the cumulative total sample rejected exceeds the number of allowables at any point in the sequence of quanta, the quantum at which this occurs shall be liable to rejection. The assessment of quality of further production quanta shall include all previous test results starting from quantum number 1 and approval of production shall be in suspense until the condition required by the scheme is again fulfilled.
(6) At least one sample shall be taken at random from each production quantum not exceeding 10,000 condoms and shall satisfy all requirements regarding dimensions as specified in paragraph 8 of this Schedule. 4. Procedure for sampling and testing of finished products by a manufacturer- A. Water Leakage Test.- (1) Statistical sampling for quality control assessment of the finished product in respect of Water Leakage Test shall be done in accordance with the plan set out in Annexure 1 to this Schedule.
(2) A test sample failing in the above test is to be considered as defective. If the cumulative total of rejects ‘R’ is found to be equal to or greater than the number shown against ‘R’ in Annexure-I, the batch or lot shall be declared as not of standard quality. B. Bursting Volume and Pressure Test.- (1) Sample condoms shall be tested for Bursting Volume and Pressure Test. Statistical sampling for this test shall be done in accordance with the plan set out in Annexure III to this Schedule. Condoms shall not leak or burst at a volume of less than that specified or at a pressure less than 1.0 kpa (gauge), when tested as per paragraph 9, both before and after oven conditioning as specified in Annexure V. Bursting Volume minimum limit in

litres shall be equal to [mean condom width

(mm)

] rounded to the nearest 0.5 litre.

151.8

(2) A test sample failing in the above test is to be considered defective. If the cumulative total of rejects ‘R’ is found to be equal or greater than the number shown against ‘R’ in Annexure III, the batch or lot shall be declared as not of standard quality.

C. Dimensions. - At least 2 samples drawn from the lot or batch shall satisfy the requirements

regarding dimensions as specified in paragraph 8 of this Schedule. 5. Procedure for sampling and testing of condoms by a purchaser.-

Water Leakage Test.- (1) Statistical sampling of condoms by a purchaser for Water Leakage Test

shall be done in accordance with the plan set out in Annexure II to this Schedule;

(2) A test sample failing in the above test is to be considered as defective. If the cumulative total of rejects ‘R’ is found to be equal to or greater than the number shown against ‘R’ in the Annexure-II, the batch or lot shall be declared as not of standard quality. B. Bursting Volume and Pressure Test.- Sample condoms shall be tested for Bursting Volume and Pressure Test. Statistical sampling for this test shall be done in accordance with the plan set out in Annexure III to this Schedule. If the cumulative total of rejects ‘R’ is found to be equal to or greater that the number shown against ‘R’ in Annexure III, the batch or lot shall be declared as not of standard quality. Condom shall not leak or burst at a volume of less than that specified or at a pressure less than 1.0 kpa (gauge), when tested as specified in paragraph 9, both before and after oven Drugs and Cosmetics Rules, 1945 conditioning as per specified in Annexure V. Bursting volume minimum limit in litres shall be equal to [mean condom width (mm) ] rounded to the nearest 0.5 litre. 151.8 C. Dimensions. - At least two samples from the lot or batch shall satisfy the requirements regarding dimensions as specified in paragraph 8 of this Schedule. 6. Sampling plan for a Drugs Inspector. - (1) Where an Inspector under the Act desires to take test samples from the premises of manufacturer or a distribution depot; twenty containers from each batch of production may be selected by him on a random basis and from each of the containers, five samples shall be taken. The hundred samples so selected shall be distributed for various tests as specified in paragraph 7 of this Schedule. In case the number of container is less than twenty, the number of samples to be taken from each container shall be proportionately increased.
(2) Where an Inspector under the Act desires to take samples from a sales premises, he shall take hundred samples from each batch of production in accordance with the procedure as specified in sub- paragraph (1). 7. Sampled condoms drawn under sub-paragraph.- (1) shall be distributed for various tests as follows: - Two samples for thickness, length and width; Forty-five samples for Water Leakage Test; Forty-five samples for Bursting Volume and Pressure Test; and Eight samples as reserve. The samples shall be declared as not of standard quality, if, - (i) the number of condoms found defective in the Water Leakage Test exceeds one; (ii) the number of condoms found defective in Bursting Volume and Pressure Test exceeds two; (iii) samples fail to conform to the requirements of dimensions as specified in paragraph 8 of this Schedule.

8. Dimensions. - (1) The length when unrolled (excluding

1[teat] shall be not less than. -

(i) 170 mm. (ii) 1* * * 180 mm.

(2) The width of a condom which laid flat and measured at any point within 85 mm from the open end shall be,–
- (i) 49 ± 2 mm for 1[170 mm] length.
- (ii) 53 ± 2 mm for 180 mm length. _______________________________________________________________________

1. Amended by Corrigenda vide G.S.R. 122(E), dt. 11.3.1996.

Drugs and Cosmetics Rules, 1945

(3) The single-wall thickness of a condom when measured at three points, one at 30 ± 2mm from the open end, 30 ± 5mm from the close end excluding the reservoir tip and at the mid distance between these two point shall be from 0.045 mm to 0.075 mm. NOTE 1. - The single-wall thickness shall be determined with a suitable micrometer dial gauge graduated in intervals of 0.01 mm. NOTE 2. - Condoms shall, prior to the measurement of thickness, have the dusting powder or the lubricant or both removed by means of water or Isopropanol. 9. Bursting Volume and Pressure Test.- Determination of Bursting Volume and Pressure Test shall be done as specified in Annexure IV. 10. Water Leakage Test.- Unroll the condom and fit the open end on a suitable mount, the condom thus being suspended open end upwards. Fill it with 300 ml water at room temperature and inspect it after a period of at least 1 minute for leakage up to 25.mm from the open end. 1[If, because of] distension of the condom the water does not extend to 25 mm from the open end, 1[raise the closed end until the water level

reaches this distance. After at] least 1 minute, inspect the newly-wetted part of the condom for leakage. The

condom shall be deemed to be defective if it bursts during test or shows any evidence of leakage or seepage of micro-droplets or does not hold 300 ml water.

11. Quantity of Lubricant. -(1) The condoms shall be dressed with silicone lubricant. The quantity

required on each individual condom should not be less than 200 mg and minimum viscosity shall be 200 centistokes.

(2) Lubricated condoms in individual foil packages shall be weighed on an Analytical Balance. Each condom shall be removed from its foil package and both condom and its foil package shall be washed in denatured ethanol or isopropanol, dried and then weighed again. All weights shall be recorded to the nearest milligram (mg.). Compliance with the requirement shall be determined by subtracting the weight of the washed and dried condom and its foil package from the weight of sample condom in individual foil package prior to the removal of lubricant. Washing and drying may be required upto a total of four times if the lubricant quantity is less than the required minimum.
(3) At least thirteen samples shall be drawn from the lot or batch and the samples shall satisfy the requirements regarding the quantity of lubricant. 12. Colour Fastness.- Not less than ten samples taken at random from each batch of coloured condoms shall pass the following test for colour fastness, namely :- Thoroughly wet inside and outside of the condom with distilled water. Make no attempt to remove any dusting material or lubricant. Wrap the wet condom in white absorbent paper so that the largest possible surface area of the condom is in contact with the paper and seal the whole in a suitable container to prevent loss of moisture. Allow the container and its contents to stand for 16 hours to 24 hours at room temperature. After removing the absorbent __________________________________________________________________________

1. Amended by Corrigenda vide G.S.R. 122(E), dt. 11.3.1996.

Drugs and Cosmetics Rules, 1945 paper from the container, examine it visually in the natural daylight for any indication of staining. No part of the absorbent paper shall be stained. If there is any indication of staining of the absorbent paper by any colouring agent present in any of the condoms or any dusting material or lubricant, the entire batch shall be declared to be not of standard quality.

13. Labelling, packing and storage. - (1) The condoms shall be individually wrapped and sealed

in laminates containing at least eight microns of aluminium foil. The individual condom shall be packed in square (non-squeeze condition) / rectangular aluminium foil. The packing shall protect the condoms from contamination and mechanical damage. The smallest packing offered to the consumer shall bear a clear permanent marking with the following particulars, namely: -

(i) Manufacturer’s name and address and the trade name of the condoms, if any;
(ii) Batch number;
(iii) Date of manufacture (Month and year only);
(iv) Date of expiry (Month and year only) which shall not be more than thirty-six months from the date of manufacture;
(v) The words “For single use only”

(2) The condoms shall be stored in a cool dry place away from heat and direct sunlight. 14. Integrity of individual package seals. - Sample condoms in individual packages shall be placed in a sealed, transparent container (such as a laboratory Bell jar) and subjected to vacuum of 50± 10 kpa (gauge) for a period of one minute. Condom packages that do not inflate or remain inflated for the period of the test shall be deemed non- compliers. In doubtful cases, the test may be repeated, and both the inflation and deflation of packages may be observed on application and removal of vacuum. An AQL of 2.5 per cent will be applied in assessing the results of this test. Thirty-two samples of condoms for a batch size less than 5 lakhs and fifty samples of condoms for batch size more than 5 lakhs shall be tested for integrity test of individual package seals and compliance limit or acceptance number shall be not more than two or three condoms respectively. II- Other Mechanical Contraceptive 15. Standards for other mechanical contraceptive - Standards for ‘Copper T’ and ‘Tubal Ring’ shall be as laid down in Annexure VI.

1[ANNEXURE I

[See Paragraph 4-A] Sampling Plan for Quality Control of Condoms at Manufacturer’s Level. BATCH SIZE: 35,001 TO 1.5 LAKH.

Single Sampling Plan

_______________________________________________________________________

1 Subs. by. G.S.R. 353(E) , for “ Annexures I to III” dt. 26-4-2000.

Drugs and Cosmetics Rules, 1945

BATCH SIZE: 150001 TO 5 LAKHS

Single Sampling Plan

BATCH SIZE: OVER 5 LAKHS

Single Sampling Plan.

Note : AQL denotes Acceptance Quality Level;

AC denotes Acceptance Number i.e. the maximum allowable number of defectives for acceptance of the Batch; and R denotes Rejection Number i.e., the minimum number of defectives for rejection of the Batch.

ANNEDURE II

[See Paragraph 5A] Sampling Plan for Quality Control of Condoms at Purchaser’s Level. BATCH SIZE: 35,001 TO 1.5 LAKHS

Single Sampling Plan

BATCH SIZE : 15,001 TO 5 LAKHS

Single Sampling Plan.

BATCH SIZE : OVER 5 LAKHS

Single Sampling Plan

Note: AQL denotes Acceptance Quality Level;

AC denotes Acceptance Number i.e. the maximum allowable number of defectives for acceptance of the Batch; and

R denotes Rejection Number i.e., the minimum number of defectives for rejection of the

Batch.

Drugs and Cosmetics Rules, 1945 ANNEXURE III [See Paragraph 4-B and 5-B] Sampling Plan for Bursting Volume and Pressure Test.

BATCH SIZE: 35,001 TO 1.5 LAKH.

Single Sampling Plan.

BATCH SIZE: OVER 5 LAKHS Single Sampling Plan.

ANNEXURE IV

(See Paragraph 9) Determination of Bursting Volume and Pressure

1. Principle. - Inflation of constant length of the condom with air and recording the volume and pressure at the moment of bursting.

2. Apparatus. - (1) Apparatus suitable for inflating the condom with clean air at a specified rate and provided with equipment for measuring volume and pressure.

(2) Suitable mount for fitting the condoms to the apparatus as shown in the figure annexed.
(3) Rod, 140 mm in length having a smooth sphere 20 mm in diameter at its top (see the figure) for hanging the unrolled condom when fixed to the apparatus. 3. Procedure. - (1) Unroll the condom, hang it on the rod (2.3), affix to the mount (2.2) and inflate with air at a rate of 0.4 to 0.5 litre/sec. (24 to 30 litres/min.)
(2) Measure and note the bursting volume, in litres rounded to the nearest 0.5 litre and the bursting pressure, in kilopascals rounded to the nearest 0.1 kpa.

4. Test report. - The test report shall include the following particulars:

(a) the identification of the sample; Drugs and Cosmetics Rules, 1945
(b) the bursting volume and bursting pressure of each tested condom;
(c) the date of testing.

ANNEXURE V

[See Paragraphs 4(B) and 5 (B) Oven Conditioning

1. Principle of the Method. - The test consists in subjecting test samples to controlled deterioration by air at an elevated temperature and at atmospheric pressure after which burst volume and pressure limits are measured. 2. Apparatus. - The air oven shall be of such a size that the total volume of the test samples does not exceed 10 per cent of the free air space of the oven. Provision shall be made for slow circulation of air in the oven of not less than three changes and not more than ten changes per hour. The temperature of the oven shall be thermostatically controlled so that the test samples are kept within ± 2 o C of the specified ageing temperature. A thermometer shall be placed near the centre of the ageing test samples to record the actual ageing temperature. Note: - Copper or copper alloys shall not be used for the material of construction of the oven prescribed.

Drugs and Cosmetics Rules, 1945 3. Test sample. - The foil laminations of individual packages should remain intact throughout all laboratory handling including over conditioning.

4. Temperature of the oven – Maintain the oven at 70 ± 2 o C.

oven at 70 ± 2 o

C for 96 hours. After heating, keep the packages at 23 ± 5

o C for at least 12 hours but not more than 96 hours. Open the packages and examine conditioned condoms for tackiness, brittleness, or other signs of deterioration. Within 96 hours but not sooner than 12 hours after conditioning, do the bursting volume and pressure Test as described in this Schedule.

ANNEXURE VI

(See Paragraph 15)

1. Standards for Copper T (200B) (IS-12418) (part 4)-1991-UDC 615.477.87). - Contraceptive

Device Copper T (200 B) shall conform to the Indian Standards laid down from time to time by the Bureau of Indian Standards.

2. Standards for Contraceptive Tubal Ring (IS 13009 : 1990-UDC 615.472.6 : 611.656).- Contraceptive Device Tubal Ring shall conform to the Indian Standards laid down from time to time by the Bureau of Indian Standards.]

Drugs and Cosmetics Rules, 1945

R1

(See Rules 109-A and 125-A)

The following medical devices shall conform to the Indian Standards specifications laid down from time to time by the Bureau of Indian Standards: -

(1) Sterile Disposable Perfusion sets for single use only (Sections 2 and 3 of item 1 of IS 9824:1981 read with Amendment number 1).
(2) Sterile Disposable Hypodermic Syringes for single use only (IS 10258 : 1982).
(3) Sterile Disposable Hypodermic Needles for single use only (IS 10654 : 1991).] ____________________________________________________________________________________________________________________ Drugs and Cosmetics Rules, 1945

¹ Ins. by G.S.R. 109(E) , dt. 22.2.1994.

S

[See Rule 150-A]

2[Bureau of Indian Standards (BIS)] Standards for cosmetics in finished form. − The following cosmetics in finished form shall conform to the Indian Standards specifications laid down from time to time by the

2[Bureau of Indian Standards (BIS)].

1. Skin Powders. 2. Skin Powder for infants. 3. Tooth Powder. 4. Toothpaste. 5. Skin Creams. 6. Hair Oils. 7. Shampoo, Soap-based. 8. Shampoo, Synthetic-Detergent based. 9. Hair Creams. 10. Oxidation hair dyes, Liquid. 11. Cologne.]

3[12

Nail Polish (Nail Enamel).

13. After Shave Lotion.

14. Pomades and Brilliantines.

15. Depliatories Chemical. 16 Shaving Creams. 17. Cosmetic Pencils. 18. Lipstick.]

4[19. Toilet Soap.

20. Liquid Toilet Soap. 21. Baby Toilet Soap. 22. Shaving Soap. 23. Transparent Toilet Soap.]

5[24. Lipsalve IS:10284.

25. Powder Hair Dye IS: 10350. 26. Bindi (Liquid) IS: 10998. 27. Kum Kum Powder IS: 10999. 28. Henna Powder IS: 11142.]

¹ Ins. by G.S.R. 510(E), dt. 26.7.1982.

__________________________________________________________________________ 2.

Drugs and Cosmetics Rules, 1945

T

(See rule 157) GOOD MANUFACTURING PRACTICES FOR AYURVEDIC, SIDDHA AND UNANI MEDICINES

The Good Manufacturing Practices (GMP) are prescribed as follows in Part I and Part II to ensure that:

(i) Raw materials used in the manufacture of drugs are authentic, of prescribed quality and are free from contamination.
(ii) The manufacturing process is as has been prescribed to maintain the standards.
(iii) Adequate quality control measures are adopted.
(iv) The manufactured drug which is released for sale is of acceptable quality.
(v) To achieve the objectives listed above, each licensee shall evolve methodology and procedures for following the prescribed process of manufacture of drugs which should be

documented as a manual and kept for reference and inspection. However, under IMCC Act 1970

registered Vaidyas, Siddhas and Hakeems who prepare medicines on their own to dispense to their

GOOD MANUFACTURING PRACTICES

Factory Premises: The manufacturing plant should have adequate space for: -

(i) Receiving and storing raw material.
(ii) Manufacturing process areas.
(iii) Quality control section.
(iv) Finished goods store.
(v) Office.
(vi) Rejected goods/drugs store.

1.2 General Requirements:

1.1(A) Location and surroundings. - The factory building for manufacture of Ayurveda, Siddha and Unani medicines shall be so situated and shall have such construction as to avoid contamination from open sewerage, drain, public lavatory for any factory which produces disagreeable or obnoxious odour or fumes or excessive soot, dust and smoke.

1.1(B) Buildings. - The buildings used for factory shall be such as to permit production of drugs under hygienic conditions and should be free from cobwebs and insects/rodents. It should have adequate provision of light and ventilation. The floor and the walls should not be damp or moist. The premises used for manufacturing, processing, packaging and labelling will be in conformity with the provisions of the Factory Act. It shall be located so as to be:

(I) Compatible with other manufacturing operations that may be carried out in the same or adjacent premises. ___________________________________________________________________________ Drugs and Cosmetics Rules, 1945
(II) Adequately provided with working space to allow orderly and logical placement of equipment and materials to avoid the risk of mix-up between different drugs or components thereof and control the possibility of cross contamination by other drugs or substances and avoid the risk of omission of any manufacturing or control step.
(III) Designed, constructed and maintained to prevent entry of insects and rodents. Interior surface (walls, floors and ceilings) shall be smooth and free from cracks and permit easy cleaning and disinfection. The walls of the room in which the manufacturing operations are carried out shall be impervious to and be capable of being kept clean. The flooring shall be smooth and even and shall be such as not to permit retention or accumulation of dust or waste products.
(IV) Provided with proper drainage system in the processing area. The sanitary fittings and electrical fixtures in the manufacturing area shall be proper and safe.
(V) Furnace/Bhatti section could be covered with tin roof and proper ventilation, but sufficient care should be taken to prevent flies and dust.
(VI) There should be fire safety measures and proper exits should be there.
(VII) Drying Space: -There should be separate space for drying of raw material, in process medicine or medicines which require drying before packing. This space will be protected from flies/ insects/dust etc., by proper flooring, wire-mash window, glass panels or other material. 1.1(C) Water Supply. - The water used in manufacture shall be pure and of potable quality. Adequate provision of water for washing the premises shall be made. 1.1(D) Disposable of Waste. - From the manufacturing section and laboratories the waste water and the residues which might be prejudicial to the workers or public health shall be disposed of. 1.1(E) Container’s Cleaning. - In factories where operations involving the use of containers such as glass bottles, vials and jars are conducted, there shall be adequate arrangements separated from the manufacturing operations for washing, cleaning and drying of such containers. 1.1(F) Stores. - Storage should have proper ventilation and shall be free from dampness. It should provide independent adequate space for storage of different types of material, such as raw material, packaging material and finished products.

¹ Subs. by G.S.R. 198(E) , dt. 7.3.2003.

1.1. (F)(A) Raw Materials. - All raw materials procured for manufacturing will be stored in the

raw materials store. The manufacture based on the experience and the characteristics of the particular raw material used in Ayurveda, Siddha and Unani system shall decide the use of appropriate containers which would protect the quality of raw materials as well as prevent it from damage due to dampness, microbiological contamination or rodent and insect infestation, etc. If certain raw materials require such controlled environmental conditions, the raw materials stores may be sub-divided with proper enclosures to provide such conditions by suitable cabinization. While designing such containers, cupboard or areas in the raw materials store, care may be taken to handle the following different categories of raw materials:-

5. Dry herbs or plant parts.

Drugs and Cosmetics Rules, 1945 6. Excipients etc. 7. Volatile oils/perfumes and flavours

8. Plant concentrates/ extracts and exudates/resins.

Each container used for raw material storage shall be properly identified with the label which indicates name of the raw material, source of supply and will also clearly state the status of raw material such as ‘UNDER TEST’ or ‘APPROVED’ or ‘REJECTED’. The labels shall further indicate the identity of the particular supply in the form of Batch No. or Lot No. and the date of receipt of the consignment.

All the raw materials shall be sampled and got tested either by the in-house Ayurvedic, Siddha and Unani experts (Quality control technical person) or by the laboratories approved by the Government and shall be used only on approval after verifying. The rejected raw material should be removed from other raw material store and should be kept in separate room. Procedure of ‘First in first out’ should be adopted for raw materials wherever necessary. Records of the receipt, testing and approval or rejection and use of raw material shall be maintained.

1.1. (F)(B) Packing Materials. - All packaging materials such as bottles, jars, capsules etc. shall be stored properly. All containers and closure shall be adequately cleaned and dried before packing the products.

1.1. (F)(C) Finished Goods Stores. - The finished goods transferred from the production area after proper packaging shall be stored in the finished goods stores within an area marked “Quarantine”. After the quality control laboratory and the experts have checked the correctness of finished goods with reference to its packing/labelling as well as the finished product quality as prescribed, then it will be moved to “Approved Finished Goods Stock” area. Only approved finished goods shall be dispatched as per marketing requirements. Distribution records shall be maintained as required.

If any Ayurvedic, Siddha and Unani drug needs special storage conditions, finished goods store shall provide necessary environmental requirements.

1.1(G) Working space. - The manufacturing area shall provide adequate space (manufacture and quality control) for orderly placement of equipment and material used in any of the operations for which these employed so as to facilitate easy and safe working and to minimize or to eliminate any risk of mix-up between different drugs, raw materials and to prevent the possibility of cross contamination of one drug by another drug that is manufactured, stored or handled in the same premises. 1.1(H) Health Clothing, Sanitation and Hygiene of Workers.- All workers employed in the Factory shall be free from contagious diseases. The clothing of the workers shall consist of proper uniform suitable to the nature of work and the climate and shall be clean. The uniform shall also include cloth or synthetic covering for hands, feet and head wherever required. Adequate facilities for personal cleanliness such as clean towels, soap and scrubbing brushes shall be provided. Separate provision shall be made for lavatories to be used by men and women, and such lavatories shall be located at places separated from the processing rooms. Workers will also be provided facilities for changing their clothes and to keep their personal belongings.

1.1. (I) Medical Services: The manufacturer shall also provide:-

(a) adequate facilities for first aid;
(b) medical examination of workers at the time of employment and periodical check up thereafter by a physician once a year, with particular attention being devoted to freedom from infections. Records thereof shall be maintained. Drugs and Cosmetics Rules, 1945

1.1(J) Machinery and Equipments. - For carrying out manufacturing depending on the size of

operation and the nature of product manufactured, suitable equipment either manually operated or operated semi-automatically (Electrical or steam based) or fully automatic machinery shall be made available. These may include machines for use in the process of manufacture such as crushing, grinding, powdering, boiling, mashing, burning, roasting, filtering, drying, filling, labelling and packing etc. to ensure ease in movement of workers and orderliness in operations a suitably adequate space will be ensured between two machines or rows of machines. These equipments have to be properly installed and maintained with proper cleaning. List of equipments and machinery recommended is indicated in Part II-A. Proper Standard Operational Procedures (SOPs) for cleaning, maintaining and performance of every machine should be laid down.

manufactured (classical preparation or patent and proprietary medicines). Manufacturing records are required to provide an account of the list of raw materials and their quantities obtained from the store, tests conducted during the various stages of manufacture like taste, colour, physical characteristics and chemical tests as may be necessary or indicated in the approved books of Ayurveda, Siddha and Unani mentioned in the First Schedule of the Drugs and Cosmetics Act, 1940 (23 of 1940). These tests may include any in-house or pharmacopoeial test adopted by the manufacturer in the raw material or in the process material and in the finished product. These records shall be duly signed by Production and Quality Control Personnel respectively. Details of transfer of manufactured drug to the finished products store including dates and quantity of drugs transferred along with record of testing of the finished product, if any, and packaging, records shall be maintained. Only after the manufactured drugs have been verified and accepted quality shall be allowed to be cleared for sale.

It should be essential to maintain the record of date, manpower, machine and equipments used and to keep in process record of various shodhana, bhavana, burning and fire and specific grindings in terms of internal use.

1.1(L) Distribution Records. - Records of sale and distribution of each batch of Ayurveda, Siddha and Unani Drugs shall be maintained in order to facilitate prompt and complete recall of the batch, if necessary.The duration of record keeping should be the date of expiry of the batch. Certain category of Ayurvedic, Siddha and Unani medicines like Bhasma, Rasa, Kupi-pakva, Parpati, Sindura, Karpu/Uppu/Puram, Kushta, Asava-arishta etc. do not have expiry date in contrast their efficacy increases with the passage of time. Hence, records need be maintained upto five years of the exhausting of stock.

1.1(M) Record of Market Complaints. - Manufacturers shall maintain a register to record all reports of market complaints received regarding the products sold in the market. The manufacturer shall enter all data received on such market complaints, investigations carried out by the manufacturers regarding the complaint as well as any corrective action initiated to prevent recurrence of such market complaints shall also be recorded. Once in a period of six months the manufacturer shall submit the record of such complaints to the licensing authority. The Register shall also be available for inspection during any inspection of the premises.

Reports of any adverse reaction resulting from the use of Ayurvedic, Siddha and Unani drugs shall also be maintained in a separate register by each manufacturer. The manufacturer shall investigate any of the adverse reaction to find if the same is due to any defect in the product, and whether such reactions are already reported in the literature or it is a new observation.

1.1(N) Quality Control. - Every licensee is required to provide facility for quality control section in his own premises or through Government approved testing laboratory. The test shall be as per the Auurveda, Siddha and Unani pharmacopoeial standard. Where the tests are not available, the test

Drugs and Cosmetics Rules, 1945 should be performed according to the manufacturers’ specification or other information available. The quality control section shall verify all the raw materials, monitor in-process quality checks and control the quality of finished product being released to finished goods store/warehouse. Preferably for such quality control there will be a separate expert. The quality control section shall have the following facilities:–

(1) There should be 150 sq. feet area for quality control section.
(2) For identification of raw drugs, reference books and reference samples should be maintained.
(3) Manufacturing record should be maintained for the various processes.
(4) To verify the finished products, controlled samples of finished products of each batch will be kept till the expiry date of product..
(5) To supervise and monitor adequacy of conditions under which raw materials, semi- finished products and finished products are stored.
(6) Keep record in establishing shelf life and storage requirements for the drugs.
(7) Manufacturers who are manufacturing patent and proprietary Ayurveda, Siddha, and

Unani medicines shall provide their own specification and control references in respect

of such formulated drugs.

(8) The record of specific method and procedure of preparation, that is, “Bhavana”, “Mardana” and “Puta” and the record of every process carried out by the manufacturer shall be maintained.
(9) The standards for identity, purity and strength as given in respective pharmacopoeias of Ayurveda, Siddha and Unani systems of medicines published by Government of India shall be complied with.
(10) All raw materials will be monitored for fungal, bacterial contamination with a view to minimize such contamination.
(11) Quality control section will have a minimum of: –
- (i) One person with Ayurveda /Siddha/ Unani qualification recognized under Schedule II of Indian Medicine Central Council Act, 1970 . Two other persons one each with Bachelor qualification in Botany/ Chemistry/ Pharmacy could be on part time or on contractual basis.
- (ii) The manufacturing unit shall have a quality control section as explained under Section 35(ii). Alternatively, these quality control provisions will be met by getting testing etc., from a recognized laboratory for Ayuveda, Siddha and Unani drugs under rule 160-A of the Drugs and Cosmetics Act. The manufacturing company will maintain all the record of various tests got done from outside recognized laboratory.
- (iii) List of equipments recommended is indicated in Part II- C. 1.2. Requirement for Sterile Product:
- (A) Manufacturing Areas: – For the manufacture of sterile Ayurvedic, Unani and Siddha drugs, separate enclosed areas specifically designed for the purpose shall be provided. These areas shall be provided with air locks for entry and shall be essentially dust free and ventilated with an air supply. For all areas where aseptic manufacture has to be carried out, air supply shall be filtered through bacteria retaining filters (HEPA Filters) and shall be at a pressure higher than in the adjacent areas. The filters shall be checked for performance on installation and periodically thereafter the record of checks shall be maintained. All the surfaces in sterile manufacturing areas shall be designed to facilitate cleaning and disinfection. For sterile manufacturing routine Drugs and Cosmetics Rules, 1945 microbial counts of all Ayurvedic, Siddha and Unani drug manufacturing areas shall be carried out during operations. Results of such count shall be checked against established in-house standards and record maintained. Access to manufacturing areas shall be restricted to minimum number of authorized personnel. Special procedure to be followed for entering and leaving the manufacturing areas shall be written down and displayed. For the manufacturing of Ayurvedic, Siddha and Unani drug that can be sterilized in their final containers, the design of the areas shall preclude the possibility of the products intended for sterilization being mixed with or taken to be products already sterilized. In case of terminally sterilized products, the design of the areas shall preclude the possibility of mix-up between non-sterile products.
- (B) Precautions against contamination and mix:
- (a) Carrying out manufacturing operations in a separate block of adequately isolated building or operating in an isolated enclosure within the building,
- (b) Using appropriate pressure differential in the process area.
- (c) Providing a suitable exhaust system.
- (d) Designing laminar flow sterile air system for sterile products.
- (e) The germicidal efficiency of UV lamps shall be checked and recorded indicating the burning hours or checked using intensity.
- (f) Individual containers of liquids and ophthalmic solutions shall be examined against black-white background fitted with diffused light after filling to ensure freedom from contamination with foreign suspended matter.
- (g) Expert technical staff approved by the Licensing Authority shall check and

compare actual yield against theoretical yield before final distribution of the batch.

All process controls as required under master formula including room temperature, relative humidity, volume filled, leakage and clarity shall be checked and recorded.

PART II

VARIOUS CATEGORIES OF AYURVEDIC, SIDDHA SYSTEM OF MEDICINES

One machine indicated for one category of medicine could be used for the manufacturing of other category of medicine also. Similarly some of the manufacturing areas like powdering,

furnace, packing of liquids and Avaleha, Paks, could also be shared for these items.

Drugs and Cosmetics Rules, 1945

Sl.No. Category of Medicine

Minimum manufacturing space required Machinery/equipment recommended

(1) (2) (3) (4) 1200 Square feet covered area with separate cabins or partitions for each activity. If Unani medicines are manufactured in same premises an additional area of 400 sq. feet will be required. 1. Anjana/Pisti 100 sq. feet. Karel/mechanized/motorized, karel.

End runner/Ball-Mill

Sieves/Shifter. 2. Churna / Nasya/ Manjan/Lepa/ Kwath Churn 200 sq feet Grinder/disintegrator/Pulveriser/ Powder mixer/sieves/shifter.

3. Pills/Vati /Gutika Matirai and tablets

sugar coating, polishing pan in case of sugar-coated tablets,mechanised chattoo (for mixing guggulu) where required.

4. Kupi pakava/Ksara/ Parpati/LavanaBhasm a Satva/Sindura Karpu/ Uppu / Param

150 sq. feet Bhatti, Karahi/Stainless steel Vessels/Patila Flask, Multani Matti/Plaster of Paris, Copper Rod, Earthern container, Gaj Put Bhatti, Mufflefurnace(Electrically operated) End/EdgeRunner, Exhaust Fan, Wooden/S.S.Spatula. 5. Kajal 100 sq. feet Earthern lamps for collection of Kajal, Triple Roller Mill, End Runner, Sieves, S.S.Patila, Filling/ packing and manufacturing room should be provided with exhaust fan and ultra violet lamps.

balance. 7. Ointment/Marham Pasai

Runner/ Mill (Where required) S.S. Storage Container S.S.Patila.

Drugs and Cosmetics Rules, 1945

Pak/Avaleh/Khand/ Modak/Lakayam

100 sq. feet

Bhatti section fitted with exhaust fan and should be fly proof, Iron Kadahi/S.S. Patila and S.S. Storage container.

Panak, Syrup / Pravahi Kwath Manapaku

150 sq, feet

Tincture press, exhaust fan fitted and fly proof, Bhatti section, Bottle washing machine, filter press / Gravity filter, liquid filling machine, P.P. Capping Machine.

Sl.No. Category of Medicine

Minimum manufacturing space required Machinery/equipment recommended

(1) (2) (3) (4) 10. Asava / Arishta 200 sq. ft Same as mentioned above. Fermentation tanks, containers and distillation plant where necessary, Filter Press.

pump.

12. Ark Tinir 100 sq. ft Maceration tank, Distillation plant,

Liquid filling tank with tap / Gravity filter/Filter press, Visual inspection box. 13. Tail/Ghrit Ney 100 sq. ft Bhatti, Kadahi/S.S. Patila S.S.Storage Containers, Filtration equipment, filling tank with tap/Liquid filling machine. 14. Aschyotan / Netra Malham Panir/Karn Bindu/Nasa- bindu 100 sq. ft Hot air oven electrically heated with thermostatic control, kettle gas or electrically heated with suitable mixing arrangements, collation mill, or ointment mill, tube filling equipment, mixing and storage tanks of stainless steel or of other suitable material sintered glass funnel, seitz filter or filter candle, liquid filling equipment, autoclave. 15. Each manufacturing unit will have a separate area for Bhatti, furnace boilers, puta, etc. This will have proper ventilation, removal of smoke, prevention of flies, insets, dust etc. The furnace section could have tin roof. 200 sq. ft

Drugs and Cosmetics Rules, 1945 B. LIST OF MACHINERY, EQUIPMENT AND MINIMUM MANUFACTURING PREMISES REQUIRED FOR THE MANUFACTURE OF VARIOUS CATEGORIES OF UNANI SYSTEM OF MEDICINES

One machine indicated for one category of medicine could be used for the manufacturing of other category of medicine also. Similarly some of the manufacturing areas like powdering,

furnace, packing of liquids could also be shared for these items.

(1) (2) (3) (4) Sl.No. Category of Medicine Minimum manufacturing space required Machinery/equipment recommended . 1200 square feet covered area with separate cabins, partitions for each activity.

of 400 square feet will be required.

1. Itrifal Tirya/majoon/

Laooq/Jawarish Khamiras 100 sq. feet Grinder/ Pulveriser, Sieves, powder mixer (if required), S.S. Patilas, Bhatti and other accessories, plant mixer for Khamiras. 2. Arq. 100 sq. feet Distillation Plant (garembic) S.S. storage tank, Boiling Vessel, Gravity filter, Bottle filling machine, Bottle washing machine, Bottle drier.

3. Habb (Pills) and

tablets. 100 sq. feet Ball Mill, Mass Mixer/Powder mixer, Granulator drier, tablet compressing machine, pill/vati cutting machine, stainless steal trays/ container for storage and sugar coating, polishing pan in case of sugar-coated tablets, mechanized chattoo, (for mixing guggul) where required.

required). 5. Raughan (oils) (Crushing and boiling) 100 sq. feet Oil Expeller, S.S. Patilas Oil filter bottle, Filling machine, Bottle drier, Bhatti.

6. Shiyaf, Surma, Kajal 100 sq. feet End runner, mixing S.S. Vessel.

Drugs and Cosmetics Rules, 1945

(1) (2) (3) (4) Sl.No. Category of Medicine Minimum manufacturing space required Machinery/equipment recommended 7. 8. Marham, Zimad (Ointment) Qurs (Tab.) 100 sq. feet 100 sq. feet Kharal, Bhatti, End runner, Grinder, Pulveriser, Triple Roller Mill (if required). Grinder/Pulveriser, Sieves, Powder mixer (where needed), Granulator, Drier, Tablet Compressing Machine, Die punches Trays, O.T. Apparatus, Balance with weights, Scoops, Sugar Coating Pan, polishing pan, Heater. 9. Kushta 100 sq. feet Bhatti, Kharal, Sil Batta, Earthen pots. 10. Murabba 100 sq. feet. Aluminium Vessels 50-100 kgs. Capacity, Gendna, Bhatti. 11. Capsule 100 sq. feet Pulveriser, Powder mixer (where needed), capsule filling machine, Air conditioner, De-humidifier, Balance with weights, storage containers, glass. 12. Sharbat and Joshanda 100 sq. feet Tinctum Press, exhaust fan fitted, Bhatti section, Bottle washing machine, Filter Press Gravity filter, Liquid filling tank with tap/liquid filling machine, hot air oven electrically heated with thermostatic control, kettle.

eye ointment) 100 sq. feet Hot air oven electrically heated with thermostatic control, kettle.

Drugs and Cosmetics Rules, 1945 C. LIST OF EQUIPMENT RECOMMENDED FOR IN-HOUSE QUALITY CONTROL SECTION

(Alternatively, unit can get testing done from the Government approved laboratory).

(A) CHEMISTRY SECTION (B) PHARMACOGNOSY SECTION 1 Alcohol Determination Apparatus (complete set) 1. Microscope Binoculor.

Type).

8. Tablet Disintegration Apparatus. 8. Chemicals, Glassware etc.

9. Moisture Meter. 10. Muffle Furnace. 11. Electronic Balance. 12. Magnetic Stirrer. 13. Hot Air Oven. 14. Refrigerator. 15. Glass/Steel Distillation Apparatus. 16. LPG Gas Cylinders with Burners. 17 Water Bath (Temperature controlled.) 18 Heating Mantles/ Hot Plates. 19. TLC Apparatus with all accessories (Manual) 20 Paper Chromatography apparatus with accessories.

21. Sieve size 10 to120 with Sieve shaker.

25. Limit Test Apparatus.

Note: - The above requirements of machinery, equipments, space are made subject to the modification at the discretion of the Licensing Authority; if he is of the opinion that having regard to the nature and extent of the manufacturing operations it is necessary to relax or alter them in the circumstances in a particular case.

Drugs and Cosmetics Rules, 1945

U

A. SUBSTANCES, OTHER THAN PARENTERAL PREPARATIONS IN GENERAL.

of expiry.

7. Name of all ingredients, specifications quantities required for the lot/Batch size and quantities actually used. All weighings and measurements shall be carried out by a responsible person and initialled by him and shall be counter-checked and signed by the competent technical staff under whose personal supervision the ingredients are used for manufacture. 8. Control Numbers of raw materials used in the formulation. 9. Date, time and duration of mixing. 10. Details of environmental controls like room temperature, relative humidity. 11.Date of granulation, wherever applicable. 12. Theoretical weight and actual weight of granules/powder blend. 13. Records of in-processes controls (Periodically whenever necessary):

(a) Uniformity of mixing.
(b) Moisture content of granules/powder in case of Tablet/Capsules.
(c) pH of solution in case of liquid.
(d) Weight variation.
(e) Disintegration time.
(f) Hardness
(g) Friability test
(h) Leak test in case of strip packing.
- (i) Filled volume of liquids.
(j) Quantity of tablets/capsules in the final container.
(k) Content of ointment in the filled containers.

17. Separate records of the disposal of the rejected batches and of batches withdrawn from the market. 18.

¹ Subs. by . G.S.R. 735(E) , dt. 24.6.1988.

The theoretical yield and actual productions yield and packing particulars indicating the size and quantity of finished packings. ___________________________________________________________________________

Drugs and Cosmetics Rules, 1945

19. Specimen of label/strip, carton with batch coding information like Batch Number, date of manufacture, date of expiry, retail price as applicable stamped thereon and inserts used in the finished packings.

20. Signature with date of competent technical staff responsible for the manufacture.

21. Counter-signature of the head of the testing units or other approved person-in-charge of testing for having verified the batch records and for having released and batch for sale and distribution, the quantity released and date of release.

22. Date of release of finished packings and quantity released for sale and distribution.

23. Quantity transferred to warehouse.

²⁴ For Hypodermic tablets and ophthalmic preparations, which are required to be manufactured

under aseptic conditions, records shall be maintained indicating the precautions taken during the process of manufacture to ensure that aseptic conditions are maintained.

B. PARENTERAL PREPARATIONS

7. Names of all ingredients, specifications and quantity required for the Lot/Batch size and quantity actually used. All weighings and measurements shall be carried out by a responsible person and initialled by him and shall be countersigned by the technical staff under whose personal supervision the stock are issued and by another competent technical staff under whose supervision the ingredients are used for manufacture.

10. Details of environmental controls like temperature, humidity, microbial count in the sterile working areas.

13. Sterility test, reference on bulk batch wherever applicable. 14. Record of check on volume filled. 15. Date of filling. 16. Records of tests employed: -

(a) To ensure that sealed ampoules are leak proof
(b) To check the presence of foreign particles.
(c) Pyrogen test, wherever applicable. Drugs and Cosmetics Rules, 1945
(d) Toxicity test, wherever applicable. 17. Records of checking of instruments and apparatus of sterilization (indicators).

18. Records of cleaning and sterilization of containers and closures, if necessary.

19. Records of sterilization in case of parenteral preparations which are heat sterilized including particulars of time, temperature and pressure employed. Such records should be marked to relate to the batch sterilized.

20. Number and size of containers filled and quantity rejected.

21. The theoretical yield and actual yield and the percentage yield thereof. 22. Reference to Analytical report numbers stating whether of standard quality or otherwise. 23. Specimen of labels, cartons, etc. with Batch coding information like batch number, date of manufacture, date of expiry, as applicable, stamped thereon, and inserts used in the finished packings.

24. Signature with date of the component technical staff responsible for manufacture.

25. Particulars regarding the precautions taken during the manufacture to ensure that aseptic conditions are maintained.

26. Countersignature of head of the testing unit or person in charge of testing for having verified

the documents and for having released the product for sale and distribution, the quantity released and date of release.

market.

29. Records of reprocessing if any and particulars of reprocessing.

II. Records of Raw Materials

Records in respect of each raw material shall be maintained indicating the date of receipt, invoice number, name and address of the manufacturer/supplier, batch number, quantity received, pack size, date of manufacture, date of expiry, if any, date of analysis and release/rejection by quality control, analytical report number with special remarks, if any, quantity issued, date of issue and the particulars of the name and batch numbers of products for the manufacture of which issued and the proper disposal of the stocks.

III. Particulars to be recorded in the Analytical Records

A. TABLETS AND CAPSULES.

1. Analytical report number. 2. Name of the sample. 3. Date of receipt of sample.

4. Batch/Lot number.

5. Protocols of tests applied.

(a) Description.
(b) Identification. Drugs and Cosmetics Rules, 1945
(c) Uniformity of weight.
(d) Uniformity of diameter (if applicable).
(e) Disintegration test (time in minutes).
(f) Any other tests.
(g) Results of Assay.

Note: Records regarding various tests applied (including readings and calculations) should be maintained

and necessary reference to these records should be entered in Col. 5 above whenever necessary.

B. PARENTERAL PREPARATIONS.

(a) Clarity.
(b) pH wherever applicable.
(c) Identification.
(d) Volume in container.
(e) Sterility – (i) Bulk sample wherever applicable (ii) container sample.
(f) Pyrogen test, wherever applicable.
(g) Toxicity test, wherever applicable.
(h) Any other tests.
- (i) Results of Assay. Note: Records regarding various tests applied (including readings and calculations) should be maintained and necessary reference to these records should be entered in Col. 7 above, wherever necessary.

PYROGEN TEST:

Drugs and Cosmetics Rules, 1945

10. Maximum temperature.

13. Signature of the Analyst. 14.Opinion and signature of the approved Analyst.

TOXICITY TEST

(a) Description.
(b) Identification.
(c) Any other tests.
(d) Results of Assay. Note:Particulars regarding various tests applied (including readings and calculations) shall be maintained and necessary reference to these records shall be entered in Column 5 above, wherever necessary.

D. RAW MATERIALS 1. Serial number.

Drugs and Cosmetics Rules, 1945

Note: Particulars regarding various tests applied (including readings and calculations) shall be maintained and necessary reference to these records shall be entered in Column 6 above, wherever necessary.

Note: Particulars regarding various tests applied shall be maintained and necessary reference to these records shall be entered in Column 6 above, wherever necessary 7. Remarks.

8. signature of the examiner.

Notes: (1) The foregoing provisions represent the minimum requirements to be complied with by the licensee. The Licensing Authority may, however, direct the nature of records to be maintained by the licensee for such products as are not covered by the categories described above.

2. The Licensing Authority may permit the licensee to maintain records in such manner as are considered satisfactory, provided the basic requirements laid down above are complied with.

3. The Licensing Authority may at its discretion direct the licensee to maintain records for such additional particulars as it may consider necessary in the circumstances of a particular case.]

Drugs and Cosmetics Rules, 1945

U(I)

(See rules 142 and 142B)

I. P

ARTICULARS TO BE SHOWN IN THE MANUFACTURING RECORDS:

1. Serial number.

2. Name of the product.

5. Date of commencement of manufacture and date when manufacture was completed. 6. Names of all ingredients, quantities required for the lot/batch size, quantities actually used. 7. Control reference numbers in respect of raw materials used in formulation. 8. Reference to analytical report numbers. 9. Actual production and packing particulars indicating the size and quantity of finished packings. 10. Date of release of finished packing for distribution or sale. 11. Signature of the expert staff responsible for the manufacture.

II. R

ECORDS OF RAW MATERIALS:

Records in respect of each raw material shall be maintained indicating the quantity received, control reference number, the quantity issued from time to time, the names and batch numbers of the products for the manufacture of which the said quantity of raw material has been issued and the particulars relating to the proper disposal of the stocks.

Notes: (1) The Licensing Authority may permit the licensee to maintain records in such manner as is

considered satisfactory, provided the basic requirements laid down above are complied with.

(2) The Licensing Authority may direct the licensee to maintain records for such additional particulars, as it may consider necessary in the circumstances of a particular case.] ___________________________________________________________________________ 1. Added by G.S.R. 1594, dt. 13-11-1976. Drugs and Cosmetics Rules, 1945 498

Schedule V

( See rule 124B) STANDARDS FOR PATENT OR PROPRIETARY MEDICINES

• * * * *

3[2. Standards for patent or proprietary medicines, containing vitamins:

Patent or proprietary medicines containing vitamins for prophylactic, therapeutic or paediatric use shall contain the vitamins in quantities not less than and not more than those specified below in single or in two divided daily doses, namely: -

• * * * *
• * * * *

5[4. General Standards for Different Categories of Patent or Proprietary Medicines. - In the

case of pharmaceutical products containing several active ingredients, the selection shall be such that the ingredients do not interact with one another and do not affect the safety and therapeutic efficacy of the product. The combination shall not also lead to analytical difficulties for the purpose of assaying the content of such ingredient separately. The substances added as additives shall be innocuous, shall not affect the safety or therapeutic efficacy of the active ingredients, and shall not affect the assays and identity tests in the amount present. Subject to the provisions of these rules, patent or proprietary medicines shall comply with the following standards, namely: - 1. Patent or proprietary medicines shall comply with the general requirements of the

dosage form under which it falls as given in the Indian Pharmacopoeia. If the dosage form

is not included in the Indian Pharmacopoeia, but is included in any other pharmacopoeia, prescribed for the purpose of the Second Schedule to the Act, it shall comply with the general requirements of the dosage of such pharmacopoeia. Without prejudice to the generality of the foregoing requirements, general requirements shall include compliance with colour consistency, clarity, stability, freedom from contamination with foreign matter or fungal growth, defects like chipping and capping of tablets, cracking of the coating, mottled appearance and other characteristic defects that can be perceived by visual inspection.

2. Without prejudice to the generality of the following paras, dosage forms of patent

or proprietary medicines shall comply with the following requirements, namely:-

____________________________________________________________________________ 1.

Added by G.S.R. No. 665, dt. 28-5-1977.

Ins. by G.S.R. 331(E) ,dt. 8.5.1984 and omitted . G.S.R. 59(E) ,dt. 22.1.1992.

Ins. by. G.S.R. 792(E) ,dt. 17.9.1987.

(a) Tablets: Medicines shall comply with requirements for tablets as laid down in the Indian Pharmacopoeia. The nature of coating shall be indicated on the label. Drugs and Cosmetics Rules, 1945 499 Permitted colours may, however, be added and declared on the label. Nature of tablets, such as uncoated, sugar coated or film coated, shall be declared on the label.
- • * * * * .
(b) Capsules : Medicines shall comply with the requirements for capsules laid down in the Indian Pharmacopoeia. However, the capsules shall be free from distortion or shape, dis-colouration and other physical defects like leakage of powder from joints, pinholes or cracks in the capsules;
(c) Liquid oral dosage forms: Emulsions and suspensions shall disperse uniformly on shaking. Homogeneous solutions shall contain no sediments. The volume of the product (net content) in the container shall be not less than the labelled volume. The limit for ethanol content of pharmaceutical products shall be not less than 90 per cent and not more than 110 per cent of the labelled contents.
(d) Injections: Medicines shall comply with the requirements for injections as laid down in the Indian Pharmacopoeia.
(e) Ointments: Medicines shall comply with the requirements for injections as laid down in the Indian Pharmacopoeia.

3. The content of active ingredients, other than vitamins, enzymes and antibiotics, in patent

or proprietary medicines shall be not less than 90 per cent and not more than 110 per cent of the labelled content; however, for enzymes and vitamins, only for lower limit of 90 per cent shall apply. In all dry formulations containing antibiotics, the limit shall be 90 to 130 per cent of the labelled contents and in case of liquid antibiotic formulations, the limit shall be 90 to 140 per cent of labelled contents. Fiducial limits for error for microbiological assay of antibiotics may be estimated depending upon the design of assay procedure. Methods, used for assaying active ingredients shall employ the same basic principles and shall use same organisms as given in the latest edition of the Indian Pharmacopoeia or shall follow any other methods as approved by the authority competent to grant licence to manufacture.

4. All patent or proprietary medicines containing aspirin shall be subjected to “Free Salicylic

Acid Test” and the limit of such acid shall be 0.75 per cent. Except in case of soluble type aspirin in which case the limit of such acid shall be 3 per cent. 5. Patent or proprietary medicine to be tested under the provisions of rule 121-A for pyrogen shall be tested by injecting into rabbits not less than the human dose of the medicine based on body weight of a 60 kg. human being. Methodology and limits shall be based on the method recorded in the Indian Pharmacopoeia. Dose selected shall be indicated in the protocol but the dose shall be not greater than 5 times the human dose based on body weight of 60 kg for man.

6. In injectable patent or proprietary medicines, the test for freedom from toxicity, shall be

¹ Omitted. by G.S.R. 59(E) ,dt. 22.1.1992.

performed as described in the Indian Pharmacopoeia. Dose selected shall be indicated in the protocol but the dose shall not be less than five times the human dose based on body weight of 60 kg. human being.] ______________________________________________________________________________

Drugs and C o smetics Rules, 1945 Vitamin Unit

Patent or proprietary

Patent or proprietary medicines containing Medicines containing

medicines containing

vitamins for paediatric use.

Vitamins for prophylactic vitamins for therapeutic

Use. ___________________________________________________________________________________________________________________ ___________ ___ (in single dose or in two divided doses) per daily dose _________________________________________________________________________________________________________________________________

For adults

For infants less than For children above one

one year.

year up to adults

Vitamin A. I.U Not less than 1600 and not more than 2,500 Not less than 5000 and not more than 10,000 Not less than 750 and not more than 3,000 Not less than 1500 and more than 5,000 Vitamin D. I.U Not less than 100 and not more than 200. Not less than 400 and not more than 1,000 Not less than 200 and not more than 400 Not less than 100 and more than 400 Vitamin B1 mg. Not less than 1 and not more than 2 Not less than 4.5 and not more than 10 Not less than 0.5 and more than 1

Not less than 1 and not more than 4.5

Vitamin B2 mg Not less than 1 and not more than 3 Not less than 5 and not more than 10 Not less than 0.5 and not more than 1.5 Not less than 1 and not more than 5. Vitamin B6 mg Not less than 0.5 and not more than 1.5 Not less than 1.5 and not more than 3 Not less than 0.5 and not more than 1.5 Not less than 1 and not more than 3 Niacinamide mg Not less than 15 and not more than 26 Not less than 45 and not more than 100 Not less than 5 and not more than 15 Not less than 10 and not more than 40.

d-Pantothenic acid or its salts and panthenol.

mg Not less than 1 and not more than 5 Not less than 5 and not more than 50 Not less than 1 and not more than 3 Not less than 2.5 and not more than 10 Folic acid mg. Not less than 50 and not more than 300 Not less than 1000 and not more than 1500 Not less than 25 and not more than 100 Not less than 100 and not more than 500

Drugs and C o smetics Rules, 1945

Vi t a m i n B m c g Not l e ss t h a n

. 5 a n d not m o r e

th an

No t less th an

5 and

n o t m o re th an

No t less th an

an d n o t m o re th an

No t less th an

1 and

n o t m o re th an

Vita m i n C m g

No t less th an

an d no t m o re th an

No t less th an

an d no t m o re t h an 1 No t less th an 20 an d no t mo r e t h a n

No t less th an

an d no t m o re th an

Vita m i n E I.U No t less th an

5 and

n o t m o re th an

No t less t h an

and

no t mo re th an

Not l e ss t h an 2.5 a nd not

mo r e t h a n

No t less th an

5 and

n o t m o re th an .

No tes :

(1 ) Pat e nt o r

p r o p ri et ary m e di ci nes co nt ai ni ng vi t a m i ns i n t e nde d f o r pr o p h y l act i c , t h era p eut i c

or pae d i a t r i c use shal l

bear o n t h e label th e word s “Fo r

Prophylactic Use” “ For T h erapeutic Use,”

or “For Pae d iatric Use” as t h e case m a y be. In the case of paedia tric preparatio n s

th e age of the infant or th e ch ild fo r wh o s e u s e it is i n tend ed, sh all b e

g i v e n in ad ditio n to t h e p a rt icu l ars requ ired to b e g i v e n un d e r t h ese ru les.

(2 )T he a b o v e s t anda rds s h al l

not ap pl y t o an y pre p a r at i o n c ont ai ni ng a si n g l e

vi t a m i n o n l y and al so t o

any

pre p arat i o n c o nt ai n ing v ita m i n s

in tend ed

fo r pare nteral use.

P r o v i d e d , ho we ver ,

t h at

i n

t h e

case of pat e nt

or pr op ri et ary

m e di ci nes con t ai ni ng vi t a m i ns whi c h are i n t e nde d for the treatm e nt of certain specific

co nd itio ns or diseases, th e Licen sing Au thority sp ecified in clau se (b) of ru le 21 , m a y p e rm it th e ad d i tio n of v itam i n s th erein

in rel a x a tio n o f

t h e li mits

sp ecif i ed above, if satisf act o r y ev id en ce is pr odu ced in

ju stif icatio n

o f su ch

r e lax a tion .

Drugs and Cosmetics Rules, 1945

W- (Omitted)

Schedule X

Amobarbital

• * * Amphetamine Methylphenidate Barbital Methylphenobarbital Cyclobarbital Pentobarbital Dexamphetamine Phencyclidine Ethclorvynol Phenometrazine Glutethimide
• * * Meprobamate Secobarbital Methamphetamine Note: 1. Any stereoisometric form of the substance specified in this Schedule, any salt of the substance and preparation containing such substances are also covered by this Schedule.

2. Preparations containing the above substances are also covered by this Schedule.

Provided, however, preparations containing Meprobamate

• * * in combination with other drugs may be exempted by the Licensing Authority specified in clause (b) of rule 21, from the provisions of this Schedule, if satisfactory evidence is adduced that these preparations are not liable to be misused.] ____________________________________________________________________________

1. Schedule W ins. by. G.S.R. 27(E) ,dt. 17.1.1981 and omitted by. G.S.R. 94(E) ,dt. 8..2. 2000.

³ Omitted by G.S.R. 647(E) ,dt. 28.10.1998.

⁴ Omitted by. G.S.R. 673(E) ,dt. 27.10.1993.

2 Ins. by G.S.R. 462(E) ,dt. 22.6.1982.

Drugs and Cosmetics Rules, 1945 503

Y

(See rules 122A, 122B, 122D, 122DA, 122DAA and 122E) REQUIREMENTS AND GUIDELINES FOR PERMISSION TO IMPORT AND / OR MANUFACTURE OF NEW DRUGS FOR SALE OR TO UNDERTAKE CLINICAL TRIALS 1. Application for permission.- (1) Application for permission to import or manufacture new drugs for sale or to undertake clinical trials shall be made in Form 44 accompanied with following data in accordance with the appendices, namely:-

(i) chemical and pharmaceutical information as prescribed in item 2 of Appendix I;
(ii) animal pharmacology data as prescribed in item 3 of Appendix I and Appendix IV;

(a) specific pharmacological actions as prescribed in item 3.2 of Appendix I, and demonstrating, therapeutic potential for humans shall be described according to the animal models and species used. Wherever possible, dose-response relationships and ED 50s shall be submitted. Special studies conducted to elucidate mode of action shall also be described (Appendix IV);
(b) general pharmacological actions as prescribed in item 3.3 of Appendix I and item 1.2 of Appendix IV;
(c) pharmacokinetic data related to the absorption, distribution, metabolism and excretion of the test substance as prescribed in item 3.5 of Appendix I. Wherever possible, the drug effects shall be corelated to the plasma drug concentrations;
- (iii) animal toxicology data as prescribed in item 4 of Appendix I and Appendix III;
- (iv) human Clinical Pharmacology Data as prescribed in items 5, 6 and 7 of Appendix I and as stated below:-
(a) for new drug substances discovered in India, clinical trials are required to be carried out in India right from Phase I and data should be submitted as required under items 1, 2, 3, 4, 5 (data, if any, from other countries), and 9 of Appendix I;
(b) for new drug substances discovered in countries other than India, Phase I data as required under items 1, 2, 3, 4, 5 (data from other countries) and 9 of Appendix I should be submitted along with the application. After submission of Phase I data

generated outside India to the Licensing Authority, permission may be granted to repeat

Phase I trials and/or to conduct Phase II trials and subsequently Phase III trials concurrently with other global trials for that drug. Phase III trials are required to be conducted in India before permission to market the drug in India is granted;

(c) the data required will depend upon the purpose of the new drug application . The number of study subjects and sites to be involved in the conduct of clinical trial will depend upon the nature and objective of the study. Permission to carry out these trials shall generally be given in stages, considering the data emerging from earlier Phase(s);
(d) application for permission to initiate specific phase of clinical trial should also accompany Investigator’s brochure, proposed protocol (Appendix X), case record form,

study subject’s informed consent document(s) (Appendix V), investigator’s undertaking

(Appendix VII) and ethics committee clearance, if available (Appendix VIII);

(e) reports of clinical studies submitted under items 5-8 of Appendix I should be in consonance with the format prescribed in Appendix II of this Schedule. The ____________________________________________________________________ Drugs and Cosmetics Rules, 1945 504 study report shall be certified by the Principal Investigator or, if no Principal Investigator is designated, then by each of the Investigators participating in the study. The certification should acknowledge the contents of the report, the accurate presentation of the study as undertaken, and express agreement with the conclusions. Each page should be numbered;
- (v) regulatory status in other countries as prescribed in item 9.2 of Appendix I,

¹ Subs. G.S.R. 32(E), dt. 20.1.2005.

including Information in respect of restrictions imposed, if any, on the use of the drug

in other countries, e.g. dosage limits, exclusion of certain age groups, warning about

adverse drug reactions,.etc. (item 9.2 of Appendix I). Likewise, if the drug has been

withdrawn in any country by the manufacturer or by regulatory authorities, such information should also be furnished along with the reasons and their relevance, if any, to India. This information must continue to be submitted by the sponsor to the Licensing Authority during the course of marketing of the drug in India;

(vi) the full prescribing information should be submitted as part of the new drug application for marketing as prescribed in item 10 of Appendix I. The prescribing information (package insert) shall comprise the following sections: generic name; composition; dosage form/s, indications; dose and method of administration; use in special populations (such as pregnant women, lactating women, paediatric patients, geriatric patients etc.); contra-indications; warnings; precautions; drug interactions; undesirable effects; overdose; pharmacodynamic and pharmacokinetic properties; incompatibilities; shelf-life; packaging information; storage and handling instructions. All package inserts, promotional literature and patient education material subsequently produced are required to be consistent with the contents of the approved full prescribing information. The drafts of label and carton texts should comply with provisions of rules 96 and 97. After submission and approval by the Licensing Authority, no changes in the package insert shall be effected without such changes being approved by the Licensing Authority; and
(vii) complete testing protocol/s for quality control testing together with a complete impurity profile and release specifications for the product as prescribed in item 11 of Appendix I should be submitted as part of new drug application for marketing. Samples of the pure drug substance and finished product are to be submitted when desired by the regulatory authority.

(2) If the study drug is intended to be imported for the purposes of examination, test or

analysis, the application for import of small quantities of drugs for such purpose should also

be made in Form 12.

(3) For drugs indicated in life threatening / serious diseases or diseases of special relevance to the Indian health scenario, the toxicological and clinical data requirements may be abbreviated, deferred or omitted, as deemed appropriate by the Licensing Authority.

2. CLINICAL TRIAL:

(1) Approval for clinical trial
- (i) Clinical trial on a new drug shall be initiated only after the permission has been granted by the Licensing Authority under rule 21 (b), and the approval obtained from the respective ethics committee(s). The Licensing Authority as defined shall be informed of the approval of the respective institutional ethics committee(s) as prescribed in Appendix VIII, and the trial initiated at each respective site only after obtaining such an approval for that site. The trial site(s) may accept the approval granted to the protocol by the ethics committee of another trial site or the approval granted by an independent ethics committee Drugs and Cosmetics Rules, 1945 505 (constituted as per Appendix VIII), provided that the approving ethics committee(s) is/are willing to accept their responsibilities for the study at such trial site(s) and the trial site(s) is/are willing to accept such an arrangement and that the protocol version is same at all trial sites.
- (ii) All trial Investigator(s) should possess appropriate qualifications, training and experience and should have access to such investigational and treatment facilities as are relevant to the proposed trial protocol. A qualified physician (or dentist, when appropriate) who is an investigator or a sub-investigator for the trial, should be responsible for all trial-related medical (or dental) decisions. Laboratories used for generating data for clinical trials should be compliant with Good Laboratory Practices. If services of a laboratory or a facilities outside the country are to be availed, its/their name(s), address(s) and specific services to be used should be stated in the protocol to avail Licensing Authority’s permission to send clinical trial related samples to such laboratory(ies) and/or facility(ies). In all cases, information about laboratory(ies) / facilities to be used for the trial, if other than those at the investigation site(s), should be furnished to the Licensing Authority prior to initiation of trial at such site(s).
- (iii) Protocol amendments if become necessary before initiation or during the course of a clinical trial, all such amendments should be notified to the Licensing Authority in writing along with the approval by the ethics committee which has granted the approval for the study. No deviations from or changes to the protocol should be implemented without prior written approval of the ethics committee and the Licensing Authority except when it is necessary to eliminate immediate hazards to the trial Subject(s) or when change(s) involve(s) only logistic or administrative aspects of the

be notified to the Licensing Authority within 30 days.

(2) Responsibilities of Sponsor:
- (i) The clinical trial Sponsor is responsible for implementing and maintaining quality assurance systems to ensure that the clinical trial is conducted and data generated, documented and reported in compliance with the protocol and Good Clinical Practice
- (GCP) Guidelines issued by the Central Drugs Standard Control Organization, Directorate General of Health Services, Government of India as well as with all

applicable statutory provisions. Standard operating procedures should be documented to

ensure compliance with GCP and applicable regulations.

(ii) Sponsors are required to submit a status report on the clinical trial to the Licensing Authority at the prescribed periodicity.
(iii) In case of studies prematurely discontinued for any reason including lack of commercial interest in pursuing the new drug application, a summary report should be submitted within 3 months. The summary report should provide a brief description of the study, the number of patients exposed to the drug, dose and duration of exposure, details of adverse drug reactions (Appendix XI), if any, and the reason for discontinuation of the study or non-pursuit of the new drug application;
(iv) Any unexpected serious adverse event (SAE) (as defined in GCP Guidelines) occurring during a clinical trial should be communicated promptly (within 14 calendar Drugs and Cosmetics Rules, 1945 506 days) by the Sponsor to the Licensing Authority and to the other Investigator(s) participating in the study (see Appendix XI).

(3) Responsibilities of the Investigator(s): The Investigator(s) shall be responsible for the conduct of the trial according to the protocol and the GCP Guidelines and also for compliance as per the undertaking given in Appendix VII. Standard operating procedures are required to be documented by the investigators for the tasks performed by them. During and following a subject’s participation in a trial, the investigator should ensure that adequate medical care is provided to the participant for any adverse events. Investigator(s) shall report all serious and unexpected adverse events to the Sponsor within 24 hours and to the Ethics Committee that accorded approval to the study protocol within 7 working days of their occurrence.
(4) Informed Consent:
- (i) In all trials, a freely given, informed, written consent is required to be obtained from each study subject. The Investigator must provide information about the study verbally as well as using a patient information sheet, in a language that is non-technical and understandable by the study subject. The Subject’s consent must be obtained in

writing using an ‘Informed Consent Form’. Both the patient information sheet as well as

the Informed Consent Form should have been approved by the ethics committee and furnished to the Licensing Authority. Any changes in the informed consent documents should be approved by the ethics committee and submitted to the Licensing Authority before such changes are implemented.

(ii) Where a subject is not able to give informed consent (e.g. an unconscious person or a minor or those suffering from severe mental illness or disability), the same may be obtained from a legally acceptable representative (a legally acceptable representative is a person who is able to give consent for or authorize

an intervention in the patient as provided by the law(s) of India). If the Subject or

his/her legally acceptable representative is unable to read/write – an impartial witness should be present during the entire informed consent process who must append his/her signatures to the consent form.

(iii) A checklist of essential elements to be included in the study subject’s informed consent document as well as a format for the Informed Consent Form for study Subjects is given in Appendix V.

(5) Responsibilities of the Ethics Committee:
- (i) It is the responsibility of the ethics committee that reviews and accords its approval

to a trial protocol to safeguard the rights, safety and well being of all trial subjects. The

ethics committee should exercise particular care to protect the rights, safety and well being of all vulnerable subjects participating in the study, e.g., members of a group with hierarchical structure (e.g. prisoners, armed forces personnel, staff and students of medical, nursing and pharmacy academic institutions), patients with incurable diseases, umemployed or impoverished persons, patients in emergency situation, ethnic minority groups, homeless persons, nomads, refugees, minors or others incapable of personally

Drugs and Cosmetics Rules, 1945 507 giving consent. Ethics committee(s) should get document ‘standard operating procedures’ and should maintain a record of its proceedings.

(ii) Ethics Committee(s) should make, at appropriate intervals, an ongoing review of the trials for which they review the protocol(s). Such a review may be based on the periodic study progress reports furnished by the investigators and/or monitoring and internal audit reports furnished by the Sponsor and/or by visiting the study sites.
(ii) In case an ethics committee revokes its approval accorded to a trial protocol, it must record the reasons for doing so and at once communicate such a decision to the Investigator as well as to the Licensing Authority.

(6) Human Pharmacology (Phase I):
- (i) The objective of studies in this Phase is the estimation of safety and tolerability with the initial administration of an investigational new drug into human(s). Studies in this Phase of development usually have non-therapeutic objectives and may be conducted in healthy volunteers subjects or certain types of patients. Drugs with significant potential toxicity e.g. cytotoxic drugs are usually studied in patients. Phase I trials should preferably be carried out by Investigators trained in clinical pharmacology with access to the necessary facilities to closely observe and monitor the Subjects.
- (ii) Studies conducted in Phase I, usually intended to involve one or a combination of the following objectives:-
- (a) Maximum tolerated dose: To determine the tolerability of the dose range expected to be needed for later clinical studies and to determine the nature of adverse reactions that can be expected. These studies include both single and multiple dose administration.
- (b) Pharmacokinetics, i.e., characterization of a drug's absorption, distribution, metabolism and excretion. Although these studies continue throughout the development plan, they should be performed to support formulation development and determine pharmacokinetic parameters in different age groups to support dosing recommendations.
- (c) Pharmacodynamics: Depending on the drug and the endpoints studied, pharmacodynamic studies and studies relating to drug blood levels (pharmacokinetic/ pharmacodynamic studies) may be conducted in healthy volunteer Subjects or in patients with the target disease. If there are appropriate validated indicators of activity and potential efficacy, pharmacodynamic data obtained from patients may guide the dosage and dose regimen to be applied in later studies.
- (d) Early Measurement of Drug Activity: Preliminary studies of activity or potential therapeutic benefit may be conducted in Phase I as a secondary objective. Such studies are generally performed in later Phases but may be appropriate when drug activity is readily measurable with a short duration of drug exposure in patients at this early stage.
(7) Therapeutic exploratory trials (Phase II):
- (i) The primary objective of Phase II trials is to evaluate the effectiveness of a drug for a particular indication or indications in patients with the condition under study and to determine the common short-term side-effects and risks associated with the drug. Studies in Phase II should be conducted in a group of patients who are selected by relatively

narrow criteria leading to a relatively homogeneous population. These studies should be

closely monitored. An important goal for this Phase is to determine the dose(s) and

Drugs and Cosmetics Rules, 1945 508

regimen for Phase III trials. Doses used in Phase II are usually (but not always) less than

the highest doses used in Phase I.

(ii) Additional objectives of Phase II studies can include evaluation of potential study endpoints, therapeutic regimens (including concomitant medications) and target populations (e.g. mild versus severe disease) for further studies in Phase II or III. These objectives may be served by exploratory analyses, examining subsets of data and by including multiple endpoints in trials.
(iii) If the application is for conduct of clinical trials as a part of multi-national clinical development of the drug, the number of sites and the patients as well as the justification for undertaking such trials in India shall be provided to the Licensing Authority.

(8) Therapeutic confirmatory trials (Phase III):
- (i) Phase III studies have primary objective of demonstration or confirmation of therapeutic benefit(s). Studies in Phase III are designed to confirm the preliminary evidence accumulated in Phase II that a drug is safe and effective for use in the intended indication and recipient population. These studies should be intended to provide an adequate basis for marketing approval. Studies in Phase III may also further explore the dose-response relationships (relationships among dose, drug concentration in blood and

clinical response), use of the drug in wider populations, in different stages of disease, or

the safety and efficacy of the drug in combination with other drug(s).

(ii) For drugs intended to be administered for long periods, trials involving extended exposure to the drug are ordinarily conducted in Phase III, although they may be initiated in Phase II. These studies carried out in Phase III complete the information needed to support adequate instructions for use of the drug (prescribing information).
(iii) For new drugs approved outside India, Phase III studies need to be carried out primarily to generate evidence of efficacy and safety of the drug in Indian patients when used as recommended in the prescribing information. Prior to conduct of Phase III studies in Indian subjects, Licensing Authority may require pharmacokinetic studies to be undertaken to verify that the data generated in Indian population is in conformity with the data already generated abroad.
(iv) If the application is for the conduct of clinical trials as a part of multi-national clinical development of the drug, the number of sites and patients as well as the justification for undertaking such trials in India should be provided to the Licensing Authority along with the application.

(9) Post Marketing Trials (Phase IV): Post Marketing trials are studies (other than routine surveillance) performed after

considered necessary at the time of new drug approval but may be required by the Licensing Authority for optimizing the drug's use. They may be of any type but should have valid scientific objectives. Phase IV trials include additional drug-drug interaction(s), dose-response or safety studies and trials designed to support use under the approved indication(s), e.g. mortality/morbidity studies, epidemiological studies etc.

3. Studies in special populations:

Information supporting the use of the drug in children, pregnant women, nursing women, elderly patients, patients with renal or other organ systems failure, and those on specific

Drugs and Cosmetics Rules, 1945 509 concomitant medication is required to be submitted if relevant to the clinical profile of the drug and its anticipated usage pattern. Any claim sought to be made for the drug product that is not based on data submitted under preceding items of this Schedule should be supported by

studies included under this item of the Schedule (Appendix I, item 8.3).

(1) Geriatrics: Geriatric patients should be included in Phase III clinical trials (and in Phase II trials, at the Sponsor's option) in meaningful numbers, if-
- (a) the disease intended to be treated is characteristically a disease of aging; or
- (b) the population to be treated is known to include substantial numbers of geriatric patients; or
- (c) when there is specific reason to expect that conditions common in the elderly are likely to be encountered; or
- (d) when the new drug is likely to alter the geriatric patient's response (with regard to safety or efficacy) compared with that of the non-geriatric patient.
(2) Paediatrics.
- (i) The timing of paediatric studies in the new drug development program will depend on the medicinal product, the type of disease being treated, safety considerations, and the efficacy and safety of available treatments. For a drug expected to be used in children, evaluations should be made in the appropriate age group. When clinical development is to include studies in children, it is usually appropriate to begin with older children before extending the trial to younger children and then infants.
- (ii) If the new drug is for diseases predominantly or exclusively affecting paediatric patients, clinical trial data should be generated in the paediatric population except for initial safety and tolerability data, which will usually be obtained in adults unless such initial safety studies in adults would yield little useful information or expose them to inappropriate risk.
- (iii) If the new drug is intended to treat serious or life-threatening diseases, occurring in both adults and paediatric patients, for which there are currently no or limited therapeutic options, paediatric population should be included in the clinical trials early, following assessment of initial safety data and reasonable evidence of potential benefit. In circumstances where this is not possible, lack of data should be justified in detail.
- (iv) If the new drug has a potential for use in paediatric patients – Paediatric studies should be conducted. These studies may be initiated at various phases of clinical development or after post marketing survelliance in adults if a safety concern exists. In cases where there is limited paediatric data at the time of submission of application – more data in paediatric patients would be expected after marketing authorisation for use in children is granted.
- (v) The paediatric studies should include -
- (a) clinical trials,
- (b) relative bioequivalence comparisons of the paediatric formulation with the adult formulation performed in adults, and
- (c) definitive pharmacokinetic studies for dose selection across the age ranges of paediatric patients in whom the drug is likely to be used. These studies should be conducted in the paediatric patient population with the disease under study. Drugs and Cosmetics Rules, 1945 510
  - (vi) If the new drug is a major therapeutic advance for the paediatric population – the studies should begin early in the drug development , and this data should be submitted with the new drug application.
  - (vii) Paediatric Subjects are legally unable to provide written informed consent, and are dependent on their parent(s)/ legal guardian to assume responsibility for their participation in clinical studies. Written informed consent should be obtained from the parent/ legal guardian. However, all paediatric participants should be informed to the fullest extent possible about the study in a language and in terms that they are able to understand. Where appropriate, paediatric participants should additionally assent to enrol in the study. Mature minors and adolescents should personally sign and date a separately designed written assent form. Although a participant’s wish to withdraw from a study must be respected, there may be circumstances in therapeutic studies for serious or life-threatening diseases in which, in the opinion of the Investigator and parent(s)/ legal guardian, the welfare of a pediatric patient would be jeopardized by his or her failing to participate in the study. In this situation, continued parental/ legal guardian consent should be sufficient to allow participation in the study.
  - (viii) For clinical trials conducted in the paediatric population, the reviewing ethics committee should include members who are knowledgeable about pediatric, ethical, clinical and psychosocial issues.
(3) Pregnant or nursing women.-
- (i) Pregnant or nursing women should be included in clinical trials only when the drug is intended for use by pregnant/nursing women or foetuses/nursing infants and where the data generated from women who are not pregnant or nursing, is not suitable.
- (ii) For new drugs intended for use during pregnancy, follow-up data (pertaining to a period appropriate for that drug) on the pregnancy, foetus and child will be required. Where applicable, excretion of the drug or its metabolites into human milk should be examined and the infant should be monitored for predicted pharmacological effects of the drug.
(4) Post Marketing Surveillance.-
- (i) Subsequent to approval of the product, new drugs should be closely monitored for their clinical safety once they are marketed. The applicants shall furnish Periodic Safety Update Reports (PSURs) in order to-
- (a) report all the relevant new information from appropriate sources;
- (b) relate these data to patient exposure ;
- (c) summarize the market authorization status in different countries and any significant variations related to safety; and
- (d) indicate whether changes should be made to product information in order to optimize the use of the product.
  - (ii) Ordinarily all dosage forms and formulations as well as indications for new drugs should be covered in one PSUR. Within the single PSUR separate presentations of data for different dosage forms, indications or separate population need to be given.
  - (iii) All relevant clinical and non-clinical safety data should cover only the period of the report (interval data). The PSURs shall be submitted every six months for the first two years

after approval of the drug is granted to the applicant. For subsequent two years – the PSURs

need to be submitted annually. Licensing authority may extend the total duration of

submission of PSURs if it is considered necessary in the interest of public health. PSURs due

for a period must be submitted within 30 calendar days of the last day of the reporting period.

Drugs and Cosmetics Rules, 1945 511 However, all cases involving serious unexpected adverse reactions must be reported to the licensing authority within 15 days of initial receipt of the information by the applicant. If marketing of the new drug is delayed by the applicant after obtaining approval to market, such data will have to be provided on the deferred basis beginning from the time the new drug is marketed.

(iv) New studies specifically planned or conducted to examine a safety issue should be described in the PSURs.
(v) A PSUR should be structured as follows:

(a) A title page stating: Periodic safety update report for the product, applicant’s name, period covered by the report, date of approval of new drug, date of marketing of

new drug and date of reporting;

(b) Introduction,
(c) Current worldwide market authorization status,
(d) Update of actions taken for safety reasons,
(e) Changes to reference safety information,
(f) Estimated patient exposure,
(g) Presentation of individual case histories,
(h) Studies, ( I) Other information,
(j) Overall safety evaluation,
(k) Conclusion,
(l) Appendix providing material relating to indications, dosing, pharmacology and other related information.

(5) Special studies: Bioavailability / Bioequivalence Studies.-
- (i) For drugs approved elsewhere in the world and absorbed systemically, bioequivalence with the reference formulation should be carried out wherever applicable. These studies should be conducted under the labelled conditions of administration. Data on the extent of systemic absorption may be required for formulations other than those designed for systemic absorption.
- (ii) Evaluation of the effect of food on absorption following oral administration should be carried out. Data from dissolution studies should also be submitted for all solid oral dosage forms.
- (iii) Dissolution and bioavailability data submitted with the new drug application must provide information that assures bioequivalence or establishes bioavailability and dosage correlations between the formulation(s) sought to be marketed and those used for clinical trials

during clinical development of the product. (See items 8.1, 8.2 and 8.3 of Appendix I).

(iv) All bioavailability and bioequivalence studies should be conducted according to the Guidelines for Bioavailability and Bioequivalence studies as prescribed. Note.- The data requirements stated in this Schedule are expected to provide adequate information to evaluate the efficacy, safety and therapeutic rationale of new drugs (as defined under rule 122-E) prior to the permission for sale. Depending upon the nature of new drugs and disease(s), additional information may be required by the Licensing Authority. The applicant shall certify the authencity of the data and documents submitted in support of an Drugs and Cosmetics Rules, 1945 512

application for new drug. The Licensing Authority reserves the right to reject any data or any

document(s) if such data or contents of such documents are found to be of doubtful integrity. APPENDIX I DATA TO BE SUBMITTED ALONG WITH THE APPLICATION TO CONDUCT CLINICAL TRIALS/IMPORT/MANUFACTURE OF NEW DRUGS FOR MARKETING IN THE COUNTRY 1. Introduction A brief description of the drug and the therapeutic class to which it belongs.

(a) Chemical name and Structure Empirical formula Molecular weight
(b) Physical properties Description Solubility Rotation Partition coefficient Dissociation constant 2.3. Analytical Data Elemental analysis Mass spectrum NMR spectra IR spectra UV spectra Polymorphic identification

2.4. Complete monograph specification including

Identification Identity/quantification of impurities Enantiomeric purity Assay 2.5. Validations Assay method Impurity estimation method Residual solvent/other volatile impurities (OVI) estimation method

Drugs and Cosmetics Rules, 1945 513

2.6. Stability Studies (for details refer Appendix IX)

Final release specification Reference standard characterization Material safety data sheet

2.7. Data on Formulation

Dosage form Composition Master manufacturing formula Details of the formulation (including inactive ingredients) In process quality control check Finished product specification Excipient compatibility study Validation of the analytical method Comparative evaluation with international brand(s) or approved Indian brands, if applicable Pack presentation Dissolution Assay Impurities Content uniformity pH Force degradation study Stability evaluation in market intended pack at proposed storage conditions Packing specifications Process validation When the application is for clinical trials only, the international non-proprietary name

(INN) or generic name, drug category, dosage form and data supporting stability in the intended container-closure system for the duration of the clinical trial (information covered in item nos. 2.1, 2.3, 2.6, 2.7) are required. 3. Animal Pharmacology (for details refer Appendix IV) 3.1. Summary

3.4. Follow-up and Supplemental Safety Pharmacology Studies

Drugs and Cosmetics Rules, 1945 514

8.3 Other studies e.g. geriatrics, paediatrics, pregnant or nursing women

a. Marketed b. Approved c. Approved as IND d. Withdrawn, if any, with reasons

doses, or more number of clinical doses if prescribed by the Licensing Authority), with testing protocol/s, full impurity profile and release specifications.

Drugs and Cosmetics Rules, 1945 515

NOTES:

(1) All items may not be applicable to all drugs. For explanation, refer text of Schedule Y.
(2) For requirements of data to be submitted with application for clinical trials refer text of this Schedule. APPENDIX IA DATA REQUIRED TO BE SUBMITTED BY AN APPLICANT FOR GRANT OF

PERMISSION TO IMPORT AND / OR MANUFACTURE A NEW DRUG ALREADY

APPROVED IN THE COUNTRY

1. Introduction A brief description of the drug and the therapeutic class 2. Chemical and pharmaceutical information 2.1 Chemical name, code name or number, if any; non-proprietary or generic name, if any, structure; physico-chemical properties

(a) active ingredients
(b) inactive ingredients

3. Marketing information

4. Special studies conducted with approval of Licensing Authority 4.1 Bioavailability / Bioequivalence and comparative dissolution studies for oral dosage forms 4.2 Sub-acute animal toxicity studies for intravenous infusions and injectables

APPENDIX II STRUCTURE, CONTENTS AND FORMAT FOR CLINICAL STUDY REPORTS 1. Title Page: This page should contain information about the title of the study, the protocol code, name of the investigational product tested, development Phase, indication studied, a brief description

of the trial design, the start and end date of patient accrual and the names of the Sponsor and

the participating Institutes (Investigators). 2.,Study Synopsis (1 to 2 pages):

Drugs and Cosmetics Rules, 1945 516 A brief overview of the study from the protocol development to the trial closure should be given here. This section will only summarize the important conclusions derived from the study. 3. Statement of compliance with the ‘Guidelines for Clinical Trials on Pharmaceutical Products in India :

GCP Guidelines’ issued by the Central Drugs Standard Control Organization, Ministry of

Health, Government of India. 4. List of Abbreviations and Definitions 5. Table of contents 6. Ethics Committee: This section should document that the study was conducted in accordance with the ethical principles of Declaration of Helsinki. A detailed description of the Ethics Committee constitution and date(s) of approvals of trial documents for each of the participating sites should be provided. A declaration should state that EC notifications as per Good Clinical Practice Guidelines issued by Central Drugs Standard Control Organization and Ethical Guidelines for Biomedical Research on Human Subjects, issued by Indian Council of Medical Research have been followed.

7. Study Team:

Briefly describe the administrative structure of the study (Investigators, site staff, Sponsor/ designates, Central laboratory etc.).

8. Introduction:

A brief description of the product development rationale should be given here. 9. Study Objective: A statement describing the overall purpose of the study and the primary and secondary objectives to be achieved should be mentioned here. 10. Investigational Plan: This section should describe the overall trial design, the Subject selection criteria, the treatment procedures, blinding / randomization techniques if any, allowed/ disallowed concomitant treatment, the efficacy and safety criteria assessed, the data quality assurance procedures and the statistical methods planned for the analysis of the data obtained. 11. Trial Subjects: A clear accounting of all trial Subjects who entered the study will be given here. Mention should also be made of all cases that were dropouts or protocol deviations. Enumerate the patients screened, randomised, and prematurely discontinued. State reasons for premature discontinuation of therapy in each applicable case. 12. Efficacy evaluation The results of evaluation of all the efficacy variables will be described in this section with appropriate tabular and graphical representation. A brief description of the demographic characteristics of the trial patients should also be provided along with a listing of patients and observations excluded from efficacy analysis.

13. Safety Evaluation:

This section should include the complete list

Drugs and Cosmetics Rules, 1945 517

as per Appendix XI). The comparison of adverse events across study groups may be presented in a tabular or graphical form. This section should also give a brief narrative of all important events considered related to the investigational product.

14. Discussion and overall Conclusion:

Discussion of the important conclusions derived from the trial and scope for further development.

List of Appendices to the Clinical Trial Report

(a) Protocol and amendments
(b) Specimen of Case Record Form
(c) Investigators’ name(s) with contact addresses, phone, e-mail etc.
(d) Patient data listings
(e) List of trial participants treated with investigational product
(f) Discontinued participants
(g) Protocol deviations
(h) CRFs of cases involving death and life threatening adverse event cases
- (i) Publications from the trial
(j) Important publications referenced in the study
(k) Audit certificate, if available
(l) Investigator’s certificate that he/she has read the report and that the report accurately describes the conduct and the results of the study. APPENDIX III ANIMAL TOXICOLOGY (NON-CLINICAL TOXICITY STUDIES) 1. General Principles: Toxicity studies should comply with the norms of Good Laboratory Practice (GLP). Briefly, these studies should be performed by suitably trained and qualified staff employing properly calibrated and standardized equipment of adequate size and

capacity. Studies should be done as per written protocols with modifications (if any)

verifiable retrospectively. Standard operating procedures (SOPs) should be followed for all managerial and laboratory tasks related to these studies. Test substances and test systems (in-vitro or in-vivo) should be properly characterized and standardized. All documents belonging to each study, including its approved protocol, raw data, draft report, final report, and histology slides and paraffin tissue blocks should be preserved for a minimum of 5 years after marketing of the drug.

Drugs and Cosmetics Rules, 1945 518 Toxicokinetic studies (generation of pharmacokinetic data either as an integral component of the conduct of non-clinical toxicity studies or in specially designed studies) should be conducted to assess the systemic exposure achieved in animals and its relationship to dose level and the time course of the toxicity study. Other objectives of toxicokinetic studies include obtaining data to relate the exposure achieved in toxicity studies to toxicological findings and contribute to the assessment of the relevance of these findings to clinical safety, to support the choice of species and treatment regimen in nonclinical toxicity studies and to provide information which, in conjunction with the toxicity findings, contributes to the design of subsequent non-clinical toxicity studies.

be carried out in 2 rodent species (mice and rats) using the same route as intended for humans. In addition, unless the intended route of administration in humans is only intravenous, at least one more route should be used in one of the species to ensure systemic absorption of the drug. This route should depend on the nature of the drug. A limit of 2g/kg (or 10 times the normal dose that is intended in humans, whichever is higher) is recommended for oral dosing. Animals should be observed for 14 days after the drug administration, and minimum lethal dose (MLD) and maximum tolerated dose (MTD) should be established. If possible, the target organ of toxicity should also be determined. Mortality should be observed for up to 7 days after parenteral administration and up to 14 days after oral administration. Symptoms, signs and mode of death should be reported, with appropriate macroscopic and microscopic findings where necessary. LD and LD should be reported preferably with 95 percent confidence limits. If LD s cannot be determined, reasons for the same should be stated. The dose causing severe toxic manifestations or death should be defined in the case of cytotoxic anticancer agents, and the post-dosing observation period should be up to 14 days.

Mice should first be used for determination of MTD. Findings should then be confirmed in

rat for establishing linear relationship between toxicity and body surface area. In case of nonlinearity, data of the more sensitive species should be used to determine the Phase I starting dose. Where rodents are known to be poor predictors of human toxicity (e.g., antifolates), or where the cytotoxic drug acts by a novel mechanism of action, MTD should be established in non-rodent species. 1.1.2 Repeated-dose Systemic Toxicity Studies: These studies (see Appendix I, item 4.2) should be carried out in at least two mammalian species, of which one should be a non- rodent. Dose ranging studies should precede the 14-, 28-, 90- or 180- day toxicity studies. Duration of the final systematic toxicity study will depend on the duration, therapeutic indication and scale of the proposed clinical trial (see item 1.8). If a species is known to metabolize the drug in the same way as humans, it should be preferred for toxicity studies. In repeated-dose toxicity studies the drug should be administered 7 days a week by the route intended for clinical use. The number of animals required for these studies, i.e. the minimum number of animals on which data should be available, is shown in Item 1.9. Wherever applicable, a control group of animals given the vehicle alone should be

included, and three other groups should be given graded doses of the drug. The highest dose

should produce observable toxicity; the lowest dose should not cause observable toxicity,

but should be comparable to the intended therapeutic dose in humans or a multiple of it . To

make allowance for the sensitivity of the species the intermediate dose should cause some symptoms, but not gross toxicity or death, and should be placed logarithmically between the other two doses.

Drugs and Cosmetics Rules, 1945 519 The parameters to be monitored and recorded in long-term toxicity studies should include

behavioral, physiological, biochemical and microscopic observations. In case of parenteral

drug administration, the sites of injection should be subjected to gross and microscopic

examination. Initial and final electrocardiogram and fundus examination should be carried

out in the non-rodent species. In the case of cytotoxic anticancer agents dosing and study design should be in accordance

with the proposed clinical schedule in terms of days of exposure and number of cycles. Two

rodent species may be tested for initiating Phase I trials. A non-rodent species should be added if the drug has a novel mechanism of action, or if permission for Phase II, III or marketing is being sought. For most compounds, it is expected that single dose tissue distribution studies with sufficient sensitivity and specificity will provide an adequate assessment of tissue distribution and the potential for accumulation. Thus, repeated dose tissue distribution studies should not be required uniformly for all compounds and should only be conducted when appropriate data cannot be derived from other sources. Repeated dose studies may be appropriate under certain circumstances based on the data from single dose tissue distribution studies, toxicity and toxicokinetic studies. The studies may be most appropriate for compounds which have an apparently long half life, incomplete elimination or unanticipated organ toxicity. Notes:

(i) Single Dose Toxicity Study: Each group should contain at least 5 animals of

either sex. At least four graded doses should be given. Animals should be exposed to the

test substance in a single bolus or by continuous infusion or several doses within 24 hours. Animals should be observed for 14 days. Signs of intoxication, effect on body weight, gross pathological changes should be reported. It is desirable to include histo-pathology of grossly affected organs, if any.

(ii) Dose-ranging Study: Objectives of this study include the identification of target organ of toxicity and establishment of MTD for subsequent studies.

(a) Rodents: Study should be performed in one rodent species (preferably rat)

by the proposed clinical route of administration. At least four graded doses including

control should be given, and each dose group as well as the vehicle control should consist of a minimum of 5 animals of each sex. Animals should be exposed to the test substance daily for 10 consecutive days. Highest dose should be the maximum tolerated dose of single-dose study. Animals should be observed daily for signs of intoxication (general appearance, activity and behaviour etc), and periodically for the body weight and laboratory parameters. Gross examination of viscera and microscopic examination of affected organs should be done.

(b) Non-rodents: One male and one female are to be taken for ascending Phase MTD study. Dosing should start after initial recording of cage-side and laboratory

parameters. Starting dose may be 3 to 5 times the extrapolated effective dose or MTD

(whichever is less), and dose escalation in suitable steps should be done every third day after drawing the samples for laboratory parameters. Dose should be lowered appropriately when clinical or laboratory evidence of toxicity are observed. Administration of test substance should then continue for 10 days at the well-tolerated dose level following which, samples for laboratory parameters should be taken. Sacrifice, autopsy and microscopic examination of affected tissues should be performed as in the case of rodents.

Drugs and Cosmetics Rules, 1945 520

(iii) 14-28 Day repeated-dose toxicity studies: One rodent (6-10/sex/group) and one non-rodent (2-3/sex/group) species are needed. Daily dosing by proposed clinical route at three dose levels should be done with highest dose having observable toxicity, mid- dose between high and low dose, and low dose. The doses should preferably be multiples

of the effective dose and free from toxicity. Observation parameters should include cage-

side observations, body weight changes, food/water intake, blood biochemistry, haematology, and gross and microscopic studies of all viscera and tissues.

(iv) 90-Day repeated-dose toxicity studies: One rodent (15-30/sex/group) and one non- rodent (4-6/sex/group) species are needed. Daily dosing by proposed clinical route at

intoxication (general appearance, activity and behaviour etc), body weight, food intake, blood biochemical parameters, haematological values, urine analysis, organ weights,

gross and microscopic study of viscera and tissues. Half the animals in “reversal” groups

(treated and control) should be sacrificed after 14 days of stopping the treatment. The remaining animals should be sacrificed after 28 days of stopping the treatment or after the recovery of signs and/or clinical pathological changes – whichever comes later, and evaluated for the parameters used for the main study.

(v) 180-Day repeated-dose toxicity studies: One rodent (15-30/sex/group) and one non-rodent (4-6/sex/group) species are needed. At least 4 groups, including control, should be taken. Daily dosing by proposed clinical route at three graded dose levels should be done. Parameters should include signs of intoxication, body weight, food intake, blood biochemistry, hematology, urine analysis, organ weights, gross and microscopic examination of organs and tissues.

1.2 Male Fertility Study

One rodent species (preferably rat) should be used. Dose selection should be done

from the results of the previous 14 or 28-day toxicity study in rat. Three dose groups, the

highest one showing minimal toxicity in systemic studies, and a control group should be taken. Each group should consist of 6 adult male animals. Animals should be treated with the test substance by the intended route of clinical use for minimum 28 days and maximum 70 days before they are paired with female animals of proven fertility in a ratio of 1:2 for mating. Drug treatment of the male animals should continue during pairing. Pairing should

be continued till the detection of vaginal plug or 10 days, whichever is earlier. Females

getting thus pregnant should be examined for their fertility index after day 13 of

gestation. All the male animals should be sacrificed at the end of the study. Weights of

each testis and epididymis should be separately recorded. Sperms from one epididymis should be examined for their motility and morphology. The other epididymis and both testes should be examined for their histology.

1.3 Female Reproduction and Developmental Toxicity Studies

These studies (see Appendix I, item 4.4) need to be carried out for all drugs proposed to be studied or used in women of child bearing age. Segment I, II and III studies (see below) are to be performed in albino mice or rats, and segment II study should include albino rabbits also as a second test species.

Drugs and Cosmetics Rules, 1945 521 On the occasion, when the test article is not compatible with the rabbit (e.g. antibiotics which are effective against gram positive, anaerobic organisms and protozoas) the Segment II data in the mouse may be substituted. 1.3.1 Female Fertility Study (Segment I): The study should be done in one rodent species (rat preferred). The drug should be administered to both males and females, beginning a sufficient number of days (28 days in males and 14 days in females) before mating. Drug treatment should continue during mating and, subsequently, during the

gestation period. Three graded doses should be used, the highest dose (usually the MTD

obtained from previous systemic toxicity studies) should not affect general health of the parent animals. At least 15 males and 15 females should be used per dose group. Control and the treated groups should be of similar size. The route of administration should be the same as intended for therapeutic use Dams should be allowed to litter and their medication should be continued till the weaning of pups. Observations on body weight, food intake, clinical signs of intoxication, mating behaviour, progress of gestation/ parturition periods, length of gestation, parturition, post-partum health and gross pathology (and histopathology of affected organs) of dams should be recorded. The pups from both treated and control groups should be observed for general signs of intoxication, sex-wise distribution in different treatment groups, body weight, growth parameters, survival, gross examination,

and autopsy. Histopathology of affected organs should be done.

drug should be administered throughout the period of organogenesis, using three dose levels as described for segment I. The highest dose should cause minimum maternal toxicity and the lowest one should be proportional to the proposed dose for clinical use in humans or a multiple of it. The route of administration should be the same as intended for human therapeutic use. The control and the treated groups should consist of at least 20 pregnant rats (or mice) and 12 rabbits, on each dose level. All foetuses should be subjected to gross examination, one of the foetuses should be examined for skeletal abnormalities and the other half for visceral abnormalities. Observation parameters should include: (Dams) signs of intoxication, effect on body weight, effect on food intake, examination of uterus, ovaries and uterine contents, number of corpora lutea, implantation sites, resorptions (if any); and for the foetuses, the total number, gender, body length, weight and gross/ visceral/ skeletal abnormalities, if any.

1.3.3 Perinatal Study (Segment III):

This study is specially recommended if the drug is to be given to pregnant or nursing mothers for long periods or where there are indications of possible adverse effects on foetal development. One rodent species (preferably rat) is needed. Dosing at levels

should be administered throughout the last trimester of pregnancy (from day 15 of gestation) and then the dose that causes low foetal loss should be continued throughout lactation and weaning. Dams should then be sacrificed and examined as described below.

Drugs and Cosmetics Rules, 1945 522 One male and one female from each litter of F generation (total 15 males and 15 females in each group) should be selected at weaning and treated with vehicle or test substance (at the dose levels described above) throughout their periods of growth to sexual maturity, pairing, gestation, parturition and lactation. Mating performance and fertility of F generation should thus be evaluated to obtain the F generation whose

growth parameters should be monitored till weaning. The criteria of evaluation should be

the same as described earlier (3.4.1). Animals should be sacrificed at the end of the study and the observation parameters should include (Dams) body weight, food intake, general signs of intoxication, progress of gestation/ parturition periods and gross pathology (if any); and for pups, the clinical signs, sex-wise distribution in dose groups, body weight, growth parameters, gross examination, survival and autopsy (if needed) and where necessary, histopathology.

1.4 Local toxicity

These studies (see Appendix I, item 4.5) are required when the new drug is proposed to be used by some special route (other than oral) in humans. The drug should be applied to an appropriate site (e.g., skin or vaginal mucous membrane) to determine local effects in a suitable species. Typical study designs for these studies should include three dose levels and untreated and/ or vehicle control, preferably use of 2 species, and increasing group size with increase in duration of treatment. Where dosing is restricted due to anatomical or humane reasons, or the drug concentration cannot be increased beyond a certain level due to the problems of solubility, pH or tonicity, a clear statement to this effect should be given. If the drug is absorbed from the site of application, appropriate systemic toxicity studies will also be required.

Notes:

(i) Dermal toxicity study: The study should be done in rabbit and rat. Daily topical (dermal) application of test substance in its clinical dosage form should be done. Test material should be applied on shaved skin covering not less than 10% of the total body surface area. Porous gauze dressing should be used to hold liquid material in place. Formulations with different concentrations (at least 3) of test substance, several fold

higher than the clinical dosage form should be used. Period of application may vary from

7 to 90 days depending on the clinical duration of use. Where skin irritation is grossly visible in the initial studies, a recovery group should be included in the subsequent repeated-dose study. Local signs (erythema, oedema and eschar formation) as well as histological examination of sites of application should be used for evaluation of results.

(ii) Photo-allergy or dermal photo-toxicity: It should be tested by Armstrong/ Harber Test in guinea pig. This test should be done if the drug or a metabolite is related to an agent causing photosensitivity or the nature of action suggests such a potential (e.g., drugs to be used in treatment of leucoderma). Pretest in 8 animals should screen 4 concentrations (patch application for 2 hours ±15 min.) with and without UV exposure (10 J/cm ). Observations recorded at 24 and 48 hours should be used to ascertain highest nonirritant dose. Main test should be performed with 10 test animals and 5 controls. Induction with the dose selected from pretest should use 0.3 ml/patch for 2 hour ±15 min. followed by 10 J/cm

between day 20 to 24 of the test with a similar 2-hour application followed by exposure to 10 J/cm

of UV light. Examination and grading of erythema and oedema formation at the

Drugs and Cosmetics Rules, 1945 523

challenge sites should be done 24 and 48 hours after the challenge. A positive control like

musk ambrett or psoralin should be used.

(iii) Vaginal Toxicity Test: Study is to be done in rabbit or dog. Test substance should be applied topically (vaginal mucosa) in the form of pessary, cream or ointment. Six to ten animals per dose group should be taken. Higher concentrations or several daily applications of test substance should be done to achieve multiples of daily human dose. The minimum duration of drug treatment is 7 days (more according to clinical use), subject to a maximum of 30 days. Observation parameters should include swelling, closure of introitus and histopathology of vaginal wall.
(iv) Rectal Tolerance Test: For all preparations meant for rectal administration this test may be performed in rabbits or dogs. Six to ten animals per dose group should be taken. Formulation in volume comparable to human dose (or the maximum possible volume) should be applied once or several times daily, per rectally, to achieve

administration of multiples of daily human dose. The minimum duration of application is

7 days (more according to clinical use), subject to a maximum of 30 days. Size of suppositories may be smaller, but the drug content should be several fold higher than the proposed human dose. Observation parameters should include clinical signs (sliding on backside), signs of pain, blood and/or mucus in faeces, condition of anal region/sphincter, gross and (if required) histological examination of rectal mucosa.

(v) Parenteral Drugs: For products meant for intravenous or intramuscular or subcutaneous or intradermal injection the sites of injection in systemic toxicity studies should be specially examined grossly and microscopically. If needed, reversibility of adverse effects may be determined on a case to case basis.
(vi) Ocular toxicity studies (for products meant for ocular instillation): These studies should be carried out in two species, one of which should be the albino rabbit which has a sufficiently large conjunctival sac. Direct delivery of drug onto the cornea in case of

be done to decide the exposure concentrations for repeated-dose studies and the need to

include a recovery group. Duration of the final study will depend on the proposed length

of human exposure subject to a maximum of 90 days. At least two different concentrations exceeding the human dose should be used for demonstrating the margin of

Slit-lamp examination should be done to detect the changes in cornea, iris and aqueous

humor. Fluorescent dyes (sodium fluorescein, 0.25 to 1.0%) should be used for detecting

the defects in surface epithelium of cornea and conjunctiva. Changes in intra-ocular

tension should be monitored by a tonometer. Histological examination of eyes should be

done at the end of the study after fixation in Davidson’s or Zenker’s fluid.

(vii) Inhalation toxicity studies: The studies are to be undertaken in one rodent and one non-rodent species using the formulation that is to be eventually proposed to be

marketed. Acute, subacute and chronic toxicity studies should be performed according to

the intended duration of human exposure. Standard systemic toxicity study designs (described above) should be used. Gases and vapours should be given in whole body exposure chambers; aerosols are to be given by nose-only method. Exposure time and concentrations of test substance (limit dose of 5mg/l) should be adjusted to ensure exposure at levels comparable to multiples of intended human exposure. Three dose

groups and a control (plus vehicle control, if needed) are required. Duration of exposure

Drugs and Cosmetics Rules, 1945 524

may vary subject to a maximum of 6 hours per day and five days a week. Food and water

should be withdrawn during the period of exposure to test substance. Temperature, humidity and flow rate of exposure chamber should be recorded and

reported. Evidence of exposure with test substance of particle size of 4 micron (especially

for aerosols) with not less that 25% being 1 micron should be provided. Effects on respiratory rate, findings of bronchial lavage fluid examination, histological examination of respiratory passages and lung tissue should be included along with the regular parameters of systemic toxicity studies or assessment of margin of safety.

1.5 Allergenicity/ Hypersensitivity:

Standard tests include guinea pig maximization test (GPMT) and local lymph node

assay (LLNA) in mouse. Any one of the two may be done.

Notes:

(i) Guinea Pig Maximization Test: The test is to be performed in two steps; first, determination of maximum nonirritant and minimum irritant doses, and second, the main test. The initial study will also have two components. To determine the intradermal induction dose, 4 dose levels should be tested by the same route in a batch of 4 male and 4

female animals (2 of each sex should be given Freund’s adjuvant). The minimum irritant

dose should be used for induction. Similarly, a topical minimum irritant dose should be determined for challenge. This should be established in 2 males and 2 females. A minimum of 6 male and 6 female animals per group should be used in the main study.

One test and one control group should be used. It is preferable to have one more positive

control group. Intradermal induction (day 1) coupled with topical challenge (day 21) should be done. If there is no response, re-challenge should be done 7-30 days after the primary challenge. Erythema and oedema (individual animal scores as well as maximization grading) should be used as evaluation criteria.

(ii) Local Lymph Node Assay: Mice used in this test should be of the same sex, either only males or only females. Drug treatment is to be given on ear skin. Three graded

on three consecutive days and on day 5, the draining auricular lymph nodes should be

dissected out 5 hours after i.v. H-thymidine or bromo-deoxy-uridine (BrdU). Increase in

H-thymidine or BrdU incorporation should be used as the criterion for evaluation of results.

1.6 Genotoxicity

Genotoxic compounds, in the absence of other data, shall be presumed to be trans- species carcinogens, implying a hazard to humans. Such compounds need not be subjected to long-term carcinogenicity studies. However, if such a drug is intended to be administered for chronic illnesses or otherwise over a long period of time - a chronic toxicity study (up to one year) may be necessary to detect early tumorigenic effects. Genotoxicity tests are in vitro and in vivo tests conducted to detect compounds which induce genetic damage directly or indirectly. These tests should enable a hazard identification with respect to damage to DNA and its fixation. The following standard test battery is generally expected to be conducted:

(i) A test for gene mutation in bacteria. Drugs and Cosmetics Rules, 1945 525
(ii) An in vitro test with cytogenetic evaluation of chromosomal damage with mammalian cells or an in vitro mouse lymphoma tic assay.
(iii) An in vivo test for chromosomal damage using rodent haematopoietic cells. Other genotoxicity tests e.g. tests for measurement of DNA adducts, DNA strand breaks, DNA repair or recombination serve as options in addition to the standard battery for further investigation of genotoxicity test results obtained in the standard battery. Only under extreme conditions in which one or more tests comprising the standard battery cannot be employed for technical reasons, alternative validated tests can serve as substitutes provided sufficient scientific justification should be provided to support the argument that a given standard battery test is not appropriate. Both in-vitro and in-vivo studies should be done. In-vitro studies should include Ames’ Salmonella assay and chromosomal aberrations (CA) in cultured cells. In-vivo studies should include micronucleus assay (MNA) or CA in rodent bone marrow. Data analysis of CA should include analysis of ‘gaps.’

Notes: Ames’ Test (Reverse mutation assay in Salmonella): S. typhimurium tester strains such as TA98, TA100, TA102, TA1535, TA97 or Escherichia coli WP2 uvrA or Escherichia coli WP2 uvrA (pKM101) should be used.

(i) In-vitro exposure (with and without metabolic activation, S9 mix) should be done at a minimum of 5 log dose levels. “Solvent” and “positive” control should be used. Positive control may include 9-amino-acridine, 2-nitrofluorine, sodium azide and

mitomycin C, respectively, in the tester strains mentioned above. Each set should consist

of at least three replicates. A 2.5 fold (or more) increase in number of revertants in comparison to spontaneous revertants would be considered positive.

(ii) In-vitro cytogenetic assay : The desired level of toxicity for in vitro cytogenetic tests using cell lines should be greater than 50% reduction in cell number or culture confluency. For lymphocyte cultures, an inhibition of mitotic index by greater than 50% is considered sufficient. It should be performed in CHO cells or on human lymphocyte in

positive control like Cyclophosphamide with metabolic activation and Mitomycin C for without metabolic activation should be used to give a reproducible and detectable increase clastogenic effect over the background which demonstrates the sensitivity of the test system. Each set should consist of at least three replicates. Increased number of aberrations in metaphase chromosomes should be used as the criteria for evaluation.

(iii) In-vivo micronucleus assay: One rodent species (preferably mouse) is needed.

and “positive” control should be tested. A positive control like mitomycin C or cyclophosphamide should be used. Dosing should be done on day 1 and 2 of study

followed by sacrifice of animals 6 hours after the last injection. Bone marrow from both

the femora should be taken out, flushed with fetal bovine serum (20 min.), pelletted and smeared on glass slides. Giemsa-MayGruenwald staining should be done and increased number of micronuclei in polychromatic erythrocytes (minimum 1000) should be used as the evaluation criteria.

Drugs and Cosmetics Rules, 1945 526

(iv) In-vivo cytogenetic assay: One rodent species (preferably rat) is to be used. Route of administration of test substance should be the same as intended for humans. Five animals/sex/dose groups should be used. At least three dose levels, plus “solvent” and “positive” control should be tested. Positive control may include cyclophosphamide. Dosing should be done on day 1 followed by intra-peritoneal colchicine administration at 22 hours. Animals should be sacrificed 2 hours after colchicine administration. Bone marrow from both the femora should be taken out, flushed with hypotonic saline (20 min.), pelletted and resuspended in Carnoy’s fluid. Once again the cells should be

pelletted and dropped on clean glass slides with a Pasteur pipette. Giemsa staining should

be done and increased number of aberrations in metaphase chromosomes (minimum 100) should be used as the evaluation criteria.

1.7 Carcinogenicity (see Appendix I, item 4.8)

Carcinogenicity studies should be performed for all drugs that are expected to be clinically used for more than 6 months as well as for drugs used frequently in an intermittent

manner in the treatment of chronic or recurrent conditions. Carcinogenicity studies are also

to be performed for drugs if there is concern about their carcinogenic potential emanating from previous demonstration of carcinogenic potential in the product class that is considered relevant to humans or where structure-activity relationship suggests carcinogenic risk or when there is evidence of preneoplastic lesions in repeated dose toxicity studies or when long-term tissue retention of parent compound or metabolite(s) results in local tissue reactions or other pathophysiological responses. For pharmaceuticals developed to treat certain serious diseases, Licensing Authority may allow carcinogenicity testing to be conducted after marketing permission has been granted. In instances where the life-expectancy in the indicated population is short (i.e., less than 2-3 years)- no long-term carcinogenicity studies may be required. In cases where the therapeutic agent for cancer is generally successful and life is significantly prolonged there may be later concerns regarding secondary cancers. When such drugs are intended for adjuvant therapy in tumour free patients or for prolonged use in non-cancer indications,

carcinogenicity studies may be / are needed. Completed rodent carcinogenicity studies are not

needed in advance of the conduct of large scale clinical trials, unless there is special concern for the patient population.

Carcinogenicity studies should be done in a rodent species (preferably rat). Mouse may be

employed only with proper scientific justification. The selected strain of animals should not have a very high or very low incidence of spontaneous tumors. At least three dose levels should be used. The highest dose should be sub-lethal, and it

should not reduce the life span of animals by more than 10% of expected normal. The lowest

dose should be comparable to the intended human therapeutic dose or a multiple of it, e.g.

2.5x; to make allowance for the sensitivity of the species. The intermediate dose to be placed

logarithmically between the other two doses. An untreated control and (if indicated) a vehicle control group should be included. The drug should be administered 7 days a week for a fraction of the life span comparable to the fraction of human life span over which the drug is

likely to be used therapeutically. Generally, the period of dosing should be 24 months for rats

and 18 months for mice. Observations should include macroscopic changes observed at autopsy and detailed histopathology of organs and tissues. Additional tests for carcinogenicity (short-term bioassays, neonatal mouse assay or tests employing transgenic animals) may also be done depending on their applicability on a case to case basis. Note:

Drugs and Cosmetics Rules, 1945 527 Each dose group and concurrent control group not intended to be sacrificed early should

contain atleast 50 animals of each sex. A high dose sattelite group for evaluation of pathology

other than neoplasia should contain 20 animals of each sex while the sattelite control group should contain 10 animals of each sex. Observation parameters should include signs of intoxication, effect on body weight, food intake, clinical chemistry parameters, hematology parameters, urine analysis, organ weights, gross pathology and detailed histopathology. Comprehensive descriptions of benign and malignant tumour development, time of their detection, site, dimensions, histological typing etc. should be given.

1.8 Animal toxicity requirements for clinical trials and marketing of a new drug.

Systemic Toxicity Studies

Route of

administration Duration of proposed human administration Human Phase(s) for which study is proposed to be conducted Long term toxicity requirements Oral or Parenteral or Transdermal Single dose or several doses in one day, Upto 1wk I,II,III 2sp,2wk > 1 wk but upto 2wk I,II,III 2sp;4wk > 2 wk but upto 4wk I,II,III 2sp;12wk Over 1mo I,II,III 2sp;24wk Inhalation (general anaesthetics, aerosols)

Upto 2 wk I,II,III 2sp;1mo; (Exposure time

3h/d, 5d/wk)

Upto 4wk I,II,III 2sp;12wk, (Exposure time

6h/d, 5d/wk)

> 1 4wk I,II,III 2sp;24wk, (Exposure time

6h/d, 5d/wk) Local Toxicity Studies

Dermal Upto 2 wk I,II 1sp;4wk III 2sp;4wk

Nasal Upto 2 wk I,II 1sp;4wk III 2sp;4wk > 2 wk I,II,III 2sp;12wk

Drugs and Cosmetics Rules, 1945 528 Vaginal or Rectal Upto 2 wk I,II 1sp;4wk III 2sp;4wk > 2 wk I,II,III 2sp;12wk Special Toxicity Studies

Male Fertility Study:

• Phase I, II, III in male volunteers/patients Female Reproduction and Developmental Toxicity Studies:
• Segment II studies in 2 species; Phase II, III involving female patients of child- bearing age.
• Segment I study; Phase III involving female patients of child-bearing age.
• Segment III study; Phase III for drugs to be given to pregnant or nursing mothers for long periods or where there are indications of possible adverse effects on foetal development. Allergenicity/Hypersensitivity:
• Phase I, II, III - when there is a cause of concern or for parenteral drugs (including dermal application) Photo-allergy or dermal photo-toxicity:
• Phase I, II, III - if the drug or a metabolite is related to an agent causing photosensitivity or the nature of action suggests such a potential. Genotoxicity:
• In-vitro studies - Phase I
• Both in-vitro and in-vivo - Phase II, III arcinogenicity:
• Phase III - when there is a cause for concern, or when the drug is to be used for more than 6 months. Abbreviations: sp-species; mo-month; wk-week; d -day; h-hour; I, II, III - Phases of clinical trial; Note:

1. Animal toxicity data generated in other countries may be accepted and may not

be asked to be repeated/duplicated in India on a case to case basis depending upon the quality of data and the credentials of the laboratory(ies) where such data has been generated.

2. Requirements for fixed dose combinations are given in Appendix VI.

Drugs and Cosmetics Rules, 1945 529

1.9 Number of animals required for repeated-dose toxicity studies

14-28 days 84-182 days Group Rodent (Rat) Non-rodent (Dog or Monkey) Rodent (Rat) Non-rodent (Dog or Monkey) M F M F M F M F Control 6- 6-10 2-3 2-3 15- 15- 4-6 4-6 Low dose 6- 6-10 2-3 2-3 15- 15- 4-6 4-6 Intermediate dose 6- 6-10 2-3 2-3 15- 15- 4-6 4-6 High dose 6- 6-10 2-3 2-3 15- 15- 4-6 4-6

2.0 Laboratory parameters to be included in toxicity studies.

Haematological parameters

• Haemoglobin • Total RBC Count
• Haematocrit • Reticulocyte Count
• Total WBC Count • Differential WBC Count
• Platelet Count Terminal Bone Marrow Examination
• ESR (Non- rodents only)
• General Blood Picture: A special mention of abnormal and immature cells should be made.
• Coagulation Parameters (Non-rodents only): Bleeding Time, Coagulation Time, Prothrombin Time, Activated Partial Thromboplastin Time Urinalysis Parameters:
• Colour • Appearance • Specific Gravity
• 24-hour urinary output
• Reaction (pH) • Albumin •Sugar
• Acetone Bile pigments Urobilinogen
• Occult Blood
• Microscopic examination of urinary sediment. Drugs and Cosmetics Rules, 1945 530 Blood Biochemical Parameters
• Glucose • Cholesterol • Triglycerides DL erol dents
• H Cholest (Non- ro only)
• ol odents
• Bilirubin • SGPT (ALT) T (AST) LDL Cholester (Non-r only)
• SGO • atase (Non-rodents only) d Urea Nitrogen
• Ceatinine Alkaline Phosph (ALP)
• GGT • Bloo
• Total Proteins
• Albumin n lculated Sodium
• Globuli (Ca values) •
• • us Calcium Potassium Phosphor • Gross and Microscopic Pathology ,
• (Spinal Cord) • Eye • (Middle Ear)
• Brain*: Cerebrum, cerebellum Midbrain
• Thyroid • Parathyroid) • Spleen • Thymus
• Adrenal* as) • (Pancre• (Trachea) • Lung*
• Heart* • Aorta • Oesophagus ch • Stoma
• Duodenum • Jejunum • • Colon Terminal ileum
• (Rectum) • Liver* • Kidney* ladder • Urinary b
• Epididymis • Testis* • Ovary • Uterus*
• Skin • ary • mph node
• Skeletal muscle Mamm gland ly Mesenteric
• Organs marked with an asterisk should be weighed. () Organs listed in parenthesis should be examined if indicated by the nature of the drug or safety evaluation data of an IND needed for the conduct of _________________________________________________________________________ observed effects.

Non-clinical toxicity testing and

different phases of clinical trials. __

Drugs and Cosmetics Rules, 1945 531

Note: Refer Appendix III (Points 1.1 through 1.7 and tables 1.8 and 1.9) for essential features

of study designs of the non-clinical toxicity studies listed below. For Phase I Clinical Trials Systemic Toxicity studies

(i) Single dose toxicity studies
(ii) Dose Ranging Studies
(iii) Repeat-dose systemic toxicity studies of appropriate duration to support the duration of proposed human exposure. Male fertility study In-vitro genotoxicity tests Relevant local toxicity studies with proposed route of clinical application (duration depending on proposed length of clinical exposure) Allergenicity/Hypersensitivity tests (when there is a cause for concern or for parenteral drugs, including dermal application) Photo-allergy or dermal photo-toxicity test (if the drug or a metabolite is related to an agent causing photosensitivity or the nature of action suggests such a potential) For Phase II Clinical Trials Provide a summary of all the non-clinical safety data (listed above) already submitted while obtaining the permissions for Phase I trial, with appropriate references. In case of an application for directly starting a Phase II trial - complete details of the non- clinical safety data needed for obtaining the permission for Phase I trial, as per the list provided above must be submitted. Repeat-dose systemic toxicity studies of appropriate duration to support the duration of proposed human exposure In-vivo genotoxicity tests. Segment II reproductive/developmental toxicity study (if female patients of child bearing age are going to be involved) For Phase III Clinical Trials Provide a summary of all the non-clinical safety data (listed above) already submitted while obtaining the permissions for Phase I and II trials, with appropriate references. In case of an application for directly initiating a Phase III trial - complete details of the non-clinical safety data needed for obtaining the permissions for Phase I and II trials, as per the list provided above must be provided. Repeat-dose systemic toxicity studies of appropriate duration to support the duration of proposed human exposure Reproductive/developmental toxicity studies Segment I (if female patients of child bearing age are going to be involved), and Segment III (for drugs to be given to pregnant or nursing mothers or where there are indications of possible adverse effects on foetal development). Drugs and Cosmetics Rules, 1945 532 Carcinogenicity studies (when there is a cause for concern or when the drug is to be used for more than 6 months). For Phase IV Clinical Trials Provide a summary of all the non-clinical safety data (listed above) already submitted while obtaining the permissions for Phase I, II and III trials, with appropriate references. In case an application is made for initiating the Phase IV trial, complete details of the non-clinical safety data needed for obtaining the permissions for Phase I, II and III trials, as per the list provided above must be submitted. Application Of Good Laboratory Practices (GLP)

The animal studies be conducted in an accredited laboratory. Where the safety pharmacology

studies are part of toxicology studies, these studies should also be conducted in an accredited laboratory.

APPENDIX IV ANIMAL PHARMACOLOGY 1. General Principles Specific and general pharmacological studies should be conducted to support use of therapeutics in humans. In the early stages of drug development enough information may not be available to rationally select study design for safety assessment. In such a situation, a general approach to safety pharmacology studies can be applied. Safety pharmacology studies are studies that investigate potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure within the therapeutic range or above. 1.1 Specific Pharmacological Actions Specific pharmacological actions are those which demonstrate the therapeutic potential for humans. The specific studies that should be conducted and their design will be different based on the individual properties and intended uses of investigational drug. Scientifically validated methods should be used. The use of new technologies and methodologies in accordance with sound scientific principles should be preferred. 1.2 General Pharmacological Actions

1.2.1 Essential Safety Pharmacology

Safety pharmacology studies need to be conducted to investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in

relation to exposure within the therapeutic range and above. These studies should be

designed to identify undesirable pharmacodynamic properties of a substance that may have relevance to its human safety; to evaluate adverse pharmacodynamic and/or pathophysiological effects observed in toxicology and/or clinical studies; and to investigate the mechanism of the adverse pharmacodynamic effects observed and/or suspected. The aim of the essential safety pharmacology is to study the effects of the test drug on vital functions. Vital organ systems such as cardiovascular, respiratory and central nervous systems should be studied. Essential safety pharmacology studies may be

excluded or supplemented based on scientific rationale. Also, the exclusion of certain

Drugs and Cosmetics Rules, 1945 533 test(s) or exploration(s) of certain organs, systems or functions should be scientifically justified. 1.2.1.1 Cardiovascular System Effects of the investigational drug should be studied on blood pressure, heart rate, and the electrocardiogram. If possible i n vitro, in vivo and/or ex vivo methods including electrophysiology should also be considered. 1.2.1.2 Central Nervous System Effects of the investigational drug should be studied on motor activity, behavioral changes, coordination, sensory and motor reflex responses and body temperature. 1.2.1.3 Respiratory System Effects of the investigational drug on respiratory rate and other functions such as tidal volume and hemoglobin oxygen saturation should be studied.

1.3 Follow-up and Supplemental Safety Pharmacology Studies

In addition to the essential safety pharmacological studies, additional supplemental and follow-up safety pharmacology studies may need to be conducted as appropriate. These depend on the pharmacological properties or chemical class of the test substance, and the data generated from safety pharmacology studies, clinical trials, pharmacovigilance, experimental in vitro or in vivo studies, or from literature reports.

1.3.1 Follow-up Studies For Essential Safety Pharmacology

Follow-up studies provide additional information or a better understanding

than that provided by the essential safety pharmacology.

1.3.1.1 Cardiovascular System These include ventricular contractility, vascular resistance and the effects of chemical mediators, their agonists and antagonists on the cardiovascular system. 1.3.1.2 Central Nervous System These include behavioral studies , learning and memory, electrophysiology

studies , neurochemistry and ligand binding studies.

1.3.1.3 Respiratory System These include airway resistance, compliance, pulmonary arterial pressure, blood gases and blood pH. 1.3.2 Supplemental Safety Pharmacology Studies These studies are required to investigate the possible adverse pharmacological effects that are not assessed in the essential safety pharmacological studies and are a cause for concern. 1.3.2.1 Urinary System These include urine volume, specific gravity, osmolality, pH, proteins, cytology and blood urea nitrogen, creatinine and plasma proteins estimation. 1.3.2.2 Autonomic Nervous System These include binding to receptors relevant for the autonomic nervous system, and functional response to agonist or antagonist responses in vivo or in vitro, and effects of direct stimulation of autonomic nerves and their effects on cardiovascular responses.

Drugs and Cosmetics Rules, 1945 534 1.3.2.3 Gastrointestinal System These include studies on gastric secretion, gastric pH measurement, gastric mucosal examination, bile secretion, gastric emptying time in vivo and ileocaecal contraction in vitro. 1.3.2.4 Other Organ Systems Effects of the investigational drug on organ systems not investigated elsewhere should be assessed when there is a cause for concern. For example dependency potential, skeletal muscle, immune and endocrine functions may be investigated. 1.4 Conditions Under Which Safety Pharmacology Studies Are Not Necessary Safety pharmacology studies are usually not required for locally applied agents e.g. dermal or ocular, in cases when the pharmacology of the investigational drug is well known, and/or when systemic absorption from the site of application is low. Safety pharmacology testing is also not necessary, in the case of a new derivative having similar pharmacokinetics and pharmacodynamics. 1.5 Timing Of Safety Pharmacology Studies In Relation To Clinical Development 1.5.1 Prior To First Administration In Humans The effects of an investigational drug on the vital functions listed in the essential safety pharmacology should be studied prior to first administration in humans. Any follow-up or supplemental studies identified, should be conducted

if necessary, based on a cause for concern.

1.5.2 During Clinical Development Additional investigations may be warranted to clarify observed or suspected adverse effects in animals and humans during clinical development 1.5.3 Before applying for marketing Approval Follow-up and supplemental safety pharmacology studies should be assessed prior to approval unless not required, in which case this should be justified. Available information from toxicology studies addressing safety pharmacology endpoints or information from clinical studies can replace such studies. 1.6 Application Of Good Laboratory Practices (GLP) The animal studies be conducted in an accredited laboratory. Where the safety pharmacology studies are part of toxicology studies, these studies should also be conducted in an accredited laboratory.

APPENDIX V INFORMED CONSENT 1. Checklist for study Subject’s informed consent documents 1.1 Essential Elements: 1. Statement that the study involves research and explanation of the purpose of the research

2. Expected duration of the Subject's participation

Drugs and Cosmetics Rules, 1945 535 3. Description of the procedures to be followed, including all invasive procedures and

4. Description of any reasonably foreseeable risks or discomforts to the Subject

5. Description of any benefits to the Subject or others reasonably expected from research. If no benefit is expected Subject should be made aware of this.

6. Disclosure of specific appropriate alternative procedures or therapies available to

the Subject.

7. Statement describing the extent to which confidentiality of records identifying the

Subject will be maintained and who will have access to Subject’s medical records 8. Trial treatment schedule(s) and the probability for random assignment to each treatment (for randomized trials) 9. Compensation and/or treatment(s) available to the Subject in the event of a trial- related injury

10. An explanation about whom to contact for trial related queries, rights of Subjects

and in the event of any injury 11. The anticipated prorated payment, if any, to the Subject for participating in the trial

12. Subject's responsibilities on participation in the trial

13. Statement that participation is voluntary, that the subject can withdraw from the study at any time and that refusal to participate will not involve any penalty or loss of benefits to which the Subject is otherwise entitled

14. Any other pertinent information

1.2 Additional elements, which may be required

(a) Statement of foreseeable circumstances under which the Subject's participation

may be terminated by the Investigator without the Subject's consent.

(b) Additional costs to the Subject that may result from participation in the study.
(c) The consequences of a Subject’s decision to withdraw from the research

and procedures for orderly termination of participation by Subject.

(d) Statement that the Subject or Subject's representative will be notified in a timely

(e). A statement that the particular treatment or procedure may involve risks to the Subject (or to the embryo or fetus, if the Subject is or may become pregnant), which are currently unforeseeable

(f) Approximate number of Subjects enrolled in the study

2. Format of informed consent form for Subjects participating in a clinical trial

Informed Consent form to participate in a clinical trial Study Title: Study Number:

Drugs and Cosmetics Rules, 1945 536

Subject’s Initials: _______________ Subject’s Name:_______________

Date of Birth / Age: _________________

Please initial box (Subject)

(i) I confirm that I have read and understood the information sheet dated ___ for the above study and have had the opportunity to ask questions.

[ ]

(ii) I understand that my participation in the study is voluntary and that I am free to withdraw at any time, without giving any reason, without my medical care or legal rights being affected.

[ ]

(iii) I understand that the Sponsor of the clinical trial, others working on the Sponsor’s behalf, the Ethics Committee and the regulatory authorities will not need my permission to look at my health records both in respect of the current study and any further research that may be conducted in relation to it, even if I withdraw from the trial. I agree to this access. However, I understand that my identity will not be revealed in any information released to third parties or published.

[ ]

(iv) I agree not to restrict the use of any data or results that arise from this study provided such a use is only for scientific purpose(s) [ ]
(v) I agree to take part in the above study.

[ ]

Signature (or Thumb impression) of the Subject/Legally Acceptable Representative:_____________

Date: _____/_____/______

Signatory’s Name: ______________________________________________________

Signature of the Investigator: ____________________________ Date: _____/_____/______

Study Investigator’s Name: __________________________________________________

Drugs and Cosmetics Rules, 1945 537

Signature of the Witness ______________________ Date:_____/_____/_______

Name of the Witness: _______________________________________________________

APPENDIX VI FIXED DOSE COMBINATIONS (FDCs) Fixed Dose Combinations refer to products containing one or more active ingredients used for a particular indication(s). FDCs can be divided into the following groups and data required for approval for marketing is described below:

(a) The first group of FDCs includes those in which one or more of the active ingredients is a new drug. For such FDCs to be approved for marketing data to be submitted will be similar to data required for any new drug (including clinical trials) [see rule 122E, item (a)]. (b)(i) The second group FDCs includes those in which active ingredients already approved/marketed individually are combined for the first time, for a particular claim and where the ingredients are likely to have significant interaction of a pharmacodynamic or

marketed abroad, the regulatory status in other countries should be stated. (see Appendix I, item 9).

(ii) For marketing permission, appropriate chemical and pharmaceutical data will be submitted. In case such a combination is not marketed anywhere in the world but these drugs are already in use concomitantly (not as an FDC but individually) for the said claim, marketing permission may be granted based on chemical and pharmaceutical data. Data showing the stability of the proposed dosage form will also have to be submitted.
(iii) For any other such FDCs, clinical trials may be required. For obtaining permission to carry out clinical trials with such FDCs a summary of available

acute toxicity data (LD 50) and pharmacological data should be submitted on the individual ingredients as well as their combination in the proposed ratio.

(c) The third group of FDCs includes those which are already marketed, but in which it is proposed either to change the ratio of active ingredients or to make a new therapeutic claim. For such FDCs, the appropriate rationale including published reports

(if any) should be submitted to obtain marketing permission. Permission will be granted

depending upon the nature of the claim and data submitted.

(d) The fourth group of FDC includes those whose individual active ingredients (or drugs from the same class) have been widely used in a particular indication(s) for years, their concomitant use is often necessary and no claim is proposed to be made other than

convenience. It will have to be demonstrated that the proposed dosage form is stable and

the ingredients are unlikely to have significant interaction of a pharmacodynamic or pharmacokinetic nature. No additional animal or human data are generally required for these FDCs, and marketing permission may be granted if the FDC has an acceptable rationale.

Drugs and Cosmetics Rules, 1945 538 APPENDIX VII UNDERTAKING BY THE INVESTIGATOR 1. Full name, address and title of the Principal Investigator (or Investigator(s) when there is no Principal Investigator)

clinical trial (Attach details including Medical Council registration number, and / or any other statement(s) of qualification(s))

3. Name and address of all clinical laboratory facilities to be used in the study.

4. Name and address of the Ethics Committee that is responsible for approval and continuing review of the study. 5. Names of the other members of the research team (Co- or sub-Investigators) who will be assisting the Investigator in the conduct of the investigation (s). 6. Protocol Title and Study number (if any) of the clinical trial to be conducted by the Investigator. 7. Commitments:

(i) I have reviewed the clinical protocol and agree that it contains all the necessary information to conduct the study. I will not begin the study until all necessary Ethics Committee and regulatory approvals have been obtained.
(ii) I agree to conduct the study in accordance with the current protocol. I will not implement any deviation from or changes of the protocol without agreement by the Sponsor and prior review and documented approval / favorable opinion from the Ethics Committee of the amendment, except where necessary to eliminate an immediate hazard(s) to the trial Subjects or when the change(s) involved are only logistical or administrative in nature.
(iii) I agree to personally conduct and/or supervise the clinical trial at my site.
(iv) I agree to inform all Subjects, that the drugs are being used for investigational purposes and I will ensure that the requirements relating to obtaining informed consent and ethics committee review and approval specified in the GCP guidelines are met.
(v) I agree to report to the Sponsor all adverse experiences that occur in the course of the investigation(s) in accordance with the regulatory and GCP guidelines.
(vi) I have read and understood the information in the Investigator's brochure, including the potential risks and side effects of the drug.
(vii) I agree to ensure that all associates, colleagues and employees assisting in the conduct of the study are suitably qualified and experienced and they have been informed about their obligations in meeting their commitments in the trial.
(viii) I agree to maintain adequate and accurate records and to make those records available for audit / inspection by the Sponsor, Ethics Committee, Licensing Authority or

their authorized representatives, in accordance with regulatory and GCP provisions. I will

fully cooperate with any study related audit conducted by regulatory officials or authorized representatives of the Sponsor.

(ix) I agree to promptly report to the Ethics Committee all changes in the clinical trial activities and all unanticipated problems involving risks to human Subjects or others. Drugs and Cosmetics Rules, 1945 539
(x) I agree to inform all unexpected serious adverse events to the Sponsor as well as the Ethics Committee within seven days of their occurence.
(xi) I will maintain confidentiality of the identification of all participating study patients

and assure security and confidentiality of study data.

(xii) I agree to comply with all other requirements, guidelines and statutory obligations as applicable to clinical Investigators participating in clinical trials

8. Signature of Investigator with Date

APPENDIX VIII ETHICS COMMITTEE 1. The number of persons in an Ethcis Committee should have atleast seven members. Ethics Committee should appoint, from among its members, a Chairperson (who is from outside the institution) and a Member Secretary. Other members should be a mix of medical/non-medical, scientific and non-scientific persons, including lay public, to reflect the different viewpoints. For review of each protocol the quorum of Ethics Committee should be atleast 5 members with the following representations:

(a) basic medical scientists (preferably one pharmacologist).
(b) clinicians
(c) legal expert
(d) social scientist / representative of non-governmental voluntary agency / philosopher / ethicist / theologian or a similar person
(e) lay person from the community. In any case, the ethics committee must include at least one member whose primary area of interest / specialization is nonscientific and at least one member who is independent of the

the requirement of research area, e.g. HIV AIDS, genetic disorders etc. specific patient groups may also be represented in the Ethics Committee as far as possible. Only those Ethics Committee members who are independent of the clinical trial and the Sponsor of the trial should vote / provide opinion in matters related to the study.

2. Format for Approval of Ethics Committee To Dr. Dear Dr. ________

The Institutional Ethics Committee / Independent Ethics Committee (state name of the committee, as appropriate) reviewed and discussed your application to conduct the clinical trial entitled “......” on .......(date).

Drugs and Cosmetics Rules, 1945 540 The following documents were reviewed:

(a) Trial Protocol (including protocol amendments), dated____________ Version no (s).__________
(b) Patient Information Sheet and Informed Consent Form (including updates if any) in English and/or vernacular language.
(c) Investigator’s Brochure, dated_________, Version no.________
(d) Proposed methods for patient accrual including advertisement (s) etc. proposed to be used for the purpose.
(e) Principal Investigator’s current CV.
(f) Insurance Policy / Compensation for participation and for serious adverse events occurring during the study participation.
(g) Investigator’s Agreement with the Sponsor.
(h) Investigator’s Undertaking (Appendix VII). The following members of the ethics committee were present at the meeting held on (date, time, place). __________ Chairman of the Ethics Committee __________ Member secretary of the Ethics Committee __________ Name of each member with designation We approve the trial to be conducted in its presented form. The Institutional Ethics Committee / Independent Ethics Committee expects to be informed about the progress of the study, any SAE occurring in the course of the study, any changes in the protocol and patient information/informed consent and asks to be provided a copy of the final report. Yours sincerely, Member Secretary, Ethics Committee. APPENDIX IX STABILITY TESTING OF NEW DRUGS Stability testing is to be performed to provide evidence on how the quality of a drug substance or formulation varies with time under the influence of various environmental factors such as temperature, humidity and light, and to establish shelf life for the formulation and recommended storage conditions. Drugs and Cosmetics Rules, 1945 541 Stability studies should include testing of those attributes of the drug substance that are susceptible to change during storage and are likely to influence quality, safety, and/or efficacy. In case of formulations the testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes, preservative content (e.g., antioxidant, antimicrobial preservative), and functionality tests (e.g., for a dose delivery system). Validated stability-indicating analytical procedures should be applied. For long term studies, frequency of testing should be sufficient to establish the stability profile of the drug substance. In general, a drug substance should be evaluated under storage conditions that test its thermal stability and, if applicable, its sensitivity to moisture. The storage conditions and the length of studies chosen should be sufficient to cover storage, shipment and subsequent use. Stress testing of the drug substance should be conducted to identify the likely degradation products, which in turn establish the degradation pathways, evaluate the intrinsic stability of the molecule and validate the stability indicating power of the analytical procedures used. The nature of the stress testing will depend on the individual drug substance and the type of formulation involved. Stress testing may generally be carried out on a single batch of the drug substance. It should include the effect of temperatures ), humidity where appropriate, oxidation, and photolysis on the drug substance. Data should be provided for (a) Photostability on at least one primary batch of the drug substance as well as the formulation, as the case may be and (b) the susceptibility of the drug substance to hydrolysis across a wide range of pH values when in solution or suspension. Long-term testing should cover a minimum of 12 months’ duration on at least three primary batches of the drug substance or the formulation at the time of submission and should be continued for a period of time sufficient to cover the proposed shelf life. Accelerated testing should cover a minimum of 6 months duration at the time of submission. In case of drug substances, the batches should be manufactured to a minimum of pilot scale by the same synthetic route and using a method of manufacture that simulates the final process

to be used for production batches. In case of formulations, two of the three batches should be

at least pilot scale and the third one may be smaller. The manufacturing process(es) used for primary batches should simulate that to be applied to production batches and should provide products of the same quality and meeting the same specifications as that intended for marketing. The stability studies for drug substances should be conducted either in the same container - closure system as proposed for storage and distribution or in a container - closure system that

simulates the proposed final packaging. In case of formulations, the stability studies should be

conducted in the final container - closure system proposed for marketing. Stability Testing of new drug substances and formulations:

(i) Study conditions for drug substances and formulations intended to be stored under general conditions

Drugs and Cosmetics Rules, 1945 542 If at any time during 6 months’ testing under the accelerated storage condition, such changes occur that cause the product to fail in complying with the prescribed standards, additional testing under an intermediate storage condition should be conducted and evaluated against significant change criteria.

(ii) Study conditions for drug substances and formulations intended to be stored in a refrigerator Study Study conditions Duration of study

(iii) Study conditions for drug substances and formulations intended to be stored in a freezer Study Study conditions Duration of study Long term - 20°C ± 5°C 12 months
(iv) Drug substances intended for storage below -20°C shall be treated on a case-by-case basis.
(v) Stability testing of the formulation after constitution or dilution, if applicable, should be conducted to provide information for the labelling on the preparation, storage condition, and in-use period of the constituted or diluted product. This testing should be performed on the constituted or diluted product through the proposed in-use period. APPENDIX X CONTENTS OF THE PROPOSED PROTOCOL FOR CONDUCTING CLINICAL TRIALS 1. Title Page

(a) Full title of the clinical study,
(b) Protocol / Study number, and protocol version number with date
(c) The IND name/number of the investigational drug
(d) Complete name and address of the Sponsor and contract research organization if any
(e) List of the Investigators who are conducting the study, their respective institutional affiliations and site locations
(f) Name(s) of clinical laboratories and other departments and/or facilities participating in the study.

2. Table of Contents

A complete Table of Contents including a list of all Appendices.

Drugs and Cosmetics Rules, 1945 543

1. Background and Introduction

(a) Preclinical experience.
(b) Clinical experience. Previous clinical work with the new drug should be reviewed here and a description of how the current protocol extends existing data should be provided. If this is an entirely new indication, how this drug was considered for this should be discussed. Relevant information regarding pharmacological, toxicological and other biological properties of the drug/biologic/medical device, and previous efficacy and safety experience should be described.

2. Study Rationale

This section should describe a brief summary of the background information relevant

to the study design and protocol methodology. The reasons for performing this study in

the particular population included by the protocol should be provided. 3. Study Objective(s) (primary as well as secondray) and their logical relation to the study design.

4. Study Design

(a) Overview of the Study Design: Including a description of the type of study (i.e., double-blind, multicentre, placebo controlled, etc.), a detail of the specific treatment groups and number of study Subjects in each group and investigative site, Subject number assignment, and the type, sequence and duration of study periods.
(b) Flow chart of the study
(c) A brief description of the methods and procedures to be used during the study.
(d) Discussion of Study Design: This discussion details the rationale for the design chosen for this study. 5. Study Population: the number of Subjects required to be enrolled in the study at the investigative site and by all sites along with a brief description of the nature of the Subject population required is also mentioned.

6. Subject Eligibility

(a) Inclusion Criteria
(b) Exclusion Criteria

7. Study Assessments – plan, procedures and methods to be described in detail

8. Study Conduct stating the types of study activities that would be included in this section would be: medical history, type of physical examination, blood or urine testing, electrocardiogram (ECG), diagnostic testing such as pulmonary function tests, symptom measurement, dispensation and retrieval of medication, Subject cohort assignment, adverse event review, etc. Each visit should be described separately as Visit 1, Visit 2, etc. Discontinued Subjects: Describes the circumstances for Subject withdrawal, dropouts, or

other reasons for discontinuation of Subjects . State how dropouts would be managed and if they

would be replaced

Describe the method of handling of protocol waivers, if any. The person(s) who approves all

such waivers should be identified and the criteria used for specific waivers should be provided.

Drugs and Cosmetics Rules, 1945 544 Describes how protocol violations will be treated, including conditions where the study will be terminated for non-compliance with the protocol. 9. Study Treatment

(a) Dosing schedule (dose, frequency, and duration of the experimental treatment) Describe the administration of placebos and/or dummy medications if they are part of the treatment plan. If applicable, concomitant drug(s), their doses, frequency, and duration of concomitant treatment should be stated.
(b) Study drug supplies and administration: A statement about who is going to provide the study medication and that the investigational drug formulation has been manufactured following all regulations Details of the product stability, storage requirements and dispensing requirements should be provided.
(c) Dose modification for study drug toxicity: Rules for changing the dose or stopping the study drug should be provided.
(d) Possible drug interactions.
(e) Concomitant therapy: The drugs that are permitted during the study and the conditions under which they may be used are detailed here. Describe the drugs that a Subject is not allowed to use during parts of or the entire study. If any washout periods for prohibited medications are needed prior to enrolment, these should be described here.
(f) Blinding procedures: A detailed description of the blinding procedure if the study employs a blind on the Investigator and/or the Subject.
(g) Unblinding procedures: If the study is blinded, the circumstances in which unblinding may be done and the mechanism to be used for unblinding should be given. 10. Adverse Events (See Appendix XI): Description of expected adverse events should be given. Procedures used to evaluate an adverse event should be described.

11`. Ethical Considerations: Give the summary of:

(a) Risk/benefit assessment:
(b) Ethics Committee review and communications.
(c) Informed consent process.
(d) Statement of Subject confidentiality including ownership of data and coding procedures. 12. Study Monitoring and Supervision: A description of study monitoring policies and procedures should be provided along with the proposed frequency of site monitoring visits, and

who is expected to perform monitoring.

Case Record Form (CRF) completion requirements, including who gets which copies of the

forms and any specifics required in filling out the forms CRF correction requirements, including

who is authorized to make corrections on the CRF and how queries about study data are handled and how errors, if any, are to be corrected should be stated. Investigator study files, including what needs to be stored following study completion should be described.

13. Investigational Product Management

Drugs and Cosmetics Rules, 1945 545

(a) Give Investigational product description and packaging (stating all Ingredients and the formulation of the investigational drug and any placebos used in the study)
(b) The precise dosing required during the study.
(c) Method of packaging, labelling, and blinding of study substances.
(d) Method of assigning treatments to Subjects and the Subject identification code numbering system.
(e) Storage conditions for study substances.
(f) Investigational product accountability: Describe instructions for the receipt, storage, dispensation, and return of the investigational products to ensure a complete accounting of all investigational products received, dispensed, and returned/destroyed. (g.)Describe policy and procedure for handling unused investigational products.

14. Data Analysis:

Provide details of the statistical approach to be followed including sample size, how the sample size was determined, including assumptions made in making this determination, efficacy endpoints (primary as well as secondary) and safety endpoints. Statistical analysis: Give complete details of how the results will be analyzed and reported along with the description of statistical tests to be used to analyze the primary and secondary endpoints defined above. Describe the level of significance, statistical tests to be

used, and the methods used for missing data; method of evaluation of the data for treatment

failures, non-compliance, and Subject withdrawals; rationale and conditions for any interim analysis if planned. Describe statistical considerations for Pharmacokinetic (PK) analysis, if applicable.

15. Undertaking by the Investigator (see Appendix VII).

16. Appendices: Provide a study synopsis, copies of the informed consent documents (patient information sheet, informed consent form etc.); CRF and other data collection forms; a summary of relevant pre-clinical safety information and any other documents referenced in the clinical protocol.

APPENDIX XI Data Elements for reporting serious adverse events occuring in a clinical trial 1. Patient Details Initials & other relevant identifier (hospital/OPD record number etc.)* Gender Age and/or date of birth Weight Height 2. Suspected Drug(s) Generic name of the drug*. Indication(s) for which suspect drug was prescribed or tested. Dosage form and strength.

Drugs and Cosmetics Rules, 1945 546 Daily dose and regimen (specify units - e.g., mg, ml, mg/kg). Route of administration. Starting date and time of day. Stopping date and time, or duration of treatment 3. Other Treatment(s) Provide the same information for concomitant drugs (including non prescription/OTC drugs) and non-drug therapies, as for the suspected drug(s). 4. Details of Suspected Adverse Drug Reaction(s) Full description of reaction(s) including body site and severity, as well as the criterion (or criteria) for regarding the report as serious. In addition to a description of the reported signs and symptoms, whenever possible, describe a specific diagnosis for the reaction.* Start date (and time) of onset of reaction. Stop date (and time) or duration of reaction. Dechallenge and rechallenge information. Setting (e.g., hospital, out-patient clinic, home, nursing home). 5. Outcome Information on recovery and any sequelae; results of specific tests and/or treatment that may have been conducted. For a fatal outcome, cause of death and a comment on its possible relationship to the suspected reaction; any post-mortem findings. Other information: anything relevant to facilitate assessment of the case, such as medical history including allergy, drug or alcohol abuse; family history; findings from special investigations etc. 6. Details about the Investigator* Name Address Telephone number Profession (speciality) Date of reporting the event to Licensing Authority: Date of reporting the event to Ethics Committee overseeing the site: Signature of the Investigator Note: Information marked * must be provided.”

Drugs and Cosmetics Rules, 1945 547 Records of amendments carried out

Amendment list number and date

Amendments carried out Initial of the person carrying

out the amendments and date