A draft of certain rules further to amend the Drugs and Cosmetics Rules, 1945, was published, as required by sections 12 and 33 of the Drugs and Cosmetics Act, 1940 (23 of 1940), at pages 7 to 18.

REGD. NO. D.L.-33004/99 The Gazette of India

EXTRAORDINARY

PART II—Section 3—Sub-section (i)

PUBLISHED BY AUTHORITY'

No. 622] NEW DELHI, WEDNESDAY, DECEMBER 12, 2001/AGRAHAYANA 21, 1923

(1)

3802 GI/20012 THE GAZETTE OF INDIA: EXTRAORDINARY [PART H—SEC. 3(i)1 3 4 THE GAZETTE OF INDIA; EXTRAORDINARY [PAKTII—Syr. 3(i)| 5 6 THE GAZETTE OF INDIA: EXTRAORDINARY [FART II—SEC. 3(i)l 1 8 THE GAZETTE OF INDIA: EXTRAORDINARY [PART II—SEC. 3(i)1 9 3802 GI/2001— 210 THE GAZETTE OF INDIA: EXTRAORDINARY [PART II—SEC. 3(i)] 11 n THE GAZhTIE OF INDIA: EXTRAORDINARY |PARTII—SEC.3(J)] 13

MINISTRY OF HEALTH AND FAMILY WELFARE

(Department of Health)

NOTIFICATION

New Delhi, the 12th December, 2001

^ S.R. 900 (E).—Where as a draft of certain rules further to amend the Drugs and Cosmetics Rules, 1945, was published, as required by sections 12 and 33 of the Drugs and Cosmetics Act, 1940 (23 of 1940), at pages 7 to 18 in Part II, Section 3, Sub- Section (i) of the Gazette ut Indid, Extraouiiiiary, dated the ?nd May, 2001 vidt notification of the Government of India in the Ministry of Health and Family Welfare (Department of Health), number G.S.R. 321 (E), dated the 2nd May, 2001 inviting objections and suggestions from all persons likely to be affected thereby before the expiry of a period of forty-five days from the date on which the copies of the Official Gazette containing the said notification were made available to the public;

And whereas the copies of the said Gazette were made available to the public on 3-5-2001

And whereas objection., or suggestions, received from the public on the said draft rules have been considered by the Central Government.

Now. therefore, in exercise of the powers conferred by sections 12 and 33 of the said Act. the Central Government, after consultation with the Drugs Technical Advisory Board, hereby makes the toll ;WIIHJ rules fuither lo amend the Diugs And Cosmetic- Rules. 1945, namely -

1. (1) These rules may be called the Drugs and Cosmetics

(9th Amendment) Rules, 2001.

(2) They shall come into force on the date of their publication in the Official Gazette.

2 In the Drugs and Cosmetics Rules, 1945 (hereinafter referred to as "the said rules"), in rule 122 A,- (i) for sub-rule (1), the following shall be substituted, namely :-

"(1)(a) No new drug shall be imported, except under, and in accordance with, the permission granted by the Licensing Authority as,defined in clause (b) of rule 21; (b) An application tor grant of permission to import a new drug shall be made in Form 44 to the Licensing Authority, accompanied by a fee of fifty thousand rupees;

Provided further that where a subsequent application by the same applicant for that drug, whether in modified dosage form or with new claims, is made, the fee to accompany such application shall be fifteen thousand rupees:

Provided further that any application received after one year of the grant of approval for the import and sale of new drug, shall be accompanied by a fee of fifteen thousand rupees and such information and data as required by Appendix I or Appendix I A of Schedule Y, as the case may be.";

(h) after sub-rule (2), the following shall be inserted, namely :-

"(3) The Licensing Authority, after being satisfied that the drug if permitted to be imported as raw material (bulk drug substance) or as finished formulation shall be effective and safe for use in the country, may issue an import permission in (orm 45 and/ or Form 45 A, subject to the conditions stated therein :

Provided that the Licensing Authority shall, where the data provided or generated on the drug is inadequate, intimate the applicant in writing, and the conditions, which shall be satisfied before permission, could be considered."

3 In rule 122B of the said rules,-

(i)for sub-rule (1), the following shall be substituted, namely .

"(1)(a) No new drug shall be manufactured for sale unless it is approved by the Licensing Authority as defined in clause (b) of rule 21.

(b) An application for grant of approval to manufacture the new drug and its formulations shall be made in Form 44 to the Licensing Authority as defined in clause (b) of rule 21 and shall be accompanied by a fee of fifty thousand rupees

Provided that where the application is for permission to import a new drug (bulk drug substance) and grant of approval to15 manufacture its formulation/s, the fee to accompany such application shall be fifty thousand rupees only.

Provided further that where a subsequent application by the same applicant for that drug, whether in modified dosage form or with new claims, is made, the fee to accompany such subsequent application shall be fifteen thousand rupees:

Provided further also that any application received after one year of the grant of approval for the manufacture for sale of the new drug, shall be accompanied by a fee of fifteen thousand rupees and such information and data as required by Appendix I or Appendix I A of Schedule Y, as the case may be.";

(ii) after sub-rule (2), the following shall be inserted, namely :-

"(2A) The Licensing Authority as defined in clause (b) of rule 21 after being satisfied that the drug if approved to be manufactured as raw material (bulk drug substance) or as finished formulation shall be effective and safe for use in the country, shall issue approval in Form 46 and/or Form 46A, as the case may be, subject to the conditions stated therein :

Provided that the Licensing Authority shall, where the data provided or generated on the drug is inadequate, intimate the applicant in writing, and the conditions, which shall be satisfied before permission could be considered.".

4 Rule 122C of the said rules shall be omitted.

5. For rule 122D of the said rules, the following shall be substituted, namely:-

"122D. Permission to import or manufacture fixed dose combination'-(i) An application for permission to import or manufacture fixed dose combination of two or more drugs as defined in clause ( c) of rule 122 E shall be made to the Licensing Authority as defined in clause (b) of rule 21 in Form 44, accompanied by a fee of fifteen thousand rupees and shall be accompanied by such information and data as is required in Appendix VI of Schedule Y.

(2) The Licensing Authority after being satisfied that the fixed dose combination, if appioved to be impoited or manufactured as finished formulation shall bv effective and safe for use in the country, shall issue permission in Form 45 oi Form 46, as the case may be, subject to the conditions stated therein :

Provided that the Licensing Authority shall where the data provided or generated on the fixed dose combination is inadequate, intimate the applicant in writing, and the conditions which shall be satisfied before grant of approval / permission could be considered:

122DA.-Application for permission to conduct clinical trials for New Drug/ Investigational New Drug.- (1) No clinical trial for a new drug, whether for clinical investigation or any clinical experiment by any Institution, shall be conducted except under, and in accordance with, the permission, in writing, of the Licensing Authority defined in clause (b) of rule 21 (2) An application for grant of permission to conduct,-

(a) human clinical trials (Phase-I) on a new drug shall be made to the Licensing Authority in Form 44 accompanied by a fee of fifty thousand rupees and such information and data, as required under Schedule Y; (b) exploratory clinical trials (Phase-ll) on a new drug shall be made on the basis of data emerging from Phase-I trial, accompanied by a fee of twenty- five thousand rupees; (c) confirmatory clinical trials (Phase-Ill) on a new drug shall be made on the basis of the data emerging from Phase-ll and where necessary, data emerging from Phase-I also, and shall be accompanied by a fee of twenty-five thousand rupees:

Provided that no separate fee shall be required to be paid along with application for import/manufacture of a new drug based on successful completion of phases clinical trials by the applicant.

Provided further that no fee shall be required to be paid alongwith the application by Central Government or State Government Institutes involved in clinical research for conducting trials for academic or research purposes

(3) The Licensing Authority after being satisfied with the clinical trials, shall grant permission in Form 45 or Form 45A or Form 46 or From 46-A, as the case may be, subject to the conditions stated therein;

Provided that the Licensing Authority shall, where the data provided on the clinical trials is inadequate, intimate the applicant in writing, within six months, from the date of such intimation or such extended period, not exceeding a further period of six months, as the Licensing Authority may, for reasons to be recorded, in writing, permit, intimating the conditions which shall be satisfied before permission could be considered:

Explanation- For the purpose of these rules Investigational New Drug means a new chemical entity or a product having therapeutic indication but which have never been earlier tested on human being.

122DB. Suspension or cancellation of Permission / Approval. - If the importer or manufacturer under this Part fails to comply with any of the conditions of the permission or approval, the Licensing Authority may, after giving an opportunity17 to show cause why such an order should not be passed, by an order in writing stating the reasons therefor, suspend or cancel it.

122DC. Appeal.- Any person aggrieved by an order passed by the Licensing Authority under this Part, may within sixty days from the date of such order, appeal to the Central Government, and the Central Government may after such enquiry into the matter as is considered necessary, may pass such order in relation thereto as it thinks fit."

⁶- In Schedule A of the said rules, after Form 43, the following Forms shall be inserted; namely:-

'FORM 44 . (See rules 122 A.122 B.122 D and 122 DA)

Application for grant of permission to import or manufacture a New Drug or to undertake clinical trial.

'/we.

_ ofM/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 . (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 nos ) 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) 3802 GI/2001—318 THE GAZETTE OF INDIA: EXTRAORDINARY |PARTI1—SI-T. 3(I)] (7) Bio-availability, dissolution and stability study Data (8) Regulatory status in other countries (9) Marketing information:

(a) Prop'osed product monograph (b) Drafts of labels and cartons

(10) Application for test license

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 suhstances)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.

A total fee of rupees

(in w o r d s ) ._ _____________________ ) has been credited to the Government under the Head of Account _ _ „ _ _ _ _ _ __ _ _ _ _ _ __ ^(Photocopy of receipt is enclosed) Dated _____ Signature _ _ _ _ _ _ _ _ _ _ _ _ _ __

Designation

Note- Delete, whichever is not applicable.

FORM 45

(See rules 122 A, 122 D and 122 DA )

Permission to import Finished Formulation of a New Drug

Number of the permission and date of issue

of M/s . (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 is 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.

(9) Each consignment of imported drug shall be accompanied by a test/analysis report.

FORM 45 A (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) : (D. __ (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."21 FORM 46 (See rules 122 B, 122 D and 122 DA ) Permission /Approval for manufacture of a new drug foimulation Number of permission and date of issue

M/s. _ _ ^ _ _ ^ _ _ _ _ _ _ _ ^ _ _ _M_ _ _ _ ^ _ _ _ ^ __ of _ _ _ _ _ ^ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ ^ _ _ _ ^ _ __ _ _„ __(address) is hereby granted Permission /Approval to manufacture following new drug formulation under rule 122 B / 122 D / 122 DA of the Drugs and Cosmetics Rules, 1945, namely:- (1) Name of the formulation : (2) Dosage form: (3) Composition: (4) Indications:

Dated

Signatuie Name and designation of Licensing Authority.

Conditions for Grant of Approval / Permission

(1) The formulation shall confoim 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 is 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 reaction 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.

FORM 46 A

(See rules 122 Band 122 DA)

Numbei of the permission / approval and date of issue_

Permission /Approval for manufacture of raw material (new bulk drug substance) 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 Druys and Cosmetics Rules, 1945:

Name of the raw mateiidl (new bulk diuy substance):

(1) ___________ _ _ _ _ _ _ __

(2)

(3). __ ._. ,

Dated

Signature

Name and designation of Licensing

Authority

Conditions lui Grant of Permission / Approval

(1) The raw material (new bulk drug substance) shall confirm to the specifications appioved by the Licensing. Authoiity.

(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.'.

7. In Schedule Y to the said rules,

(a) after item 11 relating to the marketing information , the following shall be inserted, namely :-

"12. Post-marketing surveillance study ,_

On approval of a new drug, the importer or the manufacturer shall conduct post-marketing surveillance study of that new drug after getting the protocols and the names of the investigators approved by the Licensing Authority as defined under clause (b) of rule 21 during the initial period of two years of marketing.";

(b) after Appendix I, the following shall be inserted, namely:-

"Appendix I A

(See rules 122 A and 122 B)

Data required to be submitted by an applicant for grant of permission to import / manufacture an already approved new drug

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.

2.2 Dosage form and its composition.

2.3 Test specifications

(a) active ingredients.

(b) inactive ingredients.

2.4 Tests for identification of the active ingredients and method of its assay.

2.5 Outline of the method of manufacture of active ingredients.

2.6 Stability data,

3. Marketing information-

3.1 Proposed package insert/promotional literature

3.2 Draft specimen of the label and carton.

4. Special studies conducted with approval of Licensing Authority:

4.1 Bioavailability /Bioequivalance and comparative Dissolution Studies, for oral dosage forms

4.2 Sub-acute animal toxicity studies for intravenous infusions and

injectabies.".

[No. X-11014/7/2000-DMS & PFA]

DEEPAK GUPTA, Jt. Secy.

Footnote : The Drugs and Cosmetics Rules, 1945, as amended upto the 1st May, 1979 are contained in the publication of the Ministry of Health and Family Welfare (Department of Health) containing the Drugs and Cosmetics Act, 1940 and the Rules (PDGHS-61) and last amended vide G.S.R. 700(E) dated the 28-9-2001.

Printed bv Hie Manager, Govt, of India Press, Ring Rood. Mayapuri. New Delhi-110064 and Published by the Controller of Publications, Delhi-110054.