A INTRODUCTION

B. DRAFT RULES FOR DRUG REGISTRATION UNDER FINAL NOTIFICATION

A INTRODUCTION

A drug formulation must be registered under the Drugs and Cosmetics Act, 1940 before import is allowed. However, in actual practice, we have found that import as such is allowed by the customs subject to the condition of registration with the DGHS (Director General Health Services). The drug cannot be used or put on the market unless the registration is obtained under Rule 40 of Drugs and Cosmetics Rules, 1945, a declaration from the Importer that the drugs comply with Chapter III (Import of. Drugs and Cosmetics) of the Rules is adequate. Details are in <DRUG_LICENCE>

The registration procedure is given in the Drugs and Cosmetics Act, 1940 and Drugs and Cosmetics Rules, 1945. Essentially, permission is required from the licensing authority under rule 122A. Permissions at the different stages of putting the drug to the market, including clinical trial is required in prescribed form with prescribed fee.

The rules under the Act are being revamped. The draft amendments giving the new system have been notified and are expected to be implemented in year 2003. The text of the current Act is given below. The material is self explanatory.

B. DRAFT RULES FOR DRUG REGISTRATION UNDER FINAL NOTIFICATION

G.S.R. 321(E) -The following draft of certain rules further to amend the Drugs and Cosmetics Rules, 1945, which the Central Government propose to make, after consultation with the Drugs Technical Advisory Board, in exercise of the powers conferred by sections 12 and 33 of the Drugs and Cosmetics Act, 1940 (23 of 1940), is hereby published as required by the said sections for the information of all persons likely to be affected thereby and notice is hereby given that the said draft rules will be taken into consideration after the expiry of forty five days from the date on which copies of the Official Gazette in which this notification is published are made available to the public;
Objections or suggestions may be addressed to the Secretary, Ministry of Health and Family welfare, Government of India, Nirman Bhavan, New Delhi - 110011.

Any objections suggestions which may be received from any person with respect to the said rules before the expiry of the period so specified will be taken into consideration by the Central Government.
 
DRAFT RULES

1 (I) These rules may be called the Drugs and Cosmetics (Amendment) Rules, 2001.

(ii) They shall be published 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 for 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 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".,

(ii) after the 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 Form 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:

Provided further that where the applicant fulfils the requirements of the grant of permission within six months from the date of such intimation or such extended period, not exceeding a further period of six months, as Licensing Authority is satisfied that the conditions for grant of permission have been complied with, it shall grant the permission in Form 45 and/or 45 A."
 
3. In rule 122B of the said rules,-

  1. 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 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 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 rupees and such information and data as required by Appendix IA of Schedule Y, as the case may be:"

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

"(2A) The Licensing Authority of 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 date provided or generated on the drug is inadequate, intimate applicant in writing, and the conditions which shall be satisfied before permission could be considered;

Provided further that where the applicant fulfils the requirements for the grant of approval 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 the reasons to be recorded, in writing, permit and the Licensing Authority is satisfied that the conditions for grant of approval have been complied with, it shall grant the approval in Form 46 and/or Form 46 A."
 
 

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

" 122D. Permission to import or manufacture fixed dose combination.

(1) 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 does combination, if approved to be imported or manufactured as finished as finished formulation shall be effective and safe for use in the country, shall issue permission in Form 45 or 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 does combination is inadequate, intimate the applicant in writing, and the conditions which shall be satisfied before grant of approval /permission could be considered:

Provided further that where the applicant fulfils the requirements of the grant of approval / permission 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 and the Licensing Authority is satisfied that the conditions for grant of approval / permission have been complied with, it shall grant the approval / permission in Form 45 or Form 46, as the case may be."

122DA.-Application for permission to conduct clinical trials for investigation of New Drug/ Investigation New Drug. - (1) No. clinical trial for a new drug, whether for clinical investigation or any experiment, 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, -

  1. 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;
  2. Exploratory clinical trials (Phase-II) 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;
  3. Confirmatory clinical trials (Phase-III) on a new drug shall be made on the basis of the data emerging from Phase-II and where necessary, data emerging from Phase-I also, and shall be accompanied by a fee of twenty-five thousand rupees;

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

(3) The Licensing Authority after being satisfied with the clinical trials, shall grant permission in Form 45 or Form 45A or Form 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 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;
 

Provided further that where the applicant fulfils the requirements of the grant of permission within six months from the date of such intimation and the Licensing Authority is satisfied that the conditions have been complied with, it shall grant the permission in Form 45 or Form 45A or Form 46 or Form 46A, as the case may be.
 
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 of the permission or approval, the Licensing Authority may after giving an opportunity 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 Form's shall be inserted; namely;-
 
 

FORM-44

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

Application for grant of permission / subsequent permission for import of a new drug and / or clinical trial or for approval / subsequent approval to manufacture a new drug.
 
 

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 giving below;
 
 

  1. Particulars of New Drug applied for
  1. Name of the drug;
  2. Dosage Form;
  3. Composition of the formulation;
  4. Test specification;
    1. active ingredients;
    2. inactive ingredients;
  1. Pharmacological classification of the drug;
  2. Indications for which proposed to be used;
  3. Manufacturer of the raw material (bulk drug substances);
  4. Parent status of the drug;
  1. Date submitted along with the application (as per schedule Y with indexing and page nos.)

A Permission to market new drug:-

    1. Chemical and Pharmaceutical information
    2. Animal Pharmacology
    3. Animal Toxicology
    4. Human/Clinical Pharmacology (Phase 1)
    5. Exploratory Clinical Trials (Phase 2)
    6. Confirmatory Clinical Trials (Phase 3) (including published review articles)
    7. Bio-availability dissolution and stability study Data
    8. Regulatory status in other countries
    9. Marketing information:
    1. Proposed product monograph
    2. Drafts of labels and cartons
    1. Central Drugs Laboratory Test Report
    2. 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 substances) and stability study data.
    4. Center Drugs Laboratory Test Report
  1. Raw material (bulk drug subs

(1)Manufacturing method

(2)Quality control parameters and /or analytical specification, stability repot.

(3)Animal toxicity data

(4)Central Drugs Laboratory Test Report

  1. Approval /Permission for fixed dose Combination:

(1)Therapeutic Justification

(authentic literature in pre-reviewed journals/text books)

(2)Data on pharmacokinetics/ phrmacodynamics combination

(3)Any other data generated by the applicant on the safety and efficacy of the combination.

(4)Regulatory status in other countries.

  1. Subsequent Approval/ Permission requested by an applicant, who already has permission / approval for New Drug / fixed dose combination:

(1)Number and date of approval /permission already granted,

(2)Therapeutic Justification for new claim/modified dosage from.

(3)Data generated of safety and efficacy.

(4)Regulatory status in other countries.

A total fee of rupees--------------------------------------------------------------

(in words).-------------------------------------------) has been credited to the Government under the Head of Account--------------------------------(Photocopy of receipt is enclosed).

  
 
 

Dated-------------- Signature----------------------

Name and designation

Of Licensing Authority------------
 
 

Condition for grant of Approval/ permission

 

(1) The formulation shall conform to the specification 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 then the trade name, if any which shall be shown immediately after or under the proper name of the label of the innermost container of the drug or every other covering in which the container is patched.

(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 1mm width and with out disturbing the other condition 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 in 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 name of the investigator duly approved by the Licensing Authority.

(6) The drug shall be withdrawn from sale from any source if undesirable reactions are reported following its medication. Adverse reaction leading of any infirmity, if reported shall be intimated to the Drugs Controller, India and Licensing Authority.

(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 or any other promotional literature that will be adopted for marketing for the drug in the country, shall be got approved from the Licensing Authority before the drug is marketing.

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

 

FROM 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 substance) under rules 122 A / 122 DA of the Drug 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 approved 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."
 
 

From 46

(See rules 122D and 122D A)

Permission / Approval for manufacture of a 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 122 B / 122D of the Drug and Cosmetics Rules, 1945, namely:-
 
Dated-------------------------------- Signature ------------------------------

Name and designation Licensing Authority.
 
Conditions for Grant of Approval / Permission

  1. The formulation shall conform to the specification 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 of 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 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."

  1. 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.
  2. The drug shall be withdrawn forthwith from sale from any source if undesirable reactions are reported following its medication. Adverse reaction leading to any infirmity, if reported shall be intimated to the Drugs Controller, India and Licensing Authority.
  3. No claims except those mentioned above shall be made for the drug without the prior approval of the Licensing Authority.
  4. Specimen of the carton, labels, package insert or any other promotional literature that will be adopted for marketing the drug in the country shall be got approved from the Licensing Authority before the drug is marketed.

From 46 A

(See rules 122 B and 122 DA)

Number 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 Drugs and Cosmetics Rules, 1945:

Name of the raw material (new bulk drug substance):

  1. ___________________________
  2. ___________________________
  3. ___________________________

Date. Signature

Name and designation of Licensing
 
 

Conditions for Grant of Permission / Approval

  1. The raw material (new bulk drug substance) shall confirm 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.

7. In the Schedule Y, to the said rules,

  1. 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".

"Appendix IA

(See rules 122A and 122B)

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.

  1. Chemical and Pharmaceutical information:
    1. Chemical name, code name or number, if any; non-proprietary or generic name, if any; structure; physico-chemical properties.
    2. Dosage form and its composition.
    3. Test specifications
    1. active ingredients
    2. inactive ingredients.
    1. Tests for identification of the active ingredients and method of its assay.
    2. Outline of the method of manufacture of active ingredients.
    3. Stability data.
  1. Marketing information:
    1. proposed package insert/promotional literature
    2. Draft specimen of the label and carton.
  2. Special studies conducted with approval of Licensing Authority:
    1. Bioavailability /Bioequivalance and comparative Dissolution Studies, for oral dosage forms.
    2. Sub-acute animal toxicity studies for intravenous infusions and injectables".