Import & Registration of drugs in India

Presentation overview

DRUG

All medicines for internal or external use of human or animals and all substances intended to be used for or in the diagnosis, treatment, mitigation (decreasing) or prevention of any disease or disorder in human beings or animals, including preparations applied on human body for the purpose of repelling insects like mosquitoes; and Such substances (other than food ) intended to affect the structure or any function of the human body or intended to be used for the destruction or vermin or insects which cause disease to human beings or animals. All substances intended for use as components of a drug including empty geletin capsules; and Such devices intended for internal or external use in the diagnosis, treatment, mitigation or prevention of disease or disorder in human beings or animals.

LAWS PERTAINING TO IMPORT, MANUFACTURE AND SALE OF DRUGS IN INDIA

HISTORICAL PERSPECTIVE

In Drugs and Cosmetics Act, 1940 century Drug Industry was The the beginning of the current practically non-existent in India The Pharmacy Act, 1948 Pharmaceuticals were being important from abroad. The Drugs and Magic Remedies (Objectionable Advertisement) Act, The first world war changed the situation and not only were 1954 finished and cheap drugs imported in increasing volume, the The Narcotic indigenous Psychotropic Substances Act, 1985 demand for Drugs and products also was voiced from all sides. The Medicinal and was, therefore, called upon Duties) Act, 1956 the The Government Toilet Preparations (Excise to take notice of situation and consider the matter of introducing legislation to The Drugs (Prices Control) Order 1995 (under the Essential control the Import, manufacture, distribution and sale of drugs Commodities Act) and medicines.

Drug Regulatory Structure In India

Main Departments related to Pharma

Drugs Controller General of India ( DCGI ) Dr. Surinder Singh Main duties : New drug approval, Standards of drugs, drugs import, co-ordination with State FDAs

State FDAs Maharashtra FDA commissioner Main duties: Manufacturing, sale and Distribution of drugs

National Pharmaceutical Pricing Authority ( NPPA) Chairman Main Duties: Drug Pricing

Department of Biotechnology - Secretary

Regulatory Bodies


   

Directorate General of Health Services (DGHS) Ministry of Health & Family Welfare Drug Controller General (India) (DCGI) Directorate General of Foreign Trade (DGFT) Indian Council of Medical Research (ICMR) Department of Biotechnology (DBT) Ministry of Environment & Genetic Engineering Approval Committee (GEAC)

Ministry of Chemicals & Fertilizers

Ministry of Health
Health Secretary

Ministry of Sci & Tech

DBT
Department of Biotechnology

Ministry of Enviro
Additional Secretary

NPPA
National Pharmaceutical Pricing Authority

DGHS
Director General of Health Services

GEAC
Genetic Engineering Approval Committee

DCGI
Drug Controller General of India

Pricing Regulations

CDL/CDTL
Gov. Drug Testing Laboratories

Approval of New Drug

State Drug Regulatory Authority

FDA Mfg. Lic. for New Drug after approval

Regulatory Process for Approval of a New Drug in India

Nature of Product
Life Saving Non- Biotech Clinical trial waiver NDA Expert CDL Review Testing specs. CDL waiver possible Biotech Non - Life Saving Non- Biotech Clinical trial IND CDL CT permission testing Data presentation

GEAC clearance

What is a New Drug ?

122 E NEW DRUG DEFINITION

New Drug

(a) a new substance of chemical, biological or biotechnological origin; in bulk or prepared dosage form; used for prevention, diagnosis, or treatment of disease in man or animal; which, except during local clinical trials, has not been used in the country to any significant extent; and which, except during local clinical trials, has not been recognized in the country as effective and safe for the proposed claim; (b) a drug already approved by the licensing authority mentioned in Rule 21 for certain claims, which is now proposed to be marketed with modified or new claims, namely, indications, dosage forms (including sustained release dosage form) and route of administration; (c) a fixed dose combination of two or more drugs, individually approved earlier for certain claims, which are now proposed to be combined for the first time in a fixed ratio, or if the ratio of ingredients in an already marketed combination is proposed to be changed, with certain claims, viz. indications, dosage form (including sustained release dosage form) and route of administration. [See items (b) and (c) of Appendix VI to Schedule Y.]

Exporting Country D I (Plant Master File DI) D II (Drug Master File DII ) Power Of Attorney POA

DCGI

Form 41

Importing Country India Form 40

Application for Site Registration 40 Site Registration Application Form 40 Fees: $ 1500 for site + $ 1000 drug at that site

Exporting Country Form 9

Undertaking to accompany form 8

DCGI

Form 10

Importing Country India Form 8

Application for licence to import drugs Import licence Application Form 8 Form 9
Fees Rs. 1000 (20$)

Schedule Y


Regulation and guidelines for permission to import and / or manufacture of new drugs for sale or to undertake clinical trials It has outlined extensive study criteria in line with the globally accepted formats such as ICH and US FDA guidelines REFER TO RULES 122A, 122B, 122D, 122DA, 122DAA and 122E

Part X-A of D & C Rules, 1945

   

122-A Application for permission to import new drug 122-B Application for approval to manufacture new drug 122-D Permission to import or manufacture FDC 122-DA Permission to conduct clinical trials for New Drug / Investigational New Drug

Schedule Y Highlights
No clinical trial should be conducted without the written permission from licensing authority.


For drugs not approved / marketed in India, permission is granted to initiate study a phase earlier to the phase of trials in other countries. Phase I studies of drug discovered in countries are usually not allowed. Trials in children are usually allowed Phase III in adult is completed. other only after

Schedule Y Highlights


Written Informed Consent must be obtained in prescribed format from every participant. The consent must be signed by patient and Investigator both. Unusual, unexpected or serious ADRs to be communicated to Licensing Authority and to all Investigators. Annual Status Reports to be submitted (Ongoing, at completion / termination)

Regulatory Documents
  

Clinical Trial Application (DCGI) Test License to import study drugs (DCGI) Export License to export biological samples (DGFT with NOC from DCGI)

Clinical Trial Application

Rule 122DA Application for permission to conduct clinical trials for New Drug / Investigational New Drug should be submitted in Form 44. Fees payable in cash:
  

Phase I - Rs. 50,000/Phase II - Rs. 25,000/Phase III - Rs. 25,000/-

Clinical Trial Application



Additional indication / modified dosage form of an approved drug -Rs. 15,000.00. Approval of a drug one year after its first approval - Rs. 15,000.00. Fixed Dose Combination - Rs. 15,000.00. Modifications related to approved trials e.g. additional patients / sites - No additional fees

 

PROCESS
APPLICATION FORM 44 -Imp ff -Imp rm -Mfg ff -Mfg rm -CT

Approval Form 45 (IMP FF) Approval Form 45 A (IMP RM) Approval Form 46 (MFG FF) Application Form 46 A (MFG RM)

NOC FOR CT + Test Licence for Import

FEES
       

Import ff/ Mfg ff/ Import bulk + Mfg ff of new drug Application by same applicant, for modified dosage form or with new claim Secondary applicants after 1 year of approval Import / Mfg FDC Conduct Clinical trial with ND/IND

= Rs 50,000/-

= Rs 15,000/-

= Rs 15,000/-

= Rs 15,000/-

Phase I = Rs 50,000/Phase II = Rs 25,000/Phase III = Rs 25,000/No separate fee to be paid along with application for import / mfg based on successful completion

Application Form 44
FORM 44 (See Rules 122A, 122B, 122D and 122DA) Application for grant of permission to import or manufacture a New Drug or to undertake clinical trial I/We.... of .., hereby apply for grant of permission for import and / or clinical trial or for approval to manufacture of a new drug or fixed dose combination or subsequent permission of already approved new drug. The necessary information / data is given below :  1. Particulars of New Drug :

Name of the drug : Dosage Form : Composition of the formulation : Test specifications :
 

Active ingredients : Inactive ingredients :

Pharmacological classification of the drug : Indications for which proposed to be used : Manufacturer of the raw material : Patent status :

FORM 44 Contd
2. A. 1. 2. 3. 4. 5. 6. 7. 8. 9.

Data submitted along with the application Permission to market new drug Chemical and Pharmaceutical information Animal Pharmacology Animal Toxicology Human / Clinical Pharmacology Exploratory Clinical Trials Confirmatory Clinical Trials Bioavailability / dissolution and stability data Regulatory status in other countries Marketing information :
(a) Proposed product monograph (b) Drafts of labels and cartons

10.

Application for test license :

FORM 44 Contd

Subsequent approval or approval for new indication new dosage form : Number and date of Approval already granted Justification Data on safety, efficacy and quality A total fee of Rs has been credited to the Government under the Head of Account (receipt enclosed) Signature Designation Date

FORM 44 Contd
B. a)

Subsequent approval / permission for manufacture of already approved new drug Formulation :

Bioavailability / bioequivalence Name of the investigator / centre Source of raw mat and stability Manufacturing Method QC parameters, specs, stability Animal toxicity

b)

Raw Material

FORM 44 Contd
D.

Subsequent approval or approval for new indication new dosage form :

   

Number and date of Approval already granted Justification Data on safety, efficacy and quality A total fee of Rs has been credited to the Government under the Head of Account (receipt enclosed) Signature Designation Date

  

FORM 44 Contd
C.

Approval / permission for FDC

Justification Pcokinetic / Pcodynamic data Any other data

  

Important Considerations - 1
 a)

HUMAN CLINICAL PHARMACOLOGY :Phase I (Human Pharmacology) Safety and Tolerability with the initial administration of IND MTD, Kinetics and Dynamics Phase II (Therapeutic Exploratory Trials) Effectiveness for a particular indication, small group Phase III (Therapeutic Confirmatory Trials) Therapeutic benefit in large number of patients Phase IV (Post Marketing Trials) Related to approved indication

b)

c)

d)

IMPORTANT CONSIDERATIONS
 a) b)

c) d) e)

f)

HUMAN CLINICAL PHARMACOLOGY :for new drug substances discovered in India : Trials are required to be carried out in india right from phase 1 and required data needs to be submitted. for new drug substances discovered in countries other than India : Phase I data generated outside India, permission may be granted to repeat phase 1. Application for permission to initiate specific phase of clinical trial should also accompany Investigators brochure, proposed protocol, case record form, study subjects informed consent document(s) investigators undertaking and ethics committee clearance, if available Sample size depends on type of study EC application can be in parallel to DCGI application Drugs indicated in life-threatening, serious disease or diseases of special relevance to Indian health scenario, toxiciological / clinical data abbreviated, deferred or omitted Administrative/Logistic Amendments notified to DCGI and EC within 30 days and approval obtained

Important Considerations - 2
PSUR :New drugs should be closely monitored for their clinical safety; submission of Periodic Safety Update Reports (PSURs) in order to report all the relevant new information (patient exposure)  summarize the market authorization status in different countries and any significant variations related to safety; and  indicate whether changes should be made to product information PSURs shall be submitted every 6 months for the first two years after approval For subsequent two years the PSURs need to be submitted annually PSURs due for a period must be submitted within 30 calendar days of the last day of the reporting period.

IMPORTANT CONSIDERATIONS - 3
BA/BE
i.

For drugs approved elsewhere in the world and absorbed systemically, bioequivalence with the reference formulation should be carried out. Evaluation of the effect of food Dissolution and bioavailability data to be submitted All bioavailability and bioequivalence studies should be conducted according to the Guidelines for Bioavailability and Bioequivalence studies as prescribed (ICMR guidelines)

ii. iii. iv.

TEST LICENCE
Application :  Form 12 application  Material Justification Plan  Treasury Challan of Rs 100 for first drug, followed by Rs 50 for additional drug  Test Licence obtained in FORM 11

CT Application accompanied by
 

Proposal Letter Particulars of New Drug



Name of Drug, dosage form, composition of formulation, Pharmacological classification, proposed indication, patent status and Manufacturer

Chemical and Pharmaceutical Data

CT Application accompanied by


Pre-clinical Data (Animal Pharmacology and Toxicology). Clinical Data (Phase I, II and III studies). Regulatory status in other countries Published Reports

  

CT Application accompanied by
     

Protocol. Investigators Brochure Proposed Sites / Investigators list Investigators Consent Letters EC approvals from sites Application for the Test License in Form 12 with justification.

Test License to Import Drugs

Drugs and Cosmetics Rules 1945
Rule 122 DA Form 11: License to import drugs for the purpose of examination, test or analysis Form 12: Application for License to import drugs for the purpose of examination, test or analysis Test License fees - Rs.15/Validity of Test License - 1 year

Importing Drugs for CT

      

Can be imported by Sponsor / CRO or investigator Application to be made by respective party With DCGI approval for study Justification of quantity to be imported Renewal required if imports required after validity of license expires Customs duty payable IP temp requirements to be followed during shipment

Application to DGFT
Required to export biological samples to a central laboratory outside India.  Proposal letter  Letter from Sponsor appointing the central laboratory  Letter from the Sponsor stating that no genetic testing will be done on biological samples  IEC certificate  CT NOC  POA

Application to DGFT


 

Letter from the central laboratory stating that only protocol specific laboratory tests will be carried out Justification for the quantity of biological specimen to be exported Application package to DGFT & JDGFT (cc) Permission letter issued by DGFT to Sponsor (cc to JDGFT local issues Export license)

Renewal of Export License

 

Export license expires after 1 years To be applied again within 1 years time for renewal, timelines 4 6 weeks Can be renewed twice after fresh application should be made.

Application to DGFT
Appendix 16 - Application form for the grant of Export License - 5 copies. Appendix-2 - Profile of the Exporter
To be submitted once with first application and to be resubmitted in case of any change in the information already submitted

Validity of Export License is one year

Timelines for Regulatory Approvals



DCGI - 12 to 16 weeks DGFT - 4 to 6 weeks after DCGI approval Test-license - 1 week after DCGI approval