1. Dr. Raghuveer Pharma Consultants D R P C Quality. Perfection. Confidentiality. D R P C Quality. Perfection. Confidentiality. 1

2. Summary of Presentation  Introduction on DMF  US Procedures  EU procedures D R P C Quality. Perfection. Confidentiality. D R P C Quality. Perfection. Confidentiality. 2

3. DRUG MASTER FILES- INTRODUCTION 1  DEFINITION- A Drug Master File (DMF) is a submission to the Regulatory Agencies of information, usually concerning the Chemistry, Manufacturing and Controls (CMC) of a drug product or a component of a drug product, to permit the Agency to review this information in support of a third party’s submission. D R P C Quality. Perfection. Confidentiality. D R P C Quality. Perfection. Confidentiality. 3

4. DRUG MASTER FILES- INTRODUCTION 2 Regulatory agencies and DMF  US- FDA - Originally Five types were accepted I Plant Information II Drug substance, drug product, intermediates and material used in their manufacture III Packaging IV Excipients V Other Usually clinical, toxicity data  Currently only Four types are handled (Numbering retained to avoid confusion)  EU - EMEA accepts EDMF- Currently named as ASMF (Active Substance Master File) No procedure for Packaging /Excipients D R P C Quality. Perfection. Confidentiality. D R P C Quality. Perfection. Confidentiality. 4

5. DRUG MASTER FILES- INTRODUCTION 3  Terminology 1. DMF Holder - The person or company who submits a DMF 2. AGENT - The person/company who represents a DMF HOLDER Agents for DMFs Not required, although recommended to facilitate communication for foreign company 3.APPLICANT -The person/company who references the DMF 4.DMF can be submitted in support of a.Investigational New Drug Application (IND), a. New Drug Application (NDA), b. Abbreviated New Drug Application (ANDA) c. Supplement or Amendment to a NDA /ANDA(A report of a change in an approved NDA /ANDA D R P C Quality. Perfection. Confidentiality. D R P C Quality. Perfection. Confidentiality. 5

6. DRUG MASTER FILES- INTRODUCTION 4  For a Common understanding, We will use the terminology as DMF and proceed US Type II DMF for Drug Substance - Equivalent to EU ASMF / EDMF D R P C Quality. Perfection. Confidentiality. D R P C Quality. Perfection. Confidentiality. 6

7. DRUG MASTER FILES- INTRODUCTION  Requirements for a DMF There is no legal or regulatory requirement to file a DMF A DMF may be filed to provide CMC information that the FDA reviews. Example: novel excipient Normally the CMC for a compendial excipient is not reviewed Many drug substance for OTCs (not NDA) not reviewed However if a drug substances used in non-NDA OTC products are also used in NDA OTC products. DMFs for these are reviewed. A DMF may be submitted for information that is normally reviewed as part of the CMC review.  Reasons for a DMF Maintain confidentiality of proprietary information (e.g., Manufacturing procedure) for the holder Permit review of information referenced by a number of applicants D R P C Quality. Perfection. Confidentiality. D R P C Quality. Perfection. Confidentiality. 7

8. DRUG MASTER FILES- US Address  Address (US) Holder sends the DMF (NO FEE,two copies) to Central Document Room Center for Drug Evaluation and Research 5901-B Ammendale Road Beltsville, MD 20705-1266 E-mail: dmfquestion@cder.fda.govdmfquestion@cder.fda.gov D R P C Quality. Perfection. Confidentiality. D R P C Quality. Perfection. Confidentiality. 8

9. DRUG MASTER FILES- How it works  Contents: – Transmittal (cover) letter – Administrative information – Technical information  Process: – DMF reviewed for administrative purposes ONLY, entered into - DMF database, assigned a number and acknowledgement letter sent 9

10. DRUG MASTER FILES- US Review Procedure When the reviewer receives an application that references a DMF, the reviewer requests the DMF from the CDR.  If there are deficiencies the detailed deficiencies are communicated to the holder  The APPLICANT is notified that deficiencies exist, by an IR or AE or NA letter. The nature of the deficiencies is not communicated to the applicant.  If no deficiencies, no letter, applicant not notified. (IR= Information Request, AE = Approvable, NA = Not Approvable ) D R P C Quality. Perfection. Confidentiality. D R P C Quality. Perfection. Confidentiality. 10

11. DRUG MASTER FILES- US Obligations of Holder & Applicant  HOLDER – Submit all changes as amendments – Notify FDA of change in holder name or address – Notify FDA of change in agent/representative – SUBMIT ANNUAL UPDATE (Annual Report) – Submit Letter of Authorization (LOA) - [Letter of Access in EU] for each item referenced for each customer – Notify authorized parties of changes  APPLICANT – The holder MUST submit an LOA (2 copies) to the DMF and send a copy to the APPLICANT – The applicant submits copy of LOA in their Application.  LOA to contain a Specific reference to a particular item in the DMF, by its code name, page number and most importantly DATE OF THE SUBMISSION on the cover letter D R P C Quality. Perfection. Confidentiality. D R P C Quality. Perfection. Confidentiality. 11

12. DRUG MASTER FILES- US Retiring DMFs  If a DMF has had no activity (amendment or annual report) in three years FDA will initiate retirement procedure Note: LOA does not count for activity  FDA sends overdue notice to holder and/or agent using most recent address. Highlights the importance of keeping holder/agent name and address up-to- date.  If no response is received in 90 days, one copy of DMF is sent to Federal Records Center (FRC) and the other are destroyed. Response: Close DMF or submit annual update to keep it open. D R P C Quality. Perfection. Confidentiality. D R P C Quality. Perfection. Confidentiality. 12

13. DRUG MASTER FILES- Electronic Filing of DMFs and CTD-Q  Regulatory agencies and DMF  CTD-Q not required for paper DMFs, although acceptable  Electronic DMFs may be filed as part of a pilot program http://www.fda.gov/cder/regulatory/ersr/eCTD.htm  Changes in DMF System -  Over the past decade, there have been some changes in the DMF system to help make it work better. D R P C Quality. Perfection. Confidentiality. D R P C Quality. Perfection. Confidentiality. 13

14. DRUG MASTER FILES- EU Procedures The Scenario & Procedure is by and large the same DMF Handled by 2 agencies 1.European Medicine Evaluation agency (EMEA) 7,WestferryCircus,CanaryWharf,LondonE144HB,UnitedKingdom www.emea.eu.int/ www.emea.eu.int/ ASMF - for Drug substance] in support of a Marketing eDMF - Drug product ] Authorisation Application Certification of Medicinal Product – for export 2.European Directorate for Quality Medicines (EDQM) 7 allée Kastner, CS 30026, F - 67081 Strasbourg, FRANCE. E-mail: cep@edqm.eucep@edqm.eu Certificate of Suitability (CEP) - for Drug Substance D R P C Quality. Perfection. Confidentiality. D R P C Quality. Perfection. Confidentiality. 14

15. DRUG MASTER FILES- EU Procedures(Contd.)  ASMF - for Drug substance/eDMF - Drug product Details are to be given in 2 parts 1. Applicants Part (AP) or OPEN PART 2. Restricted Part (RP) or CLOSED PART (AP is also Confidential data- Not to be disclosed by the applicant without written permission of the DMF Holder)  ASMF to contain: 1. A Covering Letter 2. Letter of Access 3. Quality Overall Summary (QOS): Separate summary - for the AP and the RP. Detailed Scientific Information as per 3.2.S Section of CTD. A written assurance that there is a formal agreement between the ASM and the Applicant D R P C Quality. Perfection. Confidentiality. D R P C Quality. Perfection. Confidentiality. 15

16. DRUG MASTER FILES- Summary  Structure / Formats used EU procedure recommends the use of appropriate CTD structure (Module -3) US procedure does not mandate the use of CTD structure, given a different list in the Guideline document,but accepts both.  Electronic submission EDQM accepts Electronic submission EMEA has not given specific detail USFDA has not given specific detail (Though both EMEA & USFDA have mentioned as accepting them) Changing of the system by the Agencies in line with CTD and CTD is expected D R P C Quality. Perfection. Confidentiality. D R P C Quality. Perfection. Confidentiality. 16

17. DRUG MASTER FILES- EU Procedures(Contd.) Similarly  eDMF - Drug product to contain: A Covering Letter Letter of Access Quality Overall Summary (QOS) Detailed Scientific Information as per 3.2.P Section of CTD. Submission ASMF  One copy of the complete ASMF, comprising the 2 parts (applicant's part and ASM's restricted part) should be sent by the ASM directly to each of the competent authorities concerned.  A copy of the applicant's part should be supplied in advance by the ASM to the applicant. This applicant's part should be included in the application for marketing authorisation. EDMF  One copy of the complete EDMF,directly to each of the competent authorities concerned.  Details Provided by ASM MFR to be included D R P C Quality. Perfection. Confidentiality. D R P C Quality. Perfection. Confidentiality. 17

18. DRUG MASTER FILES- EU Procedures(Contd.)  EDQM- Certificate of Suitability (CEP) - for Drug Substance Has a validity of 5 years CEP is Accepted equivalent to ASMF in any of the Marketing Authorisation Application (MAA) reviews In cases where the CEP contains too little information (e.g. stability) the Competent Authorities/EMEA may decide that additional information should be provided in the dossier. In such case the MAA to refer both to an ASMF and a CEP.  CEP Application to contain: - Cover Letter - Application Form (form ECEP/03) and Fee Form - A single copy of a dossier, and - A single copy of the Quality Overall Summary (QOS)  EDQM Assesses the CEP application, Communicate for Querries if any and issues a Certificate of Suitability CEP D R P C Quality. Perfection. Confidentiality. D R P C Quality. Perfection. Confidentiality. 18

19. DRUG MASTER FILES- Summary DRPC can  Provide services in organizing an application for all the above  Structure the documents in line with CTD so that you are ready for the changes to come in future D R P C Quality. Perfection. Confidentiality. D R P C Quality. Perfection. Confidentiality. 19

20. DRUG MASTER FILES Thank you for your time and patience D R P C Quality. Perfection. Confidentiality. D R P C Quality. Perfection. Confidentiality. 20