DMF CEP

1. M. Radhika Choudhary Regulatory Affairs Associate A Brief Introduction to DMF and CEP

2. CTD Format for submission for INDs and marketing applications like NDA, ANDA, BLA, etc. Introduction to CTD 3.1 Table of Contents 3.2 Body of Data 3.2.S Drug Substance 3.2.P Drug Product 3.2.A Appendices 3.2.R Regional Information 3.3 Literature References MODULE-3 (DRUG SUBSTANCE PART) 3.2. S.1 General Information 3.2. S.2 Manufacture 3.2. S.3 Characterization 3.2. S.4 Control of Drug Substance 3.2. S.5 Reference Standards or Materials 3.2. S.6 Container Closure Systems 3.2. S.7 Stability

3. Filings in FDA (Substance part)

4. DMF DMF

5. Nature of Drug Substance, Drug Product. Manufacturing process is shown to be in control Manner in which they are made DMF (Drug Master File)` A Drug Master File (DMF) is a submission to the FDA of information , usually concerning the confidential detailed information about Chemistry, Manufacturing and Controls (CMC) of the component of a drug Product . Used as support for various applications. C M C ? Who must file a DMF….? NOBODY .

6. Types of DMFs Originally Five Types … for US Market Plant information (Withdrawn) Drug substance, intermediates and material used in their manufacturing. Packaging Excipients . Other information which is generally not covered by type I to type IV drug master files. ( Usually clinical, toxicity data are covered)

7. How the System Works ? Holder sends the DMF to Central Document Room Center for Drug Evaluation and Research 5901-B Ammendale Road Beltsville, MD 20705-1266 Containing: 1 – Transmittal (cover) letter 2 – Administrative information 3 – Technical information NEW ADDRESS Submissions of Drug Master File

8. DMF is reviewed for administrative purposes ONLY by Central Document Room (CDR) staff. Entered into DMF DATABASE, As signed a number , and a letter is sent to the HOLDER . If the DMF Holder does not receive any response from FDA HOLDER can put a query on the e-mail : [email protected]

9. • Number given to DMF in database and Type . • Reminder of obligations (responsibilities) of 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) for each item referenced. Letter sent by FDA to DMF HOLDER consists of.. .

10. Letter of Authorization (LOA) The DMF will be reviewed ONLY when it is referenced in an Application or another DMF. DMF HOLDER US FDA Send a letter to remind holder obligations Send 2 copies of LOA to the FDA 1 copy of LOA to the APPLICANT The applicant submits THIS copy of LOA in their Application.

11. Letter of Authorization (LOA) DMF HOLDER 1 copy of LOA to the APPLICANT The applicant submits THIS copy of LOA in their Application. LOA to the FDA Key points - LOA Sending LOA is the only mechanism which triggers the review procedure of DMF. If the holder cross references its own DMF, the holder should supply following information in the LOA. DMF number Specific product(s) covered by the DMF Section numbers and/or page numbers to be referenced [ Authorization to refer to a DMF ]

12. Sample LOA

13. Review of the DMF REVIEWER When reviewer receives an application (IND/NDA/ANDA) with an LOA that references a DMF Requests the DMF from the CDR (central document room) but Delivery of DMF can take a couple of days. This review procedure of DMF is in Contrast with APPLICATION , where document is delivered automatically to reviewer. Next slide

14. After getting DMF,the Reviewer starts the review procedure If Reviewer found any deficiency in the content of DMF The DETAILED DEFICIENCIES are communicated to the holder The APPLICANT is also notified but, the nature of the deficiencies is not communicated to the applicant If no deficiencies, no letter, applicant not notified. HOLDER should submit the REQUESTED INFORMATION to the DMF in response to the agency's deficiency letter along with transmittal letter having subject matter .

15. DMF - Annual Update The holder should provide an annual report on the anniversary date of the original submission. If the subject matter of the DMF is unchanged , the DMF holder should provide a statement that the subject matter of the DMF is current . Failure to update can cause delays in FDA review of a pending IND, NDA, ANDA or any amendment or supplement to such application .

16. Retiring DMFs If a DMF has no activity (amendment or annual report) in three years FDA will initiate R etirement Procedure . FDA sends overdue notice letter (ONL) to holder and/or agent using most recent address. If no response in 90 days , one copy of DMF is sent to Federal Records Center (FRC) and the other is destroyed . (Note : LOA is not counted for activity)

17. PARTS OF DRUG MASTER FILE APPLICANT’S PART RESTRICTED PART 2 PARTS OPEN PART CLOSED PART What neXt ?... Information in the Drug Master File …

18. APPLICANT’S PART OF DMF OPEN PART ( AVAILABLE TO APPLICANT ) ACTIVE SUBSTANCE MANUFACTURER SUPPLIES INFORMATION TO THE APPLICANT THE INFORMATION INCLUDES: outline of the manufacturing method impurities originating from the manufacturing method, isolation procedure and degradation information on the toxicity of specific impurities

19. THE INFORMATION INCLUDES: Detailed information about… Individual steps of the manufacturing method such as Reaction conditions, temperature, Validation and evaluation data for certain critical steps of the manufacturing method , etc . (Such information is supplied to the authorities only) RESTRICTED PART OF DMF CLOSED PART ( NOT AVAILABLE TO APPLICANT )

20. Filings in EMA (Substance part)

21. CEP ASMF

22. ASMF (Active Substance Master File) Sometimes called as EDMF (European Drug Master File) This is generally used for Non-Pharmacopoeial substances in Europe. In Europe, the permission to reference an ASMF is called Letter of Access.

23. CEP (Certificate of Suitability) Role To demonstrate that the purity of the given API is suitably controlled by the relevant monographs of European Pharmacopoeia. Advantages Full confidentiality of the submitted data. Centralised evaluation by EDQM (European Directorate for the Quality of Medicines & HealthCare). Easing management of applications for MAA in Eu-countries. prevents duplication of assessment by the individual national authorities. -Issued by EDQM It’s a Separate registration process for an API with EMA

24. CEP (Certificate of Suitability) Scope of the procedure Substances covered by a specific Ph. Eur. Monographs : Active, excipients , herbal drugs/herbal preparations TSE risk products (starting materials, intermediates, reagents,…) Not applicable for biotechnological products, products from human tissues, semi-finished or finished products, substances not included in Ph. Eur. -Issued by EDQM It’s a Separate registration process for an API with EMA

25. How does the process of Evaluation by EDQM work Flow? DMF - Application Certification Division of the EDQM Validated and listed for assessment EDQM may send queries to the applicant When the queries have been resolved  EDQM sends the applicant the CEP Inspection program for manufacturing sites covered by a certificate (CEP) Checks compliance with current Good Manufacturing Practices (GMP) and the CEP application dossier

26. A CEP looks like this 

27. (www.edqm.eu) https :// extranet.edqm.eu/publications/recherches_CEP.shtml Is my CEP valid?

28. Thank you for your attentive listening!  Thank you for your attentive listening! Hope Our Paths will Cross Again!