1. DMF Procedures and Communication between API, FFP Manufacturers and Regulatory Authorities Jean-Louis ROBERT National Health Laboratory L – 1011 LUXEMBOURG CHMP co-opted member Chair CHMP/CVMP QWP Hyderabad, September 7, 2009

2. 2 Overview of topics addressed References References EU ASMF: principle EU ASMF: principle Content of the guideline Content of the guideline How to use How to use General considerations General considerations Recommendations Recommendations Conclusion Conclusion

3. 3 References Directives 2001/83 EC as amended Directives 2001/83 EC as amended Guidelines: Guidelines: Active Substance Master File Procedure (ASMF) Active Substance Master File Procedure (ASMF) Summary of Requirements for Active Substances in the Quality Part of the dossier Summary of Requirements for Active Substances in the Quality Part of the dossier Various guidelines in relation to the Active Substance Various guidelines in relation to the Active Substance Active Substance Master File (ASMF)/European Drug Master File (EDMF): synonymous Active Substance Master File (ASMF)/European Drug Master File (EDMF): synonymous See EMEA website: www.emea.europa.eu

4. 4 Structure ASMF Module 3.2.S S1 General Information S1 General Information S2 Manufacture S2 Manufacture S3 Characterisation S3 Characterisation S4 Control of Drug Substance S4 Control of Drug Substance S5 Reference Materials S5 Reference Materials S6 Container Closure System S6 Container Closure System S7 Stability S7 Stability

5. 5 ASMF Guideline - Structure Introduction Introduction Content of the active substance master file Content of the active substance master file Use of the ASMF procedure Use of the ASMF procedure Content of the MA dossier when the ASMF procedure is used Content of the MA dossier when the ASMF procedure is used Changes and updates to the ASMF Changes and updates to the ASMF Annex 1: Annex 1: Overview EDMF contents Overview EDMF contents Annex 2: Annex 2: Template letter of access Template letter of access Annex 3: Annex 3: Part of covering letter Part of covering letter Annex 4: Annex 4: List of abbreviations List of abbreviations

6. 6 Within Scope New active substances New active substances Existing active substances (pharmacopoeial/non pharmacopoeial) Existing active substances (pharmacopoeial/non pharmacopoeial) Pharmacopoeial active substances Pharmacopoeial active substances Herbals Herbals

7. 7 Out of Scope Biological Active Substances Biological Active Substances Excipients including novel excipients Excipients including novel excipients AS mixed with an excipient unless necessary for the stability of the active substance e.g. nitroglycerin AS mixed with an excipient unless necessary for the stability of the active substance e.g. nitroglycerin Plastic materials Plastic materials

8. 8 EU ASMF: Principle Marketing Authorisation Holder (MAH): Marketing Authorisation Holder (MAH): Full responsibility for the medicinal product and the quality and quality control of the active substance Active Substance Manufacturer (ASM): Active Substance Manufacturer (ASM): Allowance of valuable confidential intellectual property of know how to be protected Applicants Part (AP) Applicants Part (AP) Restricted Part (RP) Restricted Part (RP)

9. 9 Restricted (confidential) Part Manufacture Manufacture Detailed description Detailed description Control of Materials Control of Materials Control of critical steps and intermediates Control of critical steps and intermediates Process Validation Process Validation Manufacturing Process Development Manufacturing Process Development Impurities: for those impurities which do not need to be controlled in the final active substance and which are related to detailed description of the manufacturing process. Impurities: for those impurities which do not need to be controlled in the final active substance and which are related to detailed description of the manufacturing process. Justification of specification: for information related to detailed description of manufacturing process, control of materials and process validation. Justification of specification: for information related to detailed description of manufacturing process, control of materials and process validation.

10. 10 Restricted (confidential) Part (2) Exceptions Exceptions Validation data of sterilisation process may be required in Applicant’s part when no further sterilisation process of the final product Validation data of sterilisation process may be required in Applicant’s part when no further sterilisation process of the final product

11. 11 Procedure - Use ASMF can only be submitted in relation with a MA ASMF can only be submitted in relation with a MA Can also be used when no confidentiality issue between MAH and ASM Can also be used when no confidentiality issue between MAH and ASM MAA: either CEP or ASM should be submitted MAA: either CEP or ASM should be submitted Additional information might be requested from the Applicant by the Authorities in addition to the ASMF: e.g. particle size (when not present in a ASMF) Additional information might be requested from the Applicant by the Authorities in addition to the ASMF: e.g. particle size (when not present in a ASMF)

12. 12 Procedure – Use (2) ASMF holders → Applicant/MA Holder ASMF holders → Applicant/MA Holder Copy of latest version of the AP Copy of latest version of the AP Copy of QOS (latest version of AP) Copy of QOS (latest version of AP) Letter of access: Letter of access: Permission of ASMF holder to competent Authorities to access the data in the ASMF in relation to a specific access the data in the ASMF in relation to a specific application (Annex). application (Annex).

13. 13 Procedure – Use (3) ASMF holder → Competent Authorities ASMF holder → Competent Authorities The ASMF (applicant + restricted part) either once or for each MA (depends on national requirements) The ASMF (applicant + restricted part) either once or for each MA (depends on national requirements) Letter of access Letter of access Discussion between ASMs and competent authorities/ EMEA related to ASMF “legally” not possible however ……….. Discussion between ASMs and competent authorities/ EMEA related to ASMF “legally” not possible however ………..

14. 14 General considerations (1) Responsibility of ASMF holder: Responsibility of ASMF holder: One identical ASMF in EU for same API (for different applications in different member states) One identical ASMF in EU for same API (for different applications in different member states) Version number AP MP dossier should be most recent and identical to version number AP ASMF: responsibility of the applicant Version number AP MP dossier should be most recent and identical to version number AP ASMF: responsibility of the applicant Request for harmonisation requested by member states possible Request for harmonisation requested by member states possible Update of ASMF Update of ASMF Responsibility of ASMF holder Responsibility of ASMF holder Information to applicant and competent authority Information to applicant and competent authority Full supplier chain described in finished product file Full supplier chain described in finished product file

15. 15 General considerations (2) The quality control methods should be kept in line with the current regulatory and scientific requirements The quality control methods should be kept in line with the current regulatory and scientific requirements Compliance with GMP Compliance with GMP Responsibility of Manufacturing Authorisation Holder (finished product) Responsibility of Manufacturing Authorisation Holder (finished product) MAH can use different QC methods MAH can use different QC methods full description needed in application file full description needed in application file In case of more than one supplier, there should be one single compiled specification for each supplier: responsibility MAH In case of more than one supplier, there should be one single compiled specification for each supplier: responsibility MAH

16. 16 General considerations (3) MA holder legally bears full responsibility MP on the market MA holder legally bears full responsibility MP on the market MA holder also responsible for the active substance MA holder also responsible for the active substance MA holder cannot share this responsibility with ASMF MA holder cannot share this responsibility with ASMF MA holder responsible that active substance from any source is continuously manufactured and controlled in conformity with MPD MA holder responsible that active substance from any source is continuously manufactured and controlled in conformity with MPD Thus variations to ASMF can legally only be initiated by MA holder Thus variations to ASMF can legally only be initiated by MA holder Thus ASMs should continuously inform MA holders of any changes Thus ASMs should continuously inform MA holders of any changes New Variation Regulation in EU: Classification guideline not yet definitively adopted by EU Commission New Variation Regulation in EU: Classification guideline not yet definitively adopted by EU Commission ASMF holders should precisely know with MA holders are linked to their ASMFs! ASMF holders should precisely know with MA holders are linked to their ASMFs!

17. 17 Recommendation to API industry Keep the information the same for all MA-holders Keep the information the same for all MA-holders Keep a clear administration of MA holders/countries connected to a certain ASMF Keep a clear administration of MA holders/countries connected to a certain ASMF Inform MA-holders and authorities in case of variations directly Inform MA-holders and authorities in case of variations directly “As for medicinal products, EDMF holders should keep the content of their EDMFs updated with respect to the actual synthesis/manufacturing process” “As for medicinal products, EDMF holders should keep the content of their EDMFs updated with respect to the actual synthesis/manufacturing process”

18. 18 Structure MPD with linked ASMFs Module 1 regional administrative Module 2 QOS/summaries Module 3 quality Module 4 non-clinical Module 5 clinical 3.1 table of content 3.2 body of data 3.3 literature references 3.2.S substance 3.2.P drug product 3.2.A appendices 3.2.R regional information name ASMs MA holders specifications, methods & validation MA holders batch analyses if relevant reference to ASMF / data from AP ASMF copy AP ASMF LoA from ASMF holder to MA holder for named product MA dossier CTD

19. 19 Conclusion ASMF: one possibility to submit information on the API to Competent Authorities ASMF: one possibility to submit information on the API to Competent Authorities Preferred option of authorities: Preferred option of authorities: CEPs CEPs