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DMF Procedures and Communication between API, FFP Manufacturers and Regulatory Authorities

DMF Procedures and Communication between API, FFP Manufacturers and Regulatory Authorities. Hyderabad, September 7, 2009. Jean-Louis ROBERT National Health Laboratory L – 1011 LUXEMBOURG CHMP co-opted member Chair CHMP/CVMP QWP. Overview of topics addressed. References EU ASMF: principle

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DMF Procedures and Communication between API, FFP Manufacturers and Regulatory Authorities

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

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

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

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

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

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

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

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

  9. Restricted (confidential) Part • Manufacture • Detailed description • Control of Materials • Control of critical steps and intermediates • Process Validation • 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. • Justification of specification: for information related to detailed description of manufacturing process, control of materials and process validation.

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

  11. Procedure - Use • ASMF can only be submitted in relation with a MA • Can also be used when no confidentiality issue between MAH and ASM • 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)

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

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

  14. General considerations (1) • Responsibility of ASMF holder: • 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 • Request for harmonisation requested by member states possible • Update of ASMF • Responsibility of ASMF holder • Information to applicant and competent authority • Full supplier chain described in finished product file

  15. General considerations (2) • The quality control methods should be kept in line with the current regulatory and scientific requirements • Compliance with GMP • Responsibility of Manufacturing Authorisation Holder (finished product) • MAH can use different QC methods • 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

  16. General considerations (3) • MA holder legally bears full responsibility MP on the market • MA holder also responsible for the active substance • 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 • Thus variations to ASMF can legally only be initiated by MA holder • Thus ASMs should continuously inform MA holders of any changes • 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!

  17. Recommendation to API industry • Keep the information the same for all MA-holders • Keep a clear administration of MA holders/countries connected to a certain ASMF • 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”

  18. Structure MPD with linked ASMFs MA dossier CTD 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

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

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