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

Explore key topics and guidelines for API manufacturers, including ASM file structure, MA dossier content, and communication between MAH, ASM, and Authorities. Gain insights on harmonization, updates, and responsibilities for quality assurance.

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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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