Drug Master Files Global Perspectives

1. Drug Master FilesGlobal Perspectives III Symposium SINDUSFARMA – IPS/FIP - ANVISA Peter J. Schmitt Montesino Associates, LLC

2. Agenda • Executive Summary: Drug Master Files • Closed DMFs: The FDA Way • Mixed ASMFs: The European Way • Harmonizing: the eCTD challenge • Global Trends: The Future of DMFs • Questions

3. Stakeholders & DMFs

4. Executive Summary:Drug Master Files

5. Drug Submissions: US, Canada, EU

6. Role of DMFs • Supporting documents for the registration / approval of drug products • In the Chemistry, Manufacturing and Controls (CMC) sections of the drug submission, the DMF documents the drugs identity, purity, strength and quality. • Protect Proprietary and Confidential Information

7. DMFs Globally • Highly Regulated Markets (Drug Master Files used to support approval process) • United States: • Canada: • Australia • Japan • Europe: China is developing its own DMF system • Nearly Regulated Markets (Technical Package / Registration Dossier) • Brazil • Russia • South Africa • Less Regulated Markets (No Drug Master Files used in registration process) • India and many others

8. Drug Master Files: USA Drug Master File (DMF): is a submission to the Food and Drug Administration (FDA) that may be used to provide confidential, detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs. • There is no legal or regulatory requirement to file a DMF. • A DMF may be filed to provide CMC information that the FDA reviews instead of including this information in the Application (IND, NDA, ANDA). • A DMF is neither approved nor disapproved by the FDA. • It is provided for in 21 CFR 314.420 (Code of Federal Regulations)

9. The US DMF System“Closed”

10. DMF – US: Important Facts • DMFs are Confidential (Closed) • DMF Stakeholders • DMF Holder: Company or Person who submits the DMF • Applicant: Company or person who references the DMF in an application or another DMF • Information contained in a DMF may be used to : • Support an Investigational New Drug Application (IND)) • Support a New Drug Application(NDA) • Support an Abbreviated New Drug Application (ANDA) • Support another DMF • Support an Export Application • Support amendments and supplements to any of these.

11. How the US DMF System Works • Filing the DMF • Holder sends two copies of the DMF to FDA • DMF is reviewed for administrative purposes only by Central Document Room staff • DMF entered into database, assigned a number and acknowledgment letter sent to holder • A DMF is neither approved or disapproved • Accessing the DMF: Letter of Authorization (LOA) • The DMF will be reviewed only when it is referenced in an Application or another DMF • The Holder must submit a two copies of the LOA to the DMF, plus a copy to the Applicant • The Applicant submits a copy of the LOA in their Application • The LOA is the only mechanism to trigger a review of the DMF by the FDA • DMF Review Procedure • The DMF is reviewed only if referenced by an Applicant or another DMF • If the reviewer finds deficiencies in the DMF, the deficiencies are detailed in a letter to the Holder • The Applicant will be notified that deficiencies exist, but the nature of the deficiencies are not communicated to the Applicant

12. US DMFs - Types • Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel • No longer accepted by the FDA (as of January 2000) • Type II –Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product • Type III –Packaging • Type IV –Excipients, Colorant, Flavor, Essence, or Material Used in Their Preparation • Type V –FDA Accepted Reference Information • Used for sterile manufacturing plants and contract facilities for biotech products

13. US DMF’s – Statistics Considerado o status de Inativo para os DMFs sem atividade pelos últimos 3 anos, ou sob exigência do detentor do DMF. Todos os dados são para 4T 2011

14. US DMFs – Type II Active US Type II DMFs -- 2011 Active / Inactive US Type II DMFs -- 2011

15. Média 6 anos Média 6 a 7 anos 12+Meses Testes de curta duração Fase II Fase III Fase I US New Drug Approval System: IND Submetido NDA Submetido Testes Clínicos Pre-clínica R&D Teste em Animais (segurança) NDA Aprovado ! FDA- Período de Revisão FDA 30 dias IND Revisão Resultados Estabilidade

16. FDA Resources • Total Employment: 15,100 • ORA (Office of Regulatory Affairs) : 4,163 • CDER (Center for Drug Evaluation and Research): 4,156

17. The EU DMF (ASTM) System“Open & Closed”

18. EU DMF (EDMF or ASMF) • Established in 1989-1991 • Revised in 2005 and became ASMF (Active Substance Master File) after implementation of CTD in EU • Applicable only to active substances • Has been divided into 2 parts • Applicant Part (Open) • ASM Restricted Part (Closed / Confidential)

19. European Master File • The DMF contains information which includes valuable know-how which should be kept confidential and submitted to the authorities only. Therefore, it should be divided into 2 parts – an applicant’s part and an ASM Restricted Part. The applicant’s part of a DMF is provided by the ASM (Active Substance Manufacturer) to the applicant directly and becomes part of the application for marketing authorization. Both the applicant’s part and the ASM Restricted Part of the DMF are submitted to the authorities. • Applicant’s part of a DMF – opening part • The applicant must be supplied by the ASM with sufficient information to be able to take responsibility for an evaluation of the suitability of the active substance specification to control the quality of the substance. This normally includes a brief outline of the manufacturing method, information on potential impurities originating from the manufacturing method, from the isolation procedure (natural products) or from degradation and, where applicable, information on the toxicity of specific impurities. • ASM Restricted Part of DMF – closing part • Detailed information on the individual steps of the manufacturing method such as reaction conditions, temperature, validation and evaluation data for certain critical steps of the manufacturing method, etc. and on quality control during manufacture may contain valuable know-how. Such information may therefore be supplied to the authorities only.

20. EU: Documenting Quality: 4 Options In Europe there are four ways to document the quality of the drug substance for the purpose of marketing authorization: • Certificate of Suitability of the pharmacopoeia monograph (CEP) • Full details of manufacture (according to CTD Module 3 - Quality of Drug Substance) • European Active Substance Master File (ASMF; former Drug Master File, DMF) • Other evidence of suitability of the pharmacopoeial monograph

21. EU ASMF Structure: CTD • In EU, ASMF must be submitted in different sections in CTD modules • Module 1: Contains administrative and prescribing information (administrative information is only required for an ASMF) • Module 2: Contains common overall summaries (QOS) of an “Applicant’s part” (open part) and “Restricted part” (close part). It is nothing but summary of the information provided in module 3. • Module 3: Contains all Quality information. It contains applicant’s part and restricted part. Applicant’s Part contains information required for marketing authorization. The Restricted Part contains information that is extremely confidential for the ASMF holder and can share with the health authority only.

22. Other DMF Systems

23. DMF - Canada • Canada has 4 Types of DMFs • Type 1: Used for Active Pharmaceutical Ingredients (APIs) • Type II: used for packaging materials • Type III: used for excipients • Type IV: used for products • Type I & 4 have two sections • Sponsor's (Open) • Restricted (Closed)

24. DMF: Japan Principal Focus onAPIs

25. Japanese DMF Flow Chart

26. DMF: Australia • No caso de um fármaco utilizado para o fabrico de um medicamento é originado a partir de um terceiro fabricante, os dados sobre sua fabricação, controle de qualidade e estabilidade podem ser apresentadas através de um Drug Master File (DMF). • As orientações europeias relevantes para o procedimento do Arquivo Mestrado Europeu de Drogas, que foi adotado pela Therapeutic Goods Administration (TGA), estão disponíveis na web site1 TGA. • A DMF utilizando o formato Estados Unidos é aceitável se a DMF formatado de acordo com o Documento Técnico Comum (CTD) ou no formato europeu mais antigo não está disponível.

27. DMF: Australia • In the case of an API used by a producer for a medicine who’s origin is a third party manufacturer, data about its fabrication, quality control and stability can be presented by a Drug Master File (DMF). • The Europena style relavent for the procedure of a Active Substance Master File, adopted by Austrailia’s Therapeutic Goods Administration (TGA), are available on the TGA website. • A DMF format used by the US (FDA) is acceptable if the DMF is prepared according to the Common Technical Document (CTD) format or the older European format if this is not available.

28. China • Draft Guidance Issued September 2010 • Applicable to marketed drug products registered in China • Not applicable to clinical investigational materials • Does not address exported APIs or excipients manufactured in China • Filings required for: • API, Excipients and Auxiliary Materials (primary, product contact containers or packaging) • SFDA to develop system to administer filings

29. China DMA Requirements • Drug Product manufacturer shall have written agreement with identified suppliers • Drug product manufacturer is primary responsible entity for product quality • Filings will be reviewed in context of drug product filing review, not separately • Permit traceability of constituents and components of drug product • • Filings to remain confidential

30. Submission & Changes • Filing to include: • Starting materials • Intermediate products • Manufacturing processes • Quality specifications • Test methods • Report from audit of outsourced material manufacturer(s) • If changes to production of any items covered by this Provision, description of change and justification

31. Proposed Use of DMF • Failure to include all information in filing will result in rejection of the file • Center for Drug Evaluation of SFDA will review all filings in context of drug product • Manufacturer may audit manufacturers of API intermediates and stating materials • Upon inspection SFDA will use filed information to trace materials

32. Administration of Filed Information • If drug product manufacturer finds discrepancy between “actual situation and filed information” they shall immediately stop using the material • If regulatory agency inspectors find falsified information • Revoke the filed information • Not accept filing from same API / auxiliary material manufacturer for 5 years • Drug product may not use material for whicha filing has been revoked

33. Global DMF Trends • Not Yet Harmonized: • US FDA: 2 copies of each Type II DMF u sing CTD format, but not in CTD module form. FDA format combines Modules 2 & 3 as there is no Applicant vs Restricted part. • FDA moving towards eCTD applications • EU: has separate portions for Modules 2 & 3 (Applicant / Restricted), but some countries in EU have different requirements • EU wants electronic format but there are several formats; some countries still require paper • Overhead: DMFs often run in excess of 1,000 pages. Storage and care of them can be a major burden.

34. DMFs are slow to the eCTD party • US NDAs: • 2005: 2.34% filed by eCTD • 2010: 62.41% filed by eCTD • EU: New Applications • 2009: 7% filed by eCTD • 2010: 8% filed by eCTD

35. Global DMF Challenges • Open or Closed? • CTD, eCTD • Major advantages of a DMF system for Brasil? • Major disadvantages of a DMF system for Brasil?

36. THANK YOU! MUITO OBRIGADO • Sindusfarma • IPS/FIP • Anvisa • Vocês

37. Obrigado a todos! Peter J. Schmitt Montesino Associates, LLC 1719 Delaware Avenue, 3rd Floor Wilmington, DE 19806 -- U.S.A. peter.schmitt@montesino.com +1 (302) 888 2355 (escritório) -- +1 (302) 521-3203 (celular)