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 SummaryDrug Master Files
5
Drug Submissions US, Canada, EU
TYPES OF DRUG SUBMISSIONS US, Canada, EU TYPES OF DRUG SUBMISSIONS US, Canada, EU
USA New Drug Application (NDA), for new drugs Accelerated New Drug Application (ANDA)-for generics Biologic License Application (BLA), for biologic
Canada New Drug Submission (NDS)?for both drugs and biologic products
EU Marketing Authorization Application (MAA)?via the Centralized Procedure for eligible products. For other products, via the decentralized, mutual recognition or national authorization are applicable.
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 SystemClosed
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 DMFs Statistics
Description DMF Type No of DMFs
Manufacturing site, facilities, operating procedures, and personnel I 1,826
Drug substance, drug substance intermediate, and materials used in the preparation, or Drug Product II 15,230
Packaging Material III 4,511
Excipient, Color, Flavor, Essence or material used in their preparation IV 1,749
FDA Accepted reference information V 355
Blanks Blanks 1,969
GRAND TOTAL 25,640
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
US New Drug Approval System
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) SystemOpen 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 applicants part and an ASM Restricted
  Part. The applicants 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
  applicants part and the ASM Restricted Part of
  the DMF are submitted to the authorities.
• Applicants 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 Applicants 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 applicants part and restricted part.
  Applicants 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 on APIs
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 whos 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
  Austrailias 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_at_montesino.com
• 1 [phone] (escritório) -- 1 (302)
  521-3203 (celular)