Drug Master Files

Global Perspectives

III Symposium
SINDUSFARMA – IPS/FIP - ANVISA
Peter J. Schmitt
Montesino Associates, LLC

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 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
 Stakeholders & DMFs
• National • API / Excipient
Regulatory Manufacturer
Authorities /Packaging
Supplier

Safety /
Efficacy Secrecy
/ Quality

Speed
Cost /
to
Results
Market
• Pharmaceutical • Consumer
Manufacturer /
MAA
 Executive Summary:
Drug Master Files

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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.
 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
 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
 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)
The US DMF System
“Closed”
 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.

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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
 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
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US DMF’s – 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

13 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
 US DMFs – Type II

Active US Type II DMFs -- 2011

Active / Inactive US Type II DMFs -- 2011
 US New Drug Approval System:

Média 6 anos Média 6 a 7 anos 12+Meses

Pre-clínica Testes Clínicos

R&D

FDA- Período de Revisão

Fase I

FDA 30 dias IND Revisão

Teste em

NDA Aprovado !
Animais Fase II
(segurança)

Testes de Fase III

curta
duração

Resultados Estabilidade
IND Submetido NDA Submetido

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 FDA Resources

• Total Employment: 15,100

• ORA (Office of Regulatory Affairs) : 4,163
• CDER (Center for Drug Evaluation and Research): 4,156
The EU DMF (ASTM) System
“Open & Closed”
 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)
 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.

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 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
 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.
Other DMF Systems
 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)
 DMF: Japan
Principal Focus on APIs
Japanese DMF Flow Chart
 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.
 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.
 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
 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
 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
 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
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
 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.
 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
 Global DMF Challenges

• Open or Closed?
• CTD, eCTD
• Major advantages of a DMF system for Brasil?
• Major disadvantages of a DMF system for Brasil?
 THANK YOU!
MUITO OBRIGADO
• Sindusfarma
• IPS/FIP
• Anvisa
• Vocês
 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)

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