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
 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 staf
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 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

13 Considerado o status de Inativo para os DMFs sem atividade pelos ltimos 3

anos, ou sob exigncia do detentor do DMF. Todos os dados so 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:

Mdia 6 anos Mdia 6 a 7 anos 12+Meses

Pre-clnica Testes Clnicos

R&D

FDA- Perodo de Reviso

Fase I

FDA 30 dias IND Reviso

Teste em

NDA Aprovado !
Animais Fase II
(segurana)

Testes de Fase III

curta
durao

Resultados Estabilidade
IND Submetido NDA Submetido

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 FDA Resources

Total Employment: 15,100

ORA (Office of Regulatory Afairs) : 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 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.

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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
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.
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 frmaco utilizado para o fabrico de

um medicamento originado a partir de um
terceiro fabricante, os dados sobre sua fabricao,
controle de qualidade e estabilidade podem ser
apresentadas atravs de um Drug Master File
(DMF).
As orientaes europeias relevantes para o procedimento do
Arquivo Mestrado Europeu de Drogas, que foi adotado pela
Therapeutic Goods Administration (TGA), esto disponveis na
web site1 TGA.
A DMF utilizando o formato Estados Unidos aceitvel se a
DMF formatado de acordo com o Documento Tcnico Comum
(CTD) ou no formato europeu mais antigo no est disponvel.
 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.
 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 diferent
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
Vocs
 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 (escritrio) -- +1 (302) 521-3203 (celular)

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