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Drug Master Files Global Perspectives


Drug Master Files Global Perspectives III Symposium SINDUSFARMA IPS/FIP - ANVISA Peter J. Schmitt Montesino Associates, LLC * – PowerPoint PPT presentation

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Title: Drug Master Files Global Perspectives

Drug Master FilesGlobal Perspectives
  • III Symposium
  • Peter J. Schmitt
  • Montesino Associates, LLC

  • 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 SummaryDrug Master Files
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
  • 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
  • It is provided for in 21 CFR 314.420 (Code of
    Federal Regulations)

The US DMF SystemClosed
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
  • Support a New Drug Application(NDA)
  • Support an Abbreviated New Drug Application
  • Support another DMF
  • Support an Export Application
  • Support amendments and supplements to any of

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
  • 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
  • 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
  • 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

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
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
Active US Type II DMFs -- 2011
Active / Inactive US Type II DMFs -- 2011
US New Drug Approval System
FDA Resources
  • Total Employment 15,100
  • ORA (Office of Regulatory Affairs) 4,163
  • CDER (Center for Drug Evaluation and Research)

The EU DMF (ASTM) SystemOpen Closed
  • 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.

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 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 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.

  • Draft Guidance Issued September 2010
  • Applicable to marketed drug products registered
    in China
  • Not applicable to clinical investigational
  • 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
  • If changes to production of any items covered by
    this Provision, description of change and

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
  • 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

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?

  • Sindusfarma
  • Anvisa
  • Vocês

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 (302) 888 2355 (escritório) -- 1 (302)
    521-3203 (celular)
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