What is a Drug Master File?
DR ANTHONY MELVIN CRASTO
An introduction with case study of an API
LEADS: 1. Introduction to DMFs
2. Drug master file process
3. Drug master file format
4. Drug Master File contents
4.1 Submission of DMF
4.2 Authorization to refer to a drug master file
4.2.1 Format for Letter of authorization to review DMF
4.3. Processing and reviewing policies
4.4. Changes in DMFs
4.5. Closure of a drug master file
4.6. Retiring DMFs
5.Electronic Filing of DMFs and CTD
6. Changes in DMF system:
8. Difference in European DMFS compare to us DMFs
9. European DMFs
10. Difference in European DMFS compare to US DMFs
11. Case study
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
2) Drug product
Manufacturing procedures and controls for finished dosage forms
Submitted in an IND, NDA,
ANDA, or Export Application.
If cannot be submitted in an IND, NDA,
ANDA, or Export Application.
Submitted in a DMF.
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
EU Marketing Authorization Application (MAA)―via the Centralized
Procedure for eligible products. For other products, via the
decentralized, mutual recognition or national authorization are
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
Highly Regulated Markets (Drug Master Files used to support approval process)
Europe: China is developing its own DMF system
Nearly Regulated Markets (Technical Package / Registration Dossier)
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
DMF – US: Important Facts
DMFs are Confidential (Closed)
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.
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
The Applicant will be notified that deficiencies exist, but the nature of the deficiencies are not
communicated to the Applicant
US DMFs - Types
In the United States, DMFs are submitted to the Food and Drug Administration (FDA).
The Main Objective of the DMF is to support regulatory requirements and to prove the
quality, safety and efficacy of the medicinal product for obtaining an
Investigational New Drug Application (IND), a New Drug Application (NDA),As an
Abbreviated New Drug Application(ANDA), another DMF, or an Export Application.
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 13 facilities for biotech products
EU DMF (EDMF or ASMF)
The content and the format for drug master file used in United States differs from that
used in European Countries to obtain market authorization (MA). The Main Objective
of the EDMF is to support regulatory requirements of a medicinal product to prove its
quality, safety and efficacy. This helps to obtain a Marketing Authorisation grant.
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.
EU: Documenting Quality:
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
European Active Substance Master File (ASMF; former Drug Master File,
Other evidence of suitability of the pharmacopoeial monograph
Generic Drug Approval: Act 505 (j)
Brand Name Drug Generic Drug
NDA Requirements ANDA Requirements
1. Chemistry 1. Chemistry
2. Manufacturing 2. Manufacturing
3. Controls 3. Controls
4. Labeling 4. Labeling
5. Testing 5. Testing
6. Animal Studies
7. Clinical Studies 6. Bioequivalence
A Drug Master File (DMF) is a set of documents that provides detailed information
concerning facility protocols and procedures used in the manufacturing, packaging and
storing of pharmaceuticals.
A Drug Master File (DMF) is a submission to the FDA of information, usually
concerning the Chemistry, Manufacturing and Controls (CMC) of a component of a
drug product, to permit the FDA to review this information.
Drug product information or other non-CMC information may be filed in a DMF.
Generally DMFs have two parts:
(1) Applicant’s part : which contain non-confidential information that the license-holder
needs to assess for the marketing.
(2)Restricted part: which contains confidential information about the manufacturing
procedure that only needs to be disclosed to the authorities
Drug Master file Process
Two copies of the Drug Master File with one signed original of the covering letter and other necessary documents are send to the FDA’s
Central Drug Evaluation and Research (CDRL). 
The Drug Master File staff will audit the non-technical information for completeness and adequacy for submission. If the key elements are
missing, the staff will contact the proposed holder to try to obtain the necessary documents in order to file the DMF.
Once the DMFs are determined to be acceptable for filing, the document room staff assigns a DMF number and a letter is sent to the
contact person listed in the DMF.
All DMF submitted in CTD format is accepted by any authorities.
WHO MUST FILE DMF?
There is no legal or regulatory requirement to file a DMF. A DMF
may be filed to provide Chemistry, Manufacturing and Controls
(CMC) information that the FDA reviews.
It is only for Maintain confidentiality of proprietary information (e.g.,
Manufacturing procedure, key ingredients, etc.) for the holder
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.
Drug Master File or DMF is a document prepared by a pharmaceutical
manufacturer and submitted solely at its discretion to the appropriate
regulatory authority in the intended drug market.
There is no regulatory requirement to file a DMF. However, the document
provides the regulatory authority with confidential, detailed information about
facilities, processes, or articles used in the manufacturing, processing, packaging,
and storing of one or more human drugs.
Typically, a DMF is filed when two or more firms work in partnership on
developing or manufacturing a drug product.
The DMF filing allows a firm to protect its intellectual property from its partner
while complying with regulatory requirements for disclosure of processing
Drug Master File (DMF) is a document containing complete information on an
Active Pharmaceutical Ingredient (API) or finished drug dosage form. An Active Substance
Master File (ASMF)is the currently recognised term in Europe, formerly known as
European Drug Master File (EDMF) or a US-Drug Master file (US-DMF) in the United
The DMF contains factual and complete information on a drug product's chemistry,
manufacture, stability, purity, impurity profile, packaging, and the cGMP status of any
human drug product.
1. General properties 2. Structure 3. Nomenclature
B. MANUFACTURE 1. Manufacture(s). 2. Description of Manufacturing Process and
Process Control. a) Flow Chart of Manufacturing Process b) Synthetic Route of
Manufacturing Process c) Manufacturing Method. 3. Control of Material a) List of Materials.
b) Specification and routine tests of the Raw Materials. 4. Control of Critical Steps and
Intermediates. a) Critical Steps. b) Process Validation and/or evalution. 5. Specifications and
Test method for the Intermediates. 6. Manufacturing Process Development.
C. CHARACTERISATION 1. Elucidation of Structure and other characteristics. a)
Elemental Analysis b) IR Spectrum of Drug Substance. c) NMR Spectrum of Drug
Substance. d) Mass Spectrum of Drug Substance. e) U.V. Spectrum of Drug Substance. f)
X-Ray Diffraction. g) Thermal Analysis. h) Comprehensive Illustration.
2. Impurities a) Sources of Potential Impurities. b) Types of impurities. c) Test Procedure
for determining impurities.
D. CONTROL OF DRUG SUBSTANCES 1. Specifications 2. Analytical procedure (STP)
3. Validation of Analytical procedure 4. Batch Analysis a) Description of Batches b)
Certificate of Analysis 5. Justification of Specification
E. REFERENCE STANDARDS OF MATERIAL
F. CONTAINER CLOSURE SYSTEM
G. STABILITY 1. Stability summary and Conclusions 2. Post-Approval Stability protocol
and Stability Commitment. 3. Stability data a) Accelerated Stability b) Long Term
Stability Studies c) Forced Degradation Studies
H. MATERIAL DATA SAFETY SHEET
I. APPENDICES 1. FACILITIES AND EQUIPMENTS a) Building and Utilities
2. EQUIPMENTS DESIGN AND LOCATION a. Equipment List b. Equipment Flow
3. ADVENTITIOUS AGENTS SAFETY EVALUATIONS STATEMENT OF COMMENT
(1) MANUFACTURING SECTION IN DMFS
(a) Data of inputs (Raw materials/Packaging materials)
List all RMs and PMs with sources
Identify Key Starting Materials (KSMs)
Complex materials do not qualify as KSMs
(b) Manufacturing Process details
Process flow diagram
Detailed Process write up
FOLLOWING GENERAL POINTS INCLUDED IN TYPE
1. Manufacturing Section
2. Quality Controls
a. Input (Raw/Packaging Materials)
b. Intermediates and In-process
c. Finished Drug Substance
4. Stability data
6. Packaging and labeling
(2) QUALITY CONTROLS’ SECTION IN DMFS
Objective: To ensure quality at every stage of
Gradual increase in checks as the process progresses.
Specification and test methods.
Complete analytical data of study batches.
Sampling procedures adopted.
Analytical Reference Standard (ARS).
Test batches vs. ARS.
(3) ANALYTICAL VALIDATIONS
Done accordance to reference guidelines: ICH Q 2A and B.
Validation of In-house methods.
Validation of Pharmacopoeial methods.
(4) IMPURIRTIES’ SECTION
Objective: To prove that quality obtained is by design of
process, not by chance.
Justification for limits applied.
Forced Degradation Studies.
Three consecutive commercial scale batches.
Long term studies.
Study include all susceptible parameters.
All validated methods.
Labeled unidentified impurities.
(5) PACKING AND LABELING
Detailed description of complete packing configuration.
Food-grade certification of inner-most Packing Materials.
Stability sample packing must be identical.
Specification and Test methods for all Packing Materials.
Specimen label must be submitted.
Clear mention of recommended storage conditions.
There is no legal or regulatory requirement to file a DMF.
The information contained in DMF may be used to support an
- Investigational New Drug Application (IND),
- New Drug Application (NDA),
- Abbreviated New Drug Application (ANDA)
- An Export Application
DMF is NOT a substitute for IND / NDA / ANDA or export application.
BUT REMEMBER THAT,
Most of the type III DMF holders are ISO (International Organization of
Standardization) certified, but the rules for ISO and those of CDER are not
always the same. The needs of the applicant should also be considered.
Responsibility for compatibility and safety of packaging components in
finished drug product is the responsibility of the AUTHORISED
It is not the responsibility of DMF HOLDER.
To submit the data
which is not covered in type I to IV DMF
must first submit
a letter of intent
to the drug master file staff
FDA will then contact the holder
to discuss the proposed submission
V. AUTHORIZATION TO REFER TO A DRUG MASTER FILE
A. Letter of Authorization (LoA) to FDA:
The letter of authorization should include the following:
Name of DMF holder.
Name of person(s) authorized to incorporate information in
the DMF by reference.
Specific product(s) covered by the DMF.
Section numbers and/or page numbers to be referenced.
Statement of commitment that the DMF is current and that the
DMF holder will comply with the statements made in it.
Signature of authorizing official.
Typed name and title of official authorizing reference to the DMF.
LETTER OF AUTHORIZATION (LOA)
Send a letter to remind
holder obligations DMF HOLDER
1 copy of LOA to the
Send 2 copies of LOA
to the FDA
The applicant submits THIS copy of
LOA in their Application.
A DMF IS NEVER APPROVED OR DISAPPROVED.
The agency will review information in a DMF only when an IND sponsor, an applicant
for an NDA, ANDA, or Export Application, or another DMF holder incorporates material
in the DMF by reference.
As noted, the incorporation by reference must be accompanied by a
copy of the DMF holder's letter of authorization.
DRUG MASTER FILE REVIEW:-
REVIEWER When reviewer receives an application (IND/NDA/ANDA) that
Requests the DMF from
the CDR (central document room)
After getting DMF, the Reviewer
starts the review procedure
If Reviewer found any deficiency in
the content of DMF,
The APPLICANT is also notified but, the nature of the
deficiencies is not communicated to the applicant.
The DETAILED DEFICIENCIES
are communicated to the holder.
HOLDER should submit the REQUESTED
INFORMATION to the DMF in response to
the agency's deficiency letter along with
transmittal letter having subject matter.
DMF SEARCH ENGINE
DMF search engine
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
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.
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
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
Drug product manufacturer is primary responsible entity for product
Filings will be reviewed in context of drug product filing review, not
Permit traceability of constituents and components of drug product
• Filings to remain confidential
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
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.
Global DMF Challenges
Open or Closed?
Major advantages of a DMF system for Brasil?
Major disadvantages of a DMF system for Brasil?
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DR ANTHONY CRASTO