“COMPARISON STUDY FOR DRUG MASTER FILE PROCEDURE IN

USA & CANADA WITH REGARD TO REGULATORY TECHNICALITIES”

 TABLE OF CONTENTS

TABLE OF CONTENTS

PAGE
S. NO CHAPTER
NUMBER
01 INTRODUCTION 1-17

02 AIM AND OBJECTIVE 18

03 LITERATURE REVIEW 19-24

04 METHODOLOY 25-36

DISCUSSION 33-85

05 USFDA 33-64

CANADA 65-85

06 SUMMARY AND CONCLUSION 86

07 BIBILOGRAPHY 87-89

08 LIST OF ATTACHMENTS 90-96

 LIST OF
FIGURES
LIST OF FIGURES

Figure number Contents Page number

Role of Regulatory Affairs in different
01 02
departments
Organization chart of FDA
02 05

03 Regulatory Process of drugs in Health Canada 07

04 DMF Submission types 09
05 Organization of eCTD modules 12
06 Flow Chart for Review of procedure 43
07 FY 2019 GDUFA Fees 49
08 DMF Fee process that has not yet been filed 49
09 DMF Fee process that has been filed 50
Queue generation and Project Manager (PM)
10 53
processing
Full Completeness Assessment review by the
11 53
Chemist
12 Status of DMFs in 2018 54
Statistical data types of DMFs Filings in 2018
13 54
Filings of DMFs based on type of DMF
14 55
15 DMF Fees in Canada, DMF Fees form 64
 LIST OF
TABLES
LIST OF TABLES

Table number Contents Page number

Structure of Regulatory Affairs
01 Department 01

Few country wise Regulatory

02 Authorities 03

03 Sections of Module 3 13
Comparison of CTD and eCTD
04 34-35
Differences between Application and
05 DMF 41

06 Types of Master File in Canada 57

07 Timelines for filing a DMF 58
08 Format Comparison Table 60-61
09 DMF filing Fee- Type -I 64
Comparison of USDMF with Canadian
10 69-70
Master File
 LIST OF ATTACHMENTS

LIST OF ATTACHMENTS

S.No Contents Page number

01 Letter of authorization (LOA) 76-77

02 Transmittal (cover) letter original DMF 78
03 Withdrawal of Letter of Authorization 79
04 Annual report 80-81
05 Request for closure 82
 LIST OF
ABBREVIATIONS
LIST OF ABBREVIATIONS

AP Applicant Part
API Active Pharmaceutical Ingredient
ANDA Abbreviated New Drug Application
ANVISA National Sanitary Surveillance Agency
BGTD Biologics and Genetic Therapies Directorate
BLA Biological License Application
CA Complete Assessment
CCSMF Container Closure System Master File
CDER Center for Drug Evaluation and Research
CIOMS Council for International Organizations of Medical Sciences
CMC Chemistry Manufacturing and Controls
CMO Contract Manufacturing Organization
CPID Certified Product Information Document
CTD Common Technical document
eCTD Electronic Common Technical Document
DMF Drug Master File
EMA European Medicines Agency
ESG Electronic Submission Gateway
EUNDS Extraordinary Use New Drug Submission
FMA Foreign Manufacture Accreditation
FDA Food and Drug Administration
FDASIA Food and Drug Administration Safety Information Act
GDUFA Generic Drug User Fee Amendments
GMP Good Manufacturing Practices
HC Health Canada
HEW Department of Health, Education and Welfare
HPFB Health Products and Food Branch
 LIST OF
ABBREVIATIONS
ICH International Council for Harmonization
IGDRP International Generic Drug Regulators Programmed
IND Investigational New Drug Application
LOA Letter of Authorization
MAA Market Authorization Applicant
MAH Market Authorization Holder
MF Master File
MHLW Ministry of Health, Labour and Welfare
MHPD Marketed Health Products Directorate
NDA New Drug Application
NNHPD Non-prescription Health Products Directorate
NOC No Objection certificate
NPN New Product Number
OFM Office of Financial Management
OGD Office of Generic Drugs
ONL Overdue Notification Letters
OSIP Office of Submissions and Intellectual Property
PAL Pharmaceutical Affairs Law
PMDA Pharmaceuticals and Medical Devices Agency
RP Restricted Part
RPS Regulated Product Submission
QOS Quality Overall Summary
UDPV Undefined Data Post-market Vigilance
WT Web Trader
YBPR Yearly Biologic Product Reports
 ABSTRACT

ABSTRACT

Drug Master File (DMF) is a document containing complete information on drugs and its related
compounds i.e, Active Pharmaceutical Ingredient (API) or finished drug dosage form such as
drug product's chemistry, manufacture, stability, purity, impurity profile, packaging of any
human drug product, and it is prepared by the pharmaceutical manufacturer and it is submitted
completely with its context to the respected regulatory authority to support a third party
application without disclosing the information. Generally a DMF is filed when two or more
persons work in partnership or manufacturing a drug product. The DMF filing allows a firm to
protect its intellectual property from its partner contexting with regulatory requirements for
revealing of processing details. The pharmaceutical industry is one of the highly regulated and
exciting industries worldwide with many rules and regulations enacted by government to protect
the public health and well being. So without regulatory approval by the team of medical
researchers and other specialists; no drug is marketed. A drug master file comprises two parts:
the Applicant’s Part (Open Part), which contains all the accessible information, related to
administration that the DMF holder needs to assess the quality and submit an amendment
application; and the Restricted Part (Closed Part), which contains confidential information about
the manufacturing procedure that only needs to be disclosed to the authorities. In USFDA, refer
as Drug Master File and in Canada, referred as Master File (MF) respectively. The submission of
a DMF is not required by law or FDA regulation. A DMF is submitted solely at the discretion of
the holder. The information contained in the DMF may be used to support an New Drug
Application (NDA), an Abbreviated New Drug Application (ANDA), Biological License
Application another DMF, or amendments and supplements to any of these.
INTRODUCTION
CHAPTER 01
CHAPTER INTRODUCTIO
1 N
INTRODUCTION

DRUG REGULATORY AFFAIRS:

Definition

Regulatory Affairs is a comparatively new profession which has developed from the desire of
governments to protect public health, by controlling the safety and efficacy of products in areas
including pharmaceuticals, veterinary medicines, medical devices, pesticides, agrochemicals,
cosmetics and complementary medicines.

Regulatory Affairs in a Pharmaceutical industry, is a profession which acts as the interface

between the Pharmaceutical industry and Drug Regulatory Authorities across the world. It is
mainly involved in the registration of the drug products in respective countries prior to their
marketing.

Table1: Structure of Regulatory Affairs Department

Regulatory Agencies

Regulatory Affairs Department

Department B Department C

Department A Department D

Pharmaceutical company

Page 1
CHAPTER INTRODUCTIO
1 N
Role of regulatory affairs professional:

1. To keep track of the ever-changing legislation in all the global markets in which the
company wishes to distribute its products.
2. Advice on the legal and scientific restraints and requirements, and collect, collate, and
evaluate the scientific data that is obtained from research and development department.
3. Strategic and technical advice right from the beginning of the development of a product,
making an important contribution both commercially and scientific.
4. To build regulatory advocacy with Cross functional teams.
5. Presentation of registration documents to regulatory agencies, and carry out all the
subsequent negotiations necessary to obtain maintain marketing authorization for the
products concerned.

Fig. 1 Role of Regulatory Affairs in Different departments

Page 2
CHAPTER INTRODUCTIO
1 N
Need of Regulatory affairs in the Pharmacy Curriculum:
1. Regulatory affairs professionals are the link between pharmaceutical industries and
worldwide regulatory agencies

2. India is growing very rapidly in pharmaceutical sector; there is a need of regulatory

affairs professionals to cater the current needs of industries for the global competition.

3. Regulatory affairs professionals are the link between pharmaceutical industries and
worldwide regulatory agencies.

4. They are required to be well versed in the laws, regulations, guidelines and guidance of
the regulatory agencies.

5. There is a growing need to incorporate the current requirements of pharmaceutical

industries in the standard curriculum of pharmacy colleges to prepare the students with
the latest developments to serve the industries.
Why is Regulatory Affairs Needed?

1. Drug development and commercialization is highly regulated.

2. The path to drug registration (Marketing Authorization) is paved with good intention but
can be complicated.

Scope of Regulatory Affairs Professional in Industries

Regulatory affairs professionals are employed in industry, government regulatory authorities and
academics. The wide range of regulatory professionals includes in these areas:

1. Pharmaceuticals

2. Medical devices & In vitro diagnostics

3. Biologics and biotechnology

4. Nutritional Products

5. Cosmetics

6. Veterinary Products
Page 3
CHAPTER INTRODUCTIO
1 N
Regulatory bodies in the world:
Table 2: Few country wise Regulatory Authorities

COUNTRY/REG REGULATORY AUTHORITY WEBSITE ADDRESS

ION

UNITED STATES United States Food and Drug http://www.fda.gov/

Administration (FDA)
EUROPEAN European Medicines Agency (EMA) http://www.ema.europa.eu
UNION European Directorate for the Quality of
Medicines and Healthcare (EDQM) https://www.edqm.eu/
JAPAN Ministry of Health, Labor and Welfare http://www.mhlw.go.jp/
(MHLW)
Pharmaceuticals and Medical Devices https://www.pmda.go.jp/en
Agency(PMDA) glish/
KOREA Ministry of Food and Drug Safety (MFDS) https://www.mfds.go.kr/en
Korea Food & Drug Administration g
(KFDA)
CANADA Health Canada (HC) http://www.hc-sc.gc.ca/
AUSTRALIA Therapeutic Goods Administration(TGA) http://www.tga.gov.au/

BRAZIL National Sanitary Surveillance Agency http://www.anvisa.gov.br/

(ANVISA)

NEW ZEALAND Med safe - Medicines and Medical Devices http://www.medsafe.govt.n

Safety Authority z/
INDIA Central Drug Standard Control http://www.cdsco.nic.in/
Organization (CDSCO)
SOUTH AFRICA Medicines Control Council (MCC) http://www.mccza.com/

WORLD International conference on Harmonization http://www.ich.org/

ACCEPTED (ICH)
ORGANIZATIONS World Health Organization (WHO) http://www.who.int/en/

Page 4
CHAPTER INTRODUCTIO
1 N
US FOOD DRUG ADMINISTRATION:

The U S. Food and Drug Administration is a scientific, regulatory and public health
agency. Its jurisdiction encompasses most food products (other than meat and poultry), human
and animal drugs, therapeutic agents of biological origin, medical devices, radiation emitting
products for consumer, medical and occupational use; cosmetics and animal feed. Agency
scientists evaluate applications for new human drugs and biologics, complex medical devices,
food and color additives, infant formulas and animal drugs. Also, the FDA monitors the
manufacture, import, transport, storage and sale of about $1 trillion worth of products annually at
a cost to taxpayers of about $3 per person. Investigators and inspectors visit more than 16,000
facilities a year and arrange with state governments to help increase the number of facilities
checked.

FDA is an agency within the Department of Health and Human Services.

 Head Quarters: Silver Spring, Maryland, United States. The agency also has 223 field
offices and 13 laboratories located throughout the 50 states.
It was established in June 30, 1906.

US FDA Regulates:
Food
Drugs
Medical devices
Radiation -emitting products
Vaccines, Blood and Biologics
Animal and Veterinary products
Cosmetics
Tobacco products

Basic History of FDA:

Food and Drugs Act of 1906 laid the foundation for the modern food and drug law.
Safety of food additives was previously tested y the “Poison Squad”

Page 5
CHAPTER INTRODUCTIO
1 N
 Later it was discovered that the drug sulfanilamide contained a poison which killed 107
people
 The previous law did not require testing for drug safety before putting them on the
market
The next year congress passed the Federal Food, Drug and Cosmetic Law
FDA combines law and science to protect consumers.

Fig. 2 Organization chart of FDA

Center for Drug Evaluation and Research:

The Center for Drug Evaluation and Research (CDER) performs an essential public health task
by making sure that safe and effective drugs are available to improve the health of people in the
United States.

As part of the U.S. Food and Drug Administration (FDA), CDER regulates over-the-counter and
prescription drugs, including biological therapeutics and generic drugs.

Page 6
CHAPTER INTRODUCTIO
1 N
Office of Generic Drugs:
 Review applications for the approval of generic drugs (known as abbreviated new drug
applications.
 Serve as the central point of contact between applicants and the FDA Generic Drug
Program.
 Provide guidance and regulatory oversight to industry on a wide variety of clinical,
scientific, and regulatory matters relating to generic drugs.
Ensure that FDA fulfills Generic Drug User Fee Amendments review commitments.
Conduct and administer research in support of the GDUFA Regulatory Science Plan.
 Interact with external stakeholders such as physicians, pharmacists, patients, and patient
advocacy groups to investigate reports of adverse events or therapeutic in equivalence of
generic drugs.
Generic Drug User Fee Amendments (GDUFA):

Generic drug user fees make it possible for FDA and industry to continue to ensure that the
American public has access to safe and high quality generic drugs and generic drug products.
The implementation of the Generic Drug User Fee Amendments (GDUFA) encompasses a wide
range of activities that fall within the scope of regulating the generic drug industry. GDUFA was
reauthorized on August 18, 2017 (GDUFA II), with provisions that went into effect October 1,
2017 and remain in effect through September 30, 2022.

Role of GDUFA:

Submission Review
ANDA Review Enhancements
Pre-ANDA Program & Complex Generic Products
Drug Master File (DMF) Review Enhancements
Facilities Enhancements
Enhanced Accountability & Reporting.

Page 7
CHAPTER INTRODUCTIO
1 N
HEALTH CANADA:

Canada is a country situated in North America that consists of ten provinces and three territories
that extends from the Atlantic to the Pacific and northward into the Arctic Ocean. It is the
world’s second-largest country by total area and the fourth-largest country by land area with
population of 35 million. Its advanced economy is one of the largest in the world.
Health Canada, through the Food and Drugs Act, regulates the safety; efficacy and
quality of all pharmaceutical drugs for use by humans in Canada before and after the products
enter the Canadian marketplace. It aims to ensure that the public has timely access to safe and
effective pharmaceutical drugs. Health Canada is the department of government of Canada with
responsibility for national public health.

There are about 13,000 drugs on the Canadian market, many of which are critical to high
quality health care. Canadians were expected to spend about $31 billion on these drugs in 2010.
According to IMS Brogan, a well-recognized provider of data to Health Canada and the
pharmaceutical industry, about 505 million prescriptions were dispensed by Canadian retail
pharmacies in 2010.
Health Canada’s approach to the regulation of drugs focuses on well-defined points in the
regulatory process that lead to a drug’s marketing approval. However, after the Department has
authorized a drug for sale, it has limited regulatory authority to require label changes that address
new safety information or to require manufacturers to undertake additional post-market studies.

Health Canada’s responsibilities include the following core activities:

Reviewing clinical trial applications, for clinical trials to be conducted in Canada

 Reviewing drug submissions from manufacturers for market authorization and for post
market changes
 Monitoring the safety of drugs in the Canadian market and communicating safety risks to
health care professionals and the public, in collaboration with industry
 Enforcing the pharmaceutical industry’s compliance with regulations, including those
related to clinical trials, drug manufacturing, and the reporting of adverse drug reactions.

Page 8
CHAPTER INTRODUCTIO
1 N

Fig.3 Regulatory Process of drugs in Health Canada

Drug Master File (DMF):

A drug master file (DMF) is a confidential, detailed document submitted by Active

Pharmaceutical Ingredient (API) manufacturers to the U.S. Food and Drug Administration
(FDA). A DMF contains the chemistry, manufacturing, and controls of a drug component. A
drug master file 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
details. 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.
However the information described in DMF may be used as pillar for IND (Investigational
New Drug Application), NDA (New Drug Application), an ANDA (Abbreviated New Drug
Application), or another DMF application, an Export application, Supplements or Amendments

Page 9
CHAPTER INTRODUCTIO
1 N
to any of these. A DMF in support of application for approval a new drug should provide
information about [1]:
Drug substance
Intermediates
Drug products
Excipient
Packaging materials
Flavors
Essence
Colorants
Substance used to make them
Stability data of drug products
The information regarding the DMF is described in 21 CFR 314.420. This guidelines
does not inflict compulsory requirements (21 CFR 10.90(b)). However, it does offer
guidance on acceptable procedures to meeting regulatory requirements. These guidelines are
considered to provide DMF holders with acceptable procedure for preparing and submitting
DMF to the agency. DMF usually covers the CMC (Chemistry Manufacturing and Controls)
of a component of a drug product e.g. Excipient, packaging material. Drug product
information or non-CMC information may be filed in a DMF.
Chemistry Manufacturing and Control: The below mentioned data is available in open part:
Nomenclature
General properties
Name of the manufacturer and site of manufacture
Structural elucidation
Impurities
Specifications and method of analysis
Container closure system
Stability testing
Part’s of DMF:

Generally DMF contains two parts:

Page 10
CHAPTER INTRODUCTIO
1 N
1. Applicant’s part: which contains all the non- confidential information that the license
holder needs to assess the quality and submit a license for marketing.
2. Restricted part: which contain confidential information about the detailed manufacturing
procedure that only needs to be disclosed to the authorities.

Laws and regulations:

1. FD&C Act( Food Drug and Cosmetic Act)

2. FDASIA ( Food and Drug Administration Safety Information Act)
3. GDUFA ( Generic Drug User Fee Act)
4. PDUFA ( Prescription Drug User Fee Act)

Regulations: Section 21 of the Code of Federal Regulations (21 CFR):

314- New Drug Application (NDA) and Abbreviated NDA (ANDA)

1. 314.50: Content and format of an application

2. 314.70: Changes to an approved application
3. 314.420: Drug Master Files

Role of DMF submissions:

1. DMF plays a key role for the drug product manufacturers and to support the documents
for registration
2. In the CMC (Chemistry, manufacturing and Controls) of the drug submission, the DMF
documents the drugs identity, purity, strength and quality.
3. To protect proprietary and confidential information.
4. The DMF system was developed mainly to allow distributors to make use of this
information on their products directly available to FDA for its review of drug company
applications that involve the use of the distributor’s material.

DMF submission types:

 IN USA
 NDA for new drugs
 ANDA for generic drugs

Page 11
CHAPTER INTRODUCTIO
1 N
 BLA for generic drugs
 IN CANADA
 New drug submissions for both drugs and biologic products

Types of DMF: DMF submission types in USA, Australia, Canada and Europe are shown in
below mentioned Figure.

DMF

US DMF AUSTRALIA CANADIAN EUROPEAN

DMF DMF DMF

TYPE – I TYPE – I TYPE – I Open part

[ASMF] [API]
TYPE – II
TYPE – II TYPE – II Closed
TYPE – III
TYPE – III TYPE – III
TYPE – IV Fi . 3 Types of
TYPE – TYPE – IV
TYPE - V
IV
Fig. 4 DMF Submission types

Submissions required for DMF:

1. Each DMF submission should contains transmittal letters, about the DMF submission
administrative information and the specific information should be included in DMF
2. All the DMF submissions must be in English language. An accurate certified English
translation must be included whenever the DMF submission in another language.
3. The DMF should be dated and consecutively numbered to each page of each copy.

TYPES OF DMFIN USA:

The types of DMFs are:

Page 12
CHAPTER INTRODUCTIO
1 N
1. Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel (no longer
applicable)
2. Type II: Drug Substance, Drug Substance Intermediate, and Material Used in Their
Preparation, or Drug Product
3. Type III: Packaging Material
4. Type IV: Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation
5. Type V: FDA Accepted Reference Information

Filing of DMF according to recent update regarding USFDA:

DMF is now we can submit e-CTD via ESG (Electronic Submission Gateway). The deadline for
the conversion of Paper format to e-CTD is beginning May 5, 2017, all submission types NDA,
ANDA, and Master Files must be submitted in eCTD format.

REGULATION OF DMF AS PER CANADA:

A Drug Master File (DMF) is a reference that provides information about specific processes or
components used in the manufacturing, processing, and packaging of a drug. The DMF is a
useful vehicle for providing information to Health Canada, where that information is of a
proprietary nature and is not available to the manufacturer of the dosage form or to a Sponsor of
a submission when they are not the dosage form manufacturer. The DMF can be referenced by
drug manufacturers in support of their New Drug Submissions (NDSs), Abbreviated New Drug
Submissions (ANDSs), Supplement to a New Drug Submission (SNDS) Supplement to an
Abbreviated New Drug Submission (SANDS), DIN submissions, Notifiable Changes (NCs),
New Product Number (NPN) applications and Clinical Trial Applications (CTAs). DMFs may be
referenced by more than one drug manufacturer. Canadian DMF: division of formation to
Sponsor's (Open) and Restricted (Closed) part for DMFs type I and IV

In 1994, a new revision was published in the name of CANADIAN DMF which contains 2 parts
a) applicant’s part & (b) restricted part, and it is of 4 types:

Type 1- Active Substance Master File (ASMF)

 For pharmaceuticals, it includes API in the manufacturing of a drug substance.

Page 13
CHAPTER INTRODUCTIO
1 N
 For biologics, it includes process intermediates, vaccines antigens, excipient of
biological origin.

Type 2- Container Closure System Master File (CCSMF)

Type 3- Excipient Master File (EMF)

 Includes information related to excipient, coating ingredients, colorants, flavors and

other additives.

Type 4- Dosage Form Master File (DFMF)

 Includes information related to dosage form & their intermediates.

Type I DMF for API has divided into two sections:

 Sponsor's (Open)
 Restricted (Closed)

Health Canada is pleased to announce the release of the revised the 2008 Draft Guidance
Document - Drug Master Files (DMFs) is outdated and not in line with international efforts to
standardize MF terminology and MF procedures. The revised draft is administrative in nature
and was developed to facilitate information sharing initiatives that are ongoing in collaboration
with the International Generic Drug Regulators Programmed (IGDRP).These initiatives include
bringing efficiencies to MF practices. Health Canada is pleased to announce the acceptance of
Drug Master Files in "non-eCTD electronic-only" format. Electronic documents will be uploaded
onto the Health Canada viewing tool, where they will be immediately accessible to Health
Canada staff involved in the review of the regulatory activities.

Effective immediately the following should be provided in "non-eCTD electronic-only" format:

 New DMFs;
 Transactions related to existing DMFs (for example, letters of access, administrative
information);
 DMF updates (the first update must include a complete DMF conversion in "non-eCTD
electronic-only" format for the existing DMF in paper format).

Page 14
CHAPTER INTRODUCTIO
1 N
 Recent notification from Health Canada dated October 5, 2015, with file number: 15-
110442- 152

From January 1, 2016, health Canada will not accept paper copies of DMF. Any paper
received after the date will be cancelled & returned back at the owner’s cost.

From March 31, 2016, all DMFs existing in paper format must be replaced by a DMF in “non e-
CTD electronic only” format. If applicant fails to provide the electronic copy of the DMF, then
it will result in the suspension of the DMF.

Need For Filing DMF:

 To maintain confidentiality of information of the holder.

 To allow review of all the information by reviewers of Centre for Drug
Evaluation & Research (CDER) to support applications.

ORGANIZATION OF THE eCTD:

Fig. 5 Organization of eCTD modules

Page 15
CHAPTER INTRODUCTIO
1 N
Module 1- Administrative information

The administrative information should contain following elements in a specified DMF:

1. The name and address of the holder

2. The name and address of manufacturing facility
3. For the contact person:
a. Name
b. Mailing address
c. Telephone number
d. Fax number
4. The name and address of agent
5. Statement of commitment

Submission of Amendments, Annual Reports, and Letters of Authorization:

Cover letter: it contains appropriate information which supports communication within the
review process. It is suggested the cover letter include the following information:

1. Regulatory description of the submission

2. Appropriate regulatory information
3. Specified hyperlinks to submitted information
4. Technical description with approximate size up to 2 GB

Annual reports: For each study or a trial the sponsors or applicants must include bookmark that
is described in the post marketing requirement. The annual report which covers the reporting
period should be included in the eCTD leaf title.

LOA (Letters of Authorization): It is a document submitted by the holder/owner giving an

authorization for the information on another person behalf. Appointment letter of an agent is not
an LOA and should not be called as “Letter of Authorization”

Statement of Right of Reference: It should be submitted by the authorized person of LOA with
a copy of the LOA and statement of right of reference. It is submitted in DMF case only when
another DMF is referenced

Page 16
CHAPTER INTRODUCTIO
1 N
Module: 2 QOS (Quality Overall Summary)

The files in this module should be provided as PDF text with the exception of a few embedded
[15]
images, when needed with the exception of few embedded images, when needed . The name
of the folder for module 2 should be m2.

Module 3: Quality [16]

Majorly it consists of following sections.

Table 3: Sections of module 3

Description Folder name

Body of data 32-body-data
Drug substance 32s-drug-sub
General information 32s1-gen-info
Manufacture 32s2-manufac
Characterization 32s3-charac
Control of drug substance 32s4-contr-drug-sub
Specification 32s41-spec
Analytical procedure 32s42-analyt-proc
Reference standards or Materials 32s45-justif-spec
Container closure system 32s6-cont-closure-sys
Stability 32s7-stab
Module 4: Non clinical study reports

The name of the folder for module 4 should be m4.

Module 5: Clinical study reports

The name of the folder for module 5 should be m5

Page 17
AIM &OBJECTIVE
CHAPTER 02
CHAPTER 2 AIM & OBJECTIVE

AIM:

The aim of this study is to know the Preparation of DMF, Filing procedure and
Review of DMF in US (USFDA) and Canada (Health Canada)

OBJECTIVE:

The objective of this study was:

 To know about the registration of DMF in the US and Canada

 Study and analyze on the Requirements for preparation of DMF.
 To know about the eCTD submissions through ESG.
 To know about the procedure for reporting the changes through amendments.
 To know about the procedure for responding to Deficiency Letters and Additional
Information Request.

 To analyze the comparison study of regulatory requirements in USA and Canada

Page 18
LITERATURE REVIEW
CHAPTER 03
CHAPTER LITERATURE
3 REVIEW

1. Mithun E.G.1, S. B. Puranik et. al., (2016) has done the review article about: An
“Overview of Registration of API (DMF) in Regulated Markets (USFDA, CANADA,
EU and EDQM (CEP)” The purpose of their article is to present a concise overview
registration of Active pharmaceutical ingredient (API) for Generic Drugs in various
regulatory authorities such as USFDA, TPD, EU and EDQM as per ICH-CTD. The
registration process will be done by submitting technical information to the authority
i.e., Drug Master File. A Drug Master File or DMF is a reference source that provides
drug evaluator’s confidential information not available to drug product manufacturer
about the specific process and components used in the manufacturing, processing and
packaging of a drug meant for Human /Animal use. The study concludes that each
country in the world has different rules and regulations to file the drug master file
(DMF). So there is a need of harmonization on filling of DMF in the world in future.

2. Pankaj Kumar, Bharti Mangla et. al., (2017) has done the paper presentation about
“Drug master file: global regulatory issues and challenges” stating that the study gives
the information on regulatory requirements of Drug Master Files by Food and Drug
Administration (USA), European Medicines Agency (Europe), Ministry Of Health
Labor and Welfare (Japan), Central Drug and Standard Control Organization (India)
and WHO and their comparison. A DMF contains the chemistry, manufacturing, and
controls of a drug component. A drug master file is filed when two or more firms work
in partnership on developing or manufacturing a drug product. The study concludes
that the drug master file is filed in support of various applications to present drug into
the market. It is used to provide chemistry manufacturing and controls (CMCs) on
drug substance, drug product, intermediate used in their preparations etc.

3. S. Anusha, N.V.N. Mounica et. al., (2017) has done the review on “Processing and
submission of drug master file” stating that the study includes various types of Drug
Master Files, the important aspects in filing and processing. And did their work by
comparing the DMF regulatory requirements in the regulated countries so that reader
can have clear idea on how to file DMF and concluded that submission without
revealing the information to the third party. The content and the format for Drug

Page 19
CHAPTER LITERATURE
3 REVIEW

Master File are used to obtain marketing Authorization. The currently approved form
is the CTD format which contains 5 Modules so concluded that there is a need of
harmonization on filling of DMF in the world in future.

4. Yamini SPK, Jain N, et. al., (2019) has done the research study about “Filing of
DMF in US, Canada & Europe” that DMF (Drug Master File) it is a kind of
confidential document which contains complete, factual and correct information about
active pharmaceutical ingredient or finished drug dosage form. A DMF can be used by
holder who establishes the file or by one or more parties in support of their files or
applications. The purpose of the research study is to present an overview of DMF
filing in different countries which are USA, Canada, and Europe. In USA, Canada the
drug master file is known as DMF only but in EUROPE it is known as ASMF (active
substance master file) and concluded that the drug master file contains complete &
correct information about active pharmaceutical ingredient or finished drug dosage
form and CMC data i.e., chemistry, manufacture, stability, purity, impurity profile,
packaging of any drug product or excipient.

5. Shravya K., Swathi P et. al., (2014) has done the review article which was entitled as
“Regulatory dossiers of ASEM countries” The main purpose of the study is to
elucidate that DMF is to support regulatory requirements of a medicinal product to
prove its quality, safety and efficacy and this helps in obtaining a market authorization
grant. And briefly explained by demonstrating of safety and efficacy of the drug
product for human use is important before the drug product gets approval for import or
manufacturing of new drug by regulatory authority in any country. After thorough
research of dossiers in ASEM Countries they concluded that a common format of
submission will help in overcoming these difficulties. Through International
conference on Harmonization (ICH), Common Technical Document (CTD) guidance’s
have been developed for Japan, EU and United States and the Research based industry
and more recently its electronic version the electronic Common Technical Document
(eCTD).

Page 20
CHAPTER LITERATURE
3 REVIEW

6. Agarwal Pooja et. al., (2012) has done review article on “DMF filing in US, Europe
and Canada” elucidating that A Drug Master File or DMF is a reference source that
provides drug evaluator’s confidential information not available to drug product
manufacturer about the specific process and components used in the manufacturing,
processing and packaging of a drug meant for Human/Animal use. And done the work
by comparing the regulatory requirements in the above mentioned regulated countries
and concluded that 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.

7. Chennamsetti Srilakshmi (2017) had done the review article on “Regulatory

Requirements for Registration of API in US and EU”. The purpose of the study is to
elucidate about different pharmaceutical legislations and regulatory requirements for a
new MAA of an API of EU, United States (US), are discussed and analyzed in detail.
The analyses are made especially concerning the aspects required for marketing
authorization and accepted dossier requirements for the registration of API in US and
EU. To submit a marketing authorization application (MAA) in all countries, it is
important to know exactly the pharmaceutical legislations (regulations, directives and
guidelines) and the regulatory requirements in each of the country in advance and
concluded that the Drug Master File is a critical document used to support a drug
application. Deficiencies in the Drug Master File can result in the delay of approval of
drug applications. It is important that the DMF be filed in a timely manner and that the
standards used to compete it are of the same quality as the actual drug application.

8. M. VaseemAkram; D. Nagarjuna et. al., (2016) had done the review article on
“Regulatory requirements of drug master files by Food and Drug Administration
(USA), European medicines agency (Europe) and health Canada (Canada) and their
comparison”. The main objective of the study describing that DMF is to support
regulatory requirements of a medicinal product to prove its quality, safety and
efficacy. This helps to obtain a marketing authorization grant. Now from 2016
onwards most of the regulated countries will use eCTD or their electronic format for

Page 21
CHAPTER LITERATURE
3 REVIEW

their DMF submission. The review article provides information on regulatory

requirements of Drug Master Files by Food and Drug Administration (USA),
European Medicines Agency (Europe) and Health Canada (Canada) and their
comparison and concluded that the Drug Master File may be utilized either by the
holder who establishes the file, or by one or more additional parties in support of their
application.

9. M. Nagabhushanam (2017) had done the review article on “An Overview of Drug
Master Files”. The main purpose of the article is describing about A Drug Master File
(DMF) is an elective regulatory submission and is submitted at the discretion of the
DMF holder to assist their clients. In the absence of relevant information in the CMC
section of an application, the US Food and Drug Administration requires a Drug
Master File submission of a drug substance, drug product, and/or container closure
submission to allow FDA to review information. These submissions support a third
party’s application without revealing the information to the third party and maintains
the confidentiality of proprietary information (e.g., a synthetic or manufacturing
procedure) for the holder, allowing review of information by reviewers at FDA to
support applications submitted by one or more applications and concluded that the
information contained in a DMF may be used to support an Investigational New Drug
Application (IND), a New Drug Application (NDA/BLA), an Abbreviated New Drug
Application (ANDA), another DMF, an Export Application, and any amendments and
supplements to any of these applications.

10. Nareshkumar et. al., (2018) has done review article on “An Overview of Registration
of API (DMF) in Regulated Markets (USFDA, CANADA, EU and EDQM (CEP). The
purpose of this article is to present a concise overview registration of Active
pharmaceutical ingredient (API) for Generic Drugs in various regulatory authorities
such as USFDA, TPD, EU and EDQM as per ICH-CTD. The registration process will
be done by submitting technical information to the authority i.e., Drug Master File. A
Drug Master File or DMF is a reference source that provides drug evaluator‟s
confidential information not available to drug product manufacturer about the specific

Page 22
CHAPTER LITERATURE
3 REVIEW

process and components used in the manufacturing, processing and packaging of a

drug meant for Human /Animal use and concluded that applications. It is important
that the DMF be filed in a timely manner and that the standards used to compete it are
of the same quality as the actual drug application.

11. E. Gopinath et al., (2012) explained that the Regulatory Affairs is a comparatively
new profession which has developed from the desire of governments to protect public
health, by controlling the safety and efficacy of products in areas including
pharmaceuticals, veterinary medicines, medical devices, pesticides, agrochemicals,
cosmetics and complementary medicines. The companies responsible for the
discovery, testing, manufacture and marketing of these products also want to ensure
that they supply products that are safe and make a worthwhile contribution to public
health and welfare. Most companies, whether they are major multinational
pharmaceutical corporations or small, innovative biotechnology companies, have
specialist departments of Regulatory Affairs professionals.
12. Blawas (2014) explained Drug Master Files (DMFs) in the United States, Canada, and
European Union. He stated that, Unlike European and Canadian master files, all parts
of a US DMF are ‘open’ only to the FDA for review and remain ‘closed’ to the
applicant referencing the DMF in their application. The requirements in U.S DMF
submission including Letter of authorization were explained. Timelines for filing a
DMF and fees were explained in brief regarding latest USFDA guidelines.

13. Indu Gurram (2017) explained about Drug Master File Filing in US, Europe, Canada
and Australia. She stated that, 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. The content and the
format for Drug Master File is used to obtain marketing Authorization. She
approached that,Drug Master File is a submission of information to the FDA to permit
the FDA to review this information in support of a third party's submission without
revealing the information to the third party. In US, DMF filing was done through NDA

Page 23
CHAPTER LITERATURE
3 REVIEW

for drugs, ANDA for generics and BLA for Biologics. In Europe, DMF filing was
done through MAA via centralized procedure for eligible products and for other
products via decentralized procedure was used. In CANADA, DMF filing was done
through NDS for both drugs and biologic products, where as in AUSTRALIA different
application processes and regulatory requirements apply depending on the type of
therapeutic goods that is applied.
14. Marieke van Dalen (2015) provided guidance on the procedure for the European
ASMF, the US-DMF and the Japanese DMF and also described manufacturing
process, how to compile data for drug substance stability, impurities and residual
solvents. He mainly focused on the important points to consider for US DMF’s,
requirements for Japanese DMFs, how to handle changes in European, US and
Japanese DMF’s respectively.

15. Akhilesh. P (2014) explained about all the Regulatory Requirements in DMF FILING
OF UNITED STATES, EUROPE AND JAPAN. He mentioned that Drug Master File
(DMF) is a document containing complete information on an Active Pharmaceutical
Ingredient (API) or finished drug dosage form. It is known as European Drug Master
File (EDMF) or Active Substance Master File (ASMF) and US-Drug Master file (US-
DMF) in Europe and United States respectively. The required documents should
include 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. A drug master file comprises two parts: the Applicant’s Part
(USA: Open Part), which contains all the information that the license-holder needs to
assess the quality and submit a license or amendment application; and the Restricted
Part (USA: Closed Part), which contains confidential information about the
manufacturing procedure that only needs to be disclosed to the authorities.

Page 24
METHODOLOGY
CHAPTER 04
 CHAPTER METHODOLOG
4 Y

METHODOLOGY

The study was organized into 5 steps to achieve the objectives:

1. Type of study
2. Sources of data
3. Criteria for selection of study parameters
4. Study process
5. Regulatory Aspects

1. TYPE OF STUDY:

The study was conducted with an objective to chalk out the Preparation of DMF, Filing
procedure and Review of DMF in US (USFDA), Canada (Health Canada).

2. SOURCES OF DATA:

In this comparative study, primary and secondary sources of data have been referred to which
include the following:

 Literature review: Typically covered the regulatory guidelines published officially by

government authorities, including the academic journals, online journals, market
research reports, direct communication with Regulatory authorities and other
resources.
 Guidelines published officially by government authorities
 Academic journals, online journals, and books
 Market research reports, articles
 Other internet sources using numerous search engines like- Google, Pharmabiz,
Google Scholar, etc.
 Articles available on the web in various Pharma newsletters (Med Tech, Desert Hope,
Express Pharma, Pharma Times, Pub Med, Elsewhere, etc.).

 Websites of USFDA, HEALTH CANADA and ICH guidelines etc..

Page 25
 CHAPTER METHODOLOG
4 Y

 Guidelines and guidance documents issued by the regulatory authorities of the

countries included in the study.
3. CRITERIA FOR SELECTION OF STUDY PARAMETERS:

It mainly involves:

 Different types of Drug Master Files in the US.„

 How to document, procedure and review the different types of DMF.„
 Handling changes in Canadian Master File and US Drug Master Files.

 To know about the eCTD submissions through ESG.

 To know about the procedure for responding to Deficiency Letters and Additional
Information Request given by FDA.

4. STUDY PROCESS:

Defining the objectives

Collection of data

Review of collected data

Discussion

Comparison

Summary & Conclusion

Page 26
CHAPTER METHODOLOG
4 Y

USDMF

UNITED STATES FOOD AND DRUG ADMINISTRATION

Page 27
 CHAPTER METHODOLOG
4 Y

Origin of FDA:

The U S. Food and Drug Administration is a scientific, regulatory and public health agency. Its
jurisdiction encompasses most food products (other than meat and poultry), human and animal
drugs, therapeutic agents of biological origin, medical devices, radiation -emitting products for
consumer, medical and occupational use; cosmetics and animal feed.

Beginning as the Division of Chemistry and then (after July 1901) the Bureau of Chemistry, the
modern era of the FDA dates to 1906 with the passage of the Federal Food and Drugs Act, this
added regulatory functions to the agency’s scientific mission. The Bureau of Chemistry’s name
changed to the Food, Drug and Insecticide Administration in July 1927. In July 1930 the name
was shortened to the present version. FDA remained under the Department of Agriculture until
June 1940, when the agency was moved to the new Federal Security Agency. In April 1953 the
agency again was transferred to the Department of Health, Education and Welfare (HEW).
Fifteen years later FDA became part of the Public Health Service within HEW and in May 1980
the education function was removed from HEW to create the Department of Health and Human
Services.

DRUG MASTETR FILE (DMF) SYSTEM IN UNITED STATES:

A Drug Master File (DMF) is a submission to the FDA that may be used to provide
confidential detailed data about facilities, processes or articles used in manufacturing,
processing, and storing of one or more human drugs.
Typically, a drug master file 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 details.
In the United States, DMFs are submitted to the 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 IND, a NDA, an ANDA, another DMF, or an Export
Application.

Information for current DMF holders:

Page 28
 CHAPTER METHODOLOG
4 Y

If a DMF is in paper format with FDA, the same submission does not need to be resubmitted
in eCTD format. However, starting May 5, 2018, any new submissions to the existing DMF
must be done in eCTD format. The DMF holder may continue to use the same DMF number.
If the existing number is four-digits, e.g., 1234, the DMF holder will need to pad left with
zeroes to convert the DMF number to a g-digit format, e.g., 001234 when the DMF is
converted to eCTD format. In addition, if the DMF holder chooses to resubmit all of an
existing paper DMF in eCTD format, and there are any changes in the content of the DMF as
a result of the reformatting (e.g., addition of new or updated information), the Cover Letter for
the submission should specify what areas of information have been updated.

TYPES OF DMF’S: In United States there are 5 types of DMF’s.

 Type I - Manufacturing Site, Facilities, Operating Procedures and Personnel

A Type I DMF is recommended for a person outside of the United States to
assist FDA in conducting onsite inspections of their manufacturing facilities. The
DMF should describe the manufacturing site, equipment capabilities and operational
layout. A Type I DMF is normally not needed to describe domestic facilities except in
special cases, such as when a person is not registered and not routinely inspected. The
description of the site should include acreage, actual site address and a map showing
its location with respect to the nearest city. An aerial photograph and a diagram of the
site may be helpful. A diagram of major production and processing areas is helpful for
understanding the operational layout. Major equipment should be described in terms of
capabilities, application and location. A diagram of major corporate organizational
elements with key manufacturing, quality control and quality assurance positions
highlighted at both the manufacturing site and corporate headquarters is also helpful.
 Type II - Drug Substance, Drug Substance Intermediate and Material Used in Their
Preparation or Drug Product
In general, a Type II DMF should be limited to a single drug intermediate, drug
substance, and drug product or type of material used in their preparation. It
summarizes all significant steps in the manufacturing and controls of the drug
intermediate or substance. Manufacturing procedures and controls for finished dosage

Page 29
CHAPTER METHODOLOG
4 Y

forms should ordinarily be submitted in an IND, NDA, ANDA or Export Application.

If this information cannot be submitted in an IND, NDA, ANDA or Export
Application, it should be submitted in a DMF.
 Type III - Packaging Material
There is some confusion regarding when a Type III DMF (packaging material)
should be submitted. It is not required that packaging information be submitted to the
FDA in a DMF. The responsibility for providing information about packaging
components rests foremost with the applicant of an NDA, ANDA or BLA, or the
sponsor of an IND. This information may be provided to the applicant by the
manufacturer of a packaging component or material of construction and may be
included directly in the application. Any information that a manufacturer does not
wish to share with the applicant or sponsor (i.e., because it is considered proprietary)
may be placed in a Type III DMF and incorporated in the application by a letter from
the manufacturer to the applicant which authorizes reference to the DMF.
 Type IV - Excipients, Colorant, Flavour, Essence or Material Used in Their
Preparation
Each additive should be identified and characterized by its method of
manufacture, release specifications and testing methods. Toxicological data on these
materials would be included under this type of DMF, if not otherwise available by
cross reference to another document. Usually, the official compendia and FDA
regulations for colour additives (21 CFR Parts 70 through 82), direct food additives
(21 CFR Parts 170 through 173), indirect food additives (21 CFR Parts 174 through
178) and food substances (21 CFR Parts 181 through 186) may be used as sources for
release tests, specifications and safety. Guidelines suggested for a Type II DMF may
be helpful for preparing a Type IV DMF. .

 Type V - FDA Accepted Reference Information

FDA discourages the use of Type V DMF's for miscellaneous information;
duplicate information or information that should be included in one of the other types
of DMF's. If any holder wishes to submit information and supporting data in a DMF
that is not covered by Types I through IV, a holder must first submit a letter of intent

Page 30
 CHAPTER METHODOLOG
4 Y

to the drug master file staff. FDA will then contact the holder to discuss the proposed
submission.
DMF’s review -
The FDA does not send a notification to the submitter when any submission, including
a DMF is received by the document room. After receipt, the original DMF undergoes an
administrative review to determine whether it is administratively complete. This
administrative review may take 2-3 weeks. If the DMF is acceptable from an administrative
point of view, an acknowledgement letter will be issued, notifying the holder of the DMF
number. At this point the DMF is "ACTIVE." If it is not acceptable from an administrative
point of view, the holder will be notified of what deficiencies need to be corrected to make the
DMF Active.FDA does not acknowledge, whether via e-mail or letter, any submission after
the original DMF. All submissions to an existing DMF undergo an administrative review to
determine whether they are administratively complete. If a submission to an existing DMF is
not acceptable from an administrative point of view, the holder will be notified of what
deficiencies need to be corrected to make the submission acceptable. FDA mentions the letters
A and I to the DMF’s.
“A” = Active. This means that the DMF was found acceptable for filing,
administratively and has not been closed.
“I” = Inactive. This means a DMF that has been closed, either by the holder or by the
FDA.
Numbers for DMFs that are cancelled, pre-assigned and pending or have been
transferred to another centre in the FDA are not included in the list. The status not conveys
information about whether a DMF has been reviewed for technical content or whether it has
undergone a completeness assessment. Any addition, change or deletion of information in a
drug master file is required to be submitted in two copies and to describe by name, reference
number, volume and page number the information affected in the drug master file.
The DMF Guidance recommends that DMF holders update their DMFs annually. In
order to ensure that DMFs are current, FDA sends “Overdue Notification Letters” (ONLs) to
DMF holders for DMFs that have not had an annual report submitted in the past thirty six (36)
months. If a DMF holder does not respond with the submission of an Annual report to this
letter within 90 days, the DMF may be closed by the FDA.

Page 31
 CHAPTER METHODOLOG
4 Y

Reactivating an Inactive (Closed) DMF -An Inactive DMF can be returned to ACTIVE status
only by submission of a REACTIVATION, which should contain a complete re- submission
of the DMF, updated to meet current guidance. The cover letter must specify that the
submission is a REACTIVATION. Alternatively, the DMF holder can submit a new DMF. The
recommendations in the DMF Guidance are still applicable. However, the information below
provides additional information or clarification of the recommendations in the guidance falls
into four categories:
 Category 1: Recommendations which are no longer applicable due to changes in
regulations or guidance.
 Category 2: Additional clarification of recommendations in the guidance.
 Category 3: New information for aspects of DMF filing that was not in effect when the
guidance was written.
 Category 4: Information related to the Generics Drug User Fee Act (GDUFA)
Technical Review
DMFs are subjected to a complete review for technical information only under the
following circumstances:
 The DMF is ACTIVE.
 The DMF holder submits a Letter of Authorization (LOA) in two copies (if a paper
submission) to the DMF. If the DMF is in CTD format, whether electronic or paper,
the LOA should be submitted. This LOA should contain the DMF number.
 The holder sends a copy of the LOA to the authorized party.
 The authorized party applies to the FDA that contains a copy of the LOA. The copy of
the LOA should be submitted with the application.

Complete Assessment

Type II DMFs to support ANDAs under GDUFA are subject to an initial "Completeness
Assessment" under the conditions specified in the Final Guidance “Completeness
Assessments for Type II API DMFs under GDUFA." (CA Guidance)

Page 32
CHAPTER METHODOLOG
4 Y

CANADA
HEALTH CANADA

Page 33
 CHAPTER METHODOLOG
4 Y

Canada is a country situated in North America that consists of ten provinces and three
territories that extends from the Atlantic to the Pacific and northward into the Arctic Ocean. It
is the world’s second-largest country by total area and the fourth-largest country by land area
with population of 35 million. Its advanced economy is one of the largest in the world.

Health Canada has been accepting regulatory activities in electronic Common

Technical Document (eCTD) format since 2004. In the situation that a regulatory
activity/transaction is not yet accepted in eCTD format by Health Canada, an interim option is
to file the regulatory activity/transaction in the “non-eCTD electronic-only” format until it is
accepted in either the eCTD format or in the Regulated Product Submission (RPS) format.
The following regulatory activity types are eligible for filing in “non-eCTD electronic-only”
format:

1. Division 1
 Application for Drug Identification Number (DINA)
 Application for Drug Identification Number - Biologic (DINB)
 Application for Drug Identification Number - Disinfectant Product (DIND)
 Application for Drug Identification Number - Category IV Product (DINF)
 Post-Authorization Division 1 Change (PDC)
 Post-Authorization Division 1 Change - Biologics (PDC-B)

Division 5

 Clinical Trial Application (CTA)

 Clinical Trial Application - Amendment (CTA-A)
 Clinical Trial Application - Notification (CTA-N)
 Clinical Trial Site Information (CTSI) Forms
 Pre-CTA Meeting Information

Division 8

 New Drug Submission (NDS)

 Extraordinary Use New Drug Submission (EU NDS)
 Abbreviated New Drug Submission (ANDS)

Page 34
CHAPTER METHODOLOG
4 Y

 Supplement to a New Drug Submission (SNDS)

 Extraordinary Use Supplement to a New Drug Submission (EU SNDS)
 Supplement to a New Drug Submission-Confirmatory (SNDS-C)
 Supplement to an Abbreviated New Drug Submission (SANDS)
 Notifiable Change (NC)
 Request for Priority Review Status for NDS or SNDS
 Yearly Biologic Product Report (YBPR)
 Periodic Safety Update Report - Confirmatory (PSUR-C) or Periodic Benefit Risk
Evaluation Report - Confirmatory (PBRER-C) when provided to TPD, BGTD or
NNHPD
 Pre-Submission Meeting Information(MPNDS, MPSNDS, MPDIN, or MPNC)
 Undefined Regulatory Activity (UDRA)
o Response to Advisement Letter to update the Product Monograph,
when an NC is not filed
o Notification of Discontinued Sale (DIN Cancellation)
1. DSUR
 Development Safety Update Report (DSUR) when provided as a standalone
regulatory activity to Therapeutic Products Directorate (TPD), Biologics and Genetic
Therapies Directorate (BGTD) or Natural and Non-prescription Health Products
Directorate (NNHPD).
2. PV-Data
 Periodic Safety Update Report (PSUR) or Periodic Benefit Risk Evaluation Report
(PBRER) when provided to the Marketed Health Products Directorate (MHPD)
 Risk Management Plan (RMP), when provided to MHPD
 Other Post-market Vigilance data (Undefined Data Post-market Vigilance (UDPV))
requested by MHPD
o Risk communication document (e.g., Dear Health Care Professional
Letter, dissemination lists, Proposed Dissemination Strategy) should be
sent to the Office of Submissions and Intellectual Property (OSIP) with
an electronic convenience copy being provided directly to MHPD via
email

Page 35
 CHAPTER METHODOLOG
4 Y

o Post-market Surveillance (e.g., Issue-related Summary Reports,

Council for International Organizations of Medical Sciences (CIOMS),
Registry Reports, Clinical Study Reports) Benefit Risk Assessment
o Response to MHPD Requests for Additional Information
o Notification of Change in benefit-risk profile
o Meetings regarding post marketing issues with MHPD
3. Level 3
 Post NOC - Level III Changes Form
4. DMF

A Drug Master File (DMF) is a reference that provides information about specific
processes or components used in the manufacturing, processing, and packaging of a drug. The
DMF is a useful vehicle for providing information to Health Canada, where that information
is of a proprietary nature and is not available to the manufacturer of the dosage form or to a
Sponsor of a submission when they are not the dosage form manufacturer. The DMF can be
referenced by drug manufacturers in support of their New Drug Submissions (NDSs),
Abbreviated New Drug Submissions (ANDSs), Supplement to a New Drug Submission
(SNDS) Supplement to an Abbreviated New Drug Submission (SANDS), DIN submissions,
Notifiable Changes (NCs), New Product Number (NPN) applications and Clinical Trial
Applications (CTAs). DMFs may be referenced by more than one drug manufacturer.
Canadian DMF: division of formation to Sponsor's (Open) and Restricted (Closed) part for
DMFs type I and IV
 DMF Type I - Drug Substance
 DMF Type II - Container Closure Systems and Components
 DMF Type III - Excipients
 DMF Type IV- Drug Product

Guidelines in CANADA: September 05, 2008

The draft version of this Health Canada guidance document Drug Master Files (DMF)
is now available for comment. This guidance document is a revised version of the guidance
document Product Master Files published in 1994 which will replace the 1994 document
when it is officially adopted.

Page 36
DISCUSSION
CHAPTER 05
 CHAPTER DISCUSSIO
5 N

DISCUSSION

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 drug master file 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 details.

Drug Master File (DMF) is a document containing complete information on an Active

Pharmaceutical Ingredient (API) or finished drug dosage form.US-Drug Master file (US-DMF)
in the United States, Master File in Canada.

DMF system in US:

A 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.

Beginning on May 5, 2018, new DMFs, as well as all documents submitted to existing DMFs,
must be submitted using the Electronic Common Technical Document (eCTD). DMF
submissions that are not submitted in eCTD format after this date will be rejected.

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.

Types of DMF:

Page 33
 CHAPTER DISCUSSIO
5 N

There are five types of DMFs, the most common being a Type II DMF followed by a Type III
DMF. It should be noted, however, that only four DMFs (types II-V) are still actively submitted
as the Type I DMF has been phased out.

Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel (no longer
applicable)

Type II: Drug substances (Active Pharmaceutical Ingredients), substance intermediates and
materials used in their preparation, or a drug product

A Type II DMF, the most common form, can also cover dosage form drugs manufactured under
contract for another company which would file an ANDA.

Type III: Packaging materials,

From bottles and caps to PVC resin used in their manufacture must be covered in a DMF or other
FDA document such as an NDA.

Type IV: Excipient, colorant, flavor, essence or material used in their preparation.

Excipients are chemically inactive substances such as starches or cellulose used to bind drug
powder together so that it can be pressed into a tablet. Other examples include flavorings in
children's drugs, alcohol in liquids, etc.

Type V: This is basically FDA accepted reference information that is not included in the other
types of DMFs.

Finally, there is also a Type I DMF which, as noted earlier, is no longer accepted by
the FDA. However, older ones remain on file It should be noted that the manufacturer of any
materials (e.g, API, DP, container/closure components, etc.) can choose to submit the
information necessary for review directly to their customers for inclusion in the IND, NDA,
ANDA, and BLA, supplements or amendments to these applications. НLs can be accomplished
in whole or in part. If only a part is submitted, it is considered the “open part” of a DMF that is
shared, while the proprietary part is the “closed part” of the DMF.

Page 34
 CHAPTER DISCUSSIO
5 N

U.S DMF submission in eCTD:

The requirement to submit DMFs using the eCTD format is part of FDA’s overall effort to
review drug applications more efficiently. eCTD standardizes how industry submits applications,
amendments, supplements, and reports.

Beginning on May 5, 2018, new DMFs other than Type III DMFs, as well as all documents
submitted to existing DMFs other than Type III DMFs, must be submitted using the Electronic
Common Technical Document (eCTD). DMF submissions that are not submitted in eCTD
format after this date will be rejected. For Type III DMFs, the requirement goes into effect on
May 5, 2020.

eCTD:

Electronic Common Technical Document (eCTD) is currently FDA’s standard submission

format for NDA’s, IND’s, ANDA’s, certain BLA’s and DMFs through Electronic
Submission Gateway (ESG).

FDA states that DMFs are typically submissions to these applications and, as such, are
subject to electronic submission required by section 745A(a) of the Federal Food, Drug,
and Cosmetic (FD&C) Act.

 May 5, 2017: New Drug Applications (NDAs), Abbreviated NDAs (ANDAs), and
Biologics License Applications (BLAs), must be submitted using eCTD format.
 May 5, 2018: Commercial Investigational New Drug Applications (INDs) and Master
Files must be submitted using eCTD format.

Requirements for using eCTD:

When making an eCTD application, you must submit all the documents to be submitted, which
should be included in eCTD, in electronic files. Scan the relevant page signed or signed and
sealed, etc. on a paper medium, replace it with the corresponding page on the electronic medium
and save it and include it in eCTD. In that case, submit a statement indicating that the
corresponding page has been correctly scanned. Although it is not necessary to submit any
written statement at the time of application, prepare it so that you can submit it upon request

Page 35
 CHAPTER DISCUSSIO
5 N

from the regulatory authority. Include an electronic file of the statement in Section 3 of Module
1.

When responding the inquiries from the regulatory authority in the review process of the eCTD
application, if draft electronic study data are submitted by the applicant to the regulatory
authority, then use eCTD according to this document. In this case, you cannot use eCTD to
submit anything other than electronic study data (Example: The responses themselves, electronic
files other than the electronic study data to be attached to the responses). Implementing
electronic DMFs will improve the standardization of the DMF review process. After May 5,
2018, there will be no waivers or exemptions for DMFs that are not submitted in eCTD format.

Only if you confirm with the regulatory authority in advance and it is permitted, then you may
submit eCTD which deviates from the handling according to this document and Appendix 2. In
this case, submit a document containing the reason for this and points of attention. Include an
electronic file of this document in Section 13 of Module 1.

Overdue Notification Letters:

DMFs must be current at the time of review. According to the regulations regarding DMFs (21
CFR 314.420(c)):

 “Any addition, change, or deletion of information in a drug master file (except the list
required under paragraph (d) of this section) is required to be submitted in two copies and
to describe by name, reference number, volume, and page number the information
affected in the drug master file.”
 The DMF Guidance recommends that DMF holders update their DMFs annually (see
below under Annual Reports).
 In order to ensure that DMFs are current, FDA sends “Overdue Notification Letters”
(ONLs) to DMF holders for DMFs that have not had an Annual Report submitted in the
past thirty-six (36) months. If a DMF holder does not respond with the submission of an
Annual report to this letter within 90 days, the DMF may be closed.

Page 36
 CHAPTER DISCUSSIO
5 N

Comparison of CTD and eCTD:

Table 4: Comparison of CTD and eCTD

Paper format or CTD eCTD

Compiled electronically with volumes, tabs Compiled electronically with eDocuments in

and slipsheets, then printed to paper folders

Paper volumes must be A4 eDocuments can be A4 or US letter size

CTD navigation by TOCs and volume eCTD navigation by XML backbone

Cross-references includes target CTD section Cross-references are hyperlinked to targets

number

Manual document navigation by TOCs, page Electronic document navigation by TOCs,

numbers, and caption cross-references bookmarks and hyperlinks

Submitted in binders in boxes on pallets by Submitted on CD (or DVD?), or by email or

trucks portal

Electronic Submission Gateway (ESG):

The Food and Drug Administration (FDA) Electronic Submissions Gateway (ESG) is an
Agency-wide solution for accepting electronic regulatory submissions. The FDA ESG enables
the secure submission of premarket and post market regulatory information for review.

The FDA ESG is the central transmission point for sending information electronically to the
FDA. Within that context, the FDA ESG is a conduit along which submissions travel to reach the
proper FDA Center or Office.

Page 37
 CHAPTER DISCUSSIO
5 N

FDA ESG provides two methods, Web Trader (WT) and AS2, for making submissions to FDA.
FDA ESG has been in production since 2006 and is used by 100s of users to send 1,000s of
submissions every day.

 WT: A web portal designed for low volume submitters. WT allows users to login,
digitally sign and submissions, and view responses through a simple web interface.
 AS2: A system-to-system connection to exchange submissions with FDA. AS2 requires a
Gateway software implementation on submitters end.

Attention Web Trader submitters:

The FDA ESG program is implementing a policy to automatically log a user out from the Web
Trader user interface after 30 minutes of inactivity. This policy is being implemented to enhance
the security posture of FDA ESG. Please note that this change will not affect the functionality of
the Web Trader in any way.

Submissions can be sent to the FDA Electronic Submissions Gateway (ESG) via a web interface
also known as Web Trader or by a gateway to gateway connection known as AS2. After
requesting and completing the required Center compliant test and receiving the user
authentication credentials, submissions can be sent to the Gateway and then delivered to the
Centers for further processing.

DRUG MASTER FILE CONTENTS:

Types of Drug Master Files

Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel

A Type I DMF is recommended for a person outside of the United States to assist FDA in
conducting on site inspections of their manufacturing facilities. The DMF should describe the
manufacturing site, equipment capabilities, and operational layout.

A Type I DMF is normally not needed to describe domestic facilities, except in special cases,
such as when a person is not registered and not routinely inspected.

Page 38
 CHAPTER DISCUSSIO
5 N

The description of the site should include acreage, actual site address, and a map showing its
location with respect to the nearest city. An aerial photograph and a diagram of the site may be
helpful.

A diagram of major production and processing areas is helpful for understanding the operational
layout. Major equipment should be described in terms of capabilities, application, and location.
Make and model would not normally be needed unless the equipment is new or unique.

A diagram of major corporate organizational elements, with key manufacturing, quality control,
and quality assurance positions highlighted, at both the manufacturing site and corporate
headquarters, is also helpful.

Type II: Drug Substance, Drug Substance Intermediate, and Material Used in Their
Preparation, or Drug Product

A Type II DMF should, in general, be limited to a single drug intermediate, drug substance, drug
product, or type of material used in their preparation.

(1) Drug Substance Intermediates, Drug Substances, and Material Used in Their
Preparation

Summarize all significant steps in the manufacturing and controls of the drug intermediate or
substance.

(2) Drug Product

Manufacturing procedures and controls for finished dosage forms should ordinarily be submitted
in an IND, NDA, ANDA, or Export Application. If this information cannot be submitted in an
IND, NDA, ANDA, or Export Application, it should be submitted in a DMF.

Type III: Packaging Material Each packaging material should be identified by the intended
use, components, composition, and controls for its release. The names of the suppliers or
fabricators of the components used in preparing the packaging material and the acceptance
specifications should also be given.

Page 39
 CHAPTER DISCUSSIO
5 N

Toxicological data on these materials would be included under this type of DMF, if not
otherwise available by cross reference to another document.

Type IV Excipient, Colorant, Flavor, Essence, or Material Used in Their

Preparation

Each additive should be identified and characterized by its method of manufacture, release
specifications, and testing methods.

Toxicological data on these materials would be included under this type of DMF, if not
otherwise available by cross reference to another document.

Usually, the official compendia and FDA regulations for color additives (21 CFR Parts 70
through 82), direct food additives (21 CFR Parts 170 through 173), indirect food additives (21
CFR Parts 174 through 178), and food substances (21 CFR Parts 181 through 186) may be used
as sources for release tests, specifications, and safety.

Type V: FDA Accepted Reference Information

FDA discourages the use of Type V DMF's for miscellaneous information, duplicate
information, or information that should be included in one of the other types of DMF's. If any
holder wishes to submit information and supporting data in a DMF that is not covered by Types I
through IV, a holder must first submit a letter of intent to the Drug Master File Staff. FDA will
then contact the holder to discuss the proposed submission.

SUBMISSIONS TO DRUG MASTER FILES:

Each DMF submission should contain a transmittal letter, administrative information about the
submission, and the specific information to be included in the DMF as described in this section.

The DMF must be in the English language. Whenever a submission contains information in
another language, an accurate certified English translation must also be included.

Page 40
 CHAPTER DISCUSSIO
5 N

Each page of each copy of the DMF should be dated and consecutively numbered. An updated
table of contents should be included with each submission.

REVIEW OF DMFS:

Administrative Review:

Administrative information (or) prescribing information (Module 1)

The FDA does not send a notification to the submitter when any submission, including a DMF, is
received by the document room. After receipt, the original DMF undergoes an administrative
review to determine whether it is administratively complete. This administrative review may
take 2-3 weeks. See "Administrative Information in a DMF" below. If the DMF is acceptable
from an administrative point of view, an Acknowledgement Letter will be issued, notifying the
holder of the DMF number. At this point the DMF is "ACTIVE." If it is not acceptable from an
administrative point of view, the holder will be notified of what deficiencies need to be corrected
in order to make the DMF "Active".

FDA does not acknowledge, whether via e-mail or letter, any submission after the original DMF.
All submissions to an existing DMF undergo an administrative review to determine whether they
are administratively complete. If a submission to an existing DMF is not acceptable from an
administrative point of view, the holder will be notified of what deficiencies need to be corrected
in order to make the submission acceptable

Module 1 should contain the following information

 Section 1.2
o Cover Letter
o Statement of Commitment
o Generic Drug User Fee Cover Sheet (3794), where

applicable According to the DMF Guidance “The Statement of

Commitment” is:

Page 41
 CHAPTER DISCUSSIO
5 N

“A signed statement by the holder certifying that the DMF is current and that the DMF holder
will comply with the statements made in it.“

 Section 1.3: Administrative Information

o 1.3.1 Contact/sponsor/Applicant information
 1.3.1.1 Change of address or corporate name
 1.3.1.2 Change in contact/agent
 1.3. Debarment Certification.

 Section 1.4: Reference Section

o 1.4.1 - Letter of Authorization (LOA)
o 1.4.2 - Statement of Right of Reference
o 1.4.3 - List of authorized persons to incorporate by

reference As stated in 21 CFR 314.420(d):

"The drug master file is required to contain a complete list of each person currently authorized to
incorporate by reference any information in the file, identifying by name, reference number,
volume, and page number the information that each person is authorized to incorporate."

 Section 1.5 Application Status

o 1.5.3 - Reactivation request
o 1.5.5 - Withdrawal of an unapproved NDA, ANDA or Supplement
can be used to close a DMF.
 Section 1.6. Meetings
o 1.6.1 Meeting Request
o 1.6.2 Meeting background materials
o 1.6.3 Communication regarding meetings
 Section 1.11: Information Amendment: Information not covered under modules 2 to 5
o 1.11.1 Quality information amendment
o 1.11.2 Nonclinical information amendment
o 1.11.3 Clinical information amendment
o 1.11.4 Multiple module information amendment

Page 42
 CHAPTER DISCUSSIO
5 N

 Section 1.12 Other Communication

o 1.12.4 Request for comments and advice
o 1.12.14 Environmental Analysis
 Section 1.13: Annual Report
o 1.13.5 Summary of manufacturing changes
 Section 1.14: Labeling
o 1.14.2 Final labeling

Technical Review:

 DMFs are subject to a complete review for technical information only under the
following circumstances:
1. The DMF is ACTIVE.
2. The DMF holder submits a Letter of Authorization (LOA) in two copies (if a
paper submission) to the DMF. If the DMF is in CTD format, whether electronic or
paper, the LOA should be submitted in Section 1.4.1. This LOA should contain the
DMF number.
3. The holder sends a copy of the LOA to the authorized party.
4. The authorized party submits an application to the FDA that contains a copy of
the LOA. The copy of the LOA should be submitted in Section 1.4.2. of the
application.

FORMAT OF eCTD SUBMISSION FOR TYPE-II DMF:

A. General Information: 1. General properties

2. Structure

3. Nomenclature

B. Manufacture: 1. Manufacture(s).

2. Description of Manufacturing Process and Process Control.

3. Control of Material.

4. Control of Critical Steps and Intermediates.

Page 43
CHAPTER DISCUSSIO
5 N

5. Specifications and Test method for the Intermediates.

Page 44
 CHAPTER DISCUSSIO
5 N

6. Manufacturing Process Development.

C. Characterization: 1. Elucidation of Structure and other characteristics

2. Impurities

D. Control of drug substances: 1. Specifications

2. Analytical procedure (STP)

3. Validation of Analytical procedure

4. Batch Analysis

5. Justification for specifications

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

H. Material Data Safety Sheet

MECHANISM:

A DMF goes through two stages of being assessed prior to it being available for
review of its [technical] content. First, FDA assesses whether all parts of the DMF are included
and in the correct order. Once FDA determines that the eDMF is acceptable, it will then undergo
an administrative review as discussed above. If the DMF is not acceptable from an electronic
technical perspective, the holder will be informed. The holder must then satisfactorily respond to
any deficiencies for the DMF to proceed to an administrative review which will be conducted by
the DMF staff in the Office of Pharmaceutical Quality (OPQ). If the DMF passes the
administrative review and is found to be acceptable, OPQ sends an Acknowledgement Letter at
which point the DMF is available for review of the technical content. However, if the DMF is
not acceptable from an administrative point of view, OPQ sends an Administrative Filing Issues
(AFI) letter. The holder must respond adequately for the DMF to be available for review of the
technical content. The time frame for this could be from 2-3 weeks.

Page 45
 CHAPTER DISCUSSIO
5 N

US AGENTS:

The US FDA requires that all foreign firms conducting business in the FDA
regulatory sphere do so with the use of a U.S. Agent, who acts as an intermediary between FDA
and the foreign firm US Agent information must be included in all DMF submissions to FDA
and any updates of US Agent contact information should be submitted as well. Should FDA
reviewers have questions regarding the DMF, they will contact the US Agent with those
questions in addition to the submitter and provide a timeline in which those responses must be
provided.

DMF submissions are technical reports to FDA concerning a number of

variables in the drug application, all of which relate to the safety and efficacy of pharmaceutical
products marketed in the US. Close attention should be paid to not only the content but the
format in which the documentation is provided to FDA. It is likely that FDA will have follow-on
questions of the submitter, but a competent US Agent as well as competent review of the
materials by a qualified pharmaceutical consultant with expertise in the drug submission process
will make the process go more smoothly. One final caveat-DMF’s must be updated when new
information is available. The new information could be a new plasticizer for a container/closure
system, new route of synthesis, an improvement to a dosage form, or any other change that has
the potential for compromising the safety of the pharmaceutical. It is incumbent upon DMF
holders to communicate any changes in advance of the change to their clients to allow them time
to make their own plans and changes. This is critical! It is also important that any deficiency
letters sent by the FDA to the DMF holder be communicated to their clients who can be
impacted by the deficiency letter. The DMF holder needs to respond to the deficiencies in the
most expeditious manner to prevent FDA holding back approvals of submissions. This too is
very critical. A consultant could be invaluable in demystifying these types of issues.

TYPES OF DMF SUBMISSION:

USA:

 New Drug Application (NDA), for new drugs.

 Abbreviated New Drug Application (ANDA)-for generics.
 Type-II DMF for Drug Substances and Drug Products

Page 46
 CHAPTER DISCUSSIO
5 N

Differences between Application and DMF:

Table 5: Differences between Application and DMF

APPLICATION DMF

1. Comes under regulatory status must be filed 1. Does not come under regulatory status it
by applicant. is not mandatory to file a DMF.
2. Each application and its supplement are 2. DMFs are entered into database as per
entered into a common database. their types. (Separate database for each type
of DMF)
3. Submitted to a particular review division. 3. Submitted to CDER.
4. Assignment to a reviewer and each 4. No assignment to a reviewer, no due date.
submission has a due date.
5. Review procedure quite different than DMF 5. DMFs are reviewed only when referenced
by an application or another DMF.
6. If the anniversary date for annual update is 6. If the anniversary date for annual update is
missed FDA sends a reminder. missed FDA will not send a reminder.

US DMF FILING SYSTEM:

FILING DMFs AND PATENT EXPIRATION AND EXCLUSIVITY ISSUES:

DMFs may be filed at any time. The Patent Expiration date and the Exclusivity Expiration dates
listed in the Orange Book have no impact on DMF filing.

The submission of Abbreviated New Drug Applications (ANDAs) that reference DMFs is
subject to the regulations regarding filing of ANDAs.

1. Filing the DMF

• Holder sends two copies of the DMF to FDA.

• DMF is reviewed for administrative purposes only by Central Document Room staff.

Page 47
 CHAPTER DISCUSSIO
5 N

• DMF entered into database, assigned a number and acknowledgment letter sent to holder.

• A DMF is neither approved nor disapproved.

2. 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 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.

LETTERS OF AUTHORIZATION

 All Letters of Authorization (LOAs) should be submitted in two copies to the DMF, if the
DMF is in paper format. If the DMF is in CTD format, whether in paper or eCTD, the
LOA should be submitted in Section 1.4.1 and it is attached as Attachment 01.
 A copy of the LOA must then be sent by the DMF holder to the Authorized Party
(company or individual authorized to incorporate the DMF by reference). Failure to
submit the original LOA to the DMF may result in a delay in review of the DMF.
 LOAs should specify the name of the specific item being referenced and the date of the
submission of information about that item. The LOA should not be called a “Letter of
Access.”

3. 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 is
not communicated to the Applicant.

Page 48
 CHAPTER DISCUSSIO
5 N

Flow chart for review of procedure:

API Manufacturer (DMF holder) ANDA application holder

LOA
eCTD summary ANDA
LOA

Authorized Agent (or) Regulatory Agency

In-Country care taker

Deficiency Letter (DL)

Page 49
 CHAPTER DISCUSSIO
5 N

Additional Information
Request Letter
Regulatory Agency

FDA (or) PMDA Review of Application

Acknowledgment of receipt by FDA Acknowledgment of receipt by FDA

Review of DMF
[deficiencies (or) Lack of data]

If no Deficiencies (or)
after clearing the Deficiencies

No Further comments Letter from FDA

Fig.6 Flow chart for review of procedure

Page 50
CONVERSION OF PAPER DMFS TO ELECTRONIC DMFS:

 An existing DMF number may be used when converting a paper DMF to electronic
format. If the existing number is 4-digits, e.g. 1234, the DMF holder should pad left with
zeroes to convert to a 6-digit format, e.g. 001234.
 There is no requirement to submit or resubmit DMFs in electronic format. However, if a
paper DMF is converted to eCTD format, and there are any changes in the technical
content of the DMF as a result of reformatting, e.g. addition of new information, the
cover letter for the new submission should specify what areas of technical information
have been changed. The numbering of the submissions should start with 0001.

REPORTING CHANGES TO A DMF:

Any addition, change, or deletion of information in a DMF is required to be submitted to the

DMF. In addition the DMF holder must notify each person authorized to reference the DMF
(authorized party) (See 21 CFR 314.420(c)) There are no reporting categories for DMFs. All
changes must be reported as amendments.

The DMF holder should notify each authorized party of the nature of the changes, providing as
much detail as is consistent with the confidentiality agreement between the DMF holder and the
authorized party, so that the authorized party can determine how to report the changes in their
approved NDA or ANDA.

Format, Font, Font Size and Paper used for submission to USFDA, whether DMF gets
approved or rejected by USFDA

 Electronic DMF should be filed. In Common Technical Document, the display of

information should be unambiguous and transparent, in order to facilitate the review of
the basic data and to help a reviewer become quickly oriented to the application contents.
 Text and tables should be prepared using margins that allow the document to be printed
on both A4 paper (Japan) and 8.5 x 11” paper (U.S.). The left-hand margin should be
sufficiently large that information is not obscured by the method of binding. Font sizes
 for text and tables should be of a style and size that are large enough to be easily legible,
even after photocopying.
 Times New Roman, 12-point font is recommended for narrative text. Every page should
be numbered, according to the granularity document. Acronyms and abbreviations should
be defined the first time they are used in each module.
 DMF neither approved nor disapproved by USFDA.
 U.S. standard paper size (8.5 by 11 inches) is preferred.
 Paper length should not be less than 10 inches nor more than 12 inches. However, it may
occasionally be necessary to use individual pages larger than standard paper size to
present a floor plan, synthesis diagram, batch formula, or manufacturing instructions.
Those pages should be folded and mounted to allow the page to be opened for review
without disassembling the jacket and refolded without damage when the volume is
shelved.
 The agency's system for filing DMF's provides for assembly on the left side of the page.
The left margin should be at least three fourths of an inch to assure that text is not
obscured in the fastened area. The right margin should be at least one half of an inch. The
submitter should punch holes 8 1/2 inches apart in each page.

COVER LETTER:

Provide a clear, concise description of the submission. If providing a response to an information

request, include a hyperlink to the location of the response document and it is attached as
Attachment 02.

Always include the U.S. agent’s information in case we need to contact the sponsor.

Provide a point of contact for technical issues with electronic submissions.

Provide the correct email address and fax number for technical rejection notices.

Tips on submitting:

• Request an application number from Center for Drug Evaluation and Research (CDER) when
planning to submit a new MF
When submitting a MF to CDER via ESG, choose “CDER” as the center and “eCTD” as the
submission type.

When replacing a document submitted in a previous sequence, use the eCTD replace life cycle
operation rather than submitting the file as new.

Annual Reports for DMFs in eCTD can be submitted on the same date as any other submission
but they must have a different Sequence Number.

Amendments (Supporting Documents) are named by a Category and

Subcategory For the Application Type “Drug Master File” the Submission Types

are:

 Original: Amendments containing changes to technical information are filed in the

“Original” submission and the Category/Subcategory should be specified in the header of
the Cover Letter. A new DMF does not need a “Category/Subcategory” designation by
the holder.
 Annual Report: There is only one Category with two Subcategories:
o Annual Report
o Amendment
 Letter of Authorization: There is only one Category with two Subcategories:
o Letter of Authorization
o Withdrawal of Authorization
 General Information (Reactivation, Closure Request, Administrative Information)
o Categories of Amendments (Supporting Documents) in General Information
 Category: Closure Request
 Category: Reactivation (Used only when a DMF has been Closed.)
 Category: Administrative
Subcategories under Administrative Category
 change in the holder name
 change in holder address
 change in ownership of the DMF (either internal name change, or
change in ownership)
  Change in the agent name or address.
 Change in the contact person at the holder or agent.
 Change in the subject of the DMF.
 change in the type of DMF
 response to an Administrative Filing Letter

ANNUAL REPORTS:

According to the DMF Guidance, Annual Reports are NOT to be used to report changes in the
DMF. As noted above, Annual Reports submitted at the same time as amendments in eCTD
must have separate Sequence Numbers.

The Annual Report should contain

1. An administrative page containing the Administrative Information specified

above (Administrative Information in a DMF)
AND
2. One of the following

 Date(s) of the amendment(s) reporting changes since the last Annual Report or the
original DMF filing date, whichever is most recent.
Or
 A statement that no amendments have been submitted since the last Annual Report or
the original DMF filing date, whichever is most recent.

AND
3. One of the following:
A complete list of all parties authorized to make reference to the DMF, identifying by name,
reference number, volume, date, and page number the information that each person is authorized
to incorporate by reference and the date of the LOA.
Or
A statement that there are no Authorized Parties.
AND
4. List of all parties whose authorization has been withdrawn

Note that the DMF Guidance uses the terms “Annual Update” and “Annual Report”
interchangeably. All submissions of Annual Reports should be labeled “Annual Report.” The
term “Annual Update” should not be used.

Note that the Annual Report should contain a COMPLETE list of Authorized Parties, even if the
list of Authorized Parties is unchanged.

CLOSURE OF A DRUG MASTER FILE:

A holder who wishes to close a DMF should submit a request to the Drug Master File Staff
stating the reason for the closure.

Drug Master File Staff

Food and Drug Administration
5901-B Ammendale Rd.
Beltsville, MD 20705-1266
Delivery charges to the above address must be prepaid.

The request should include a statement that the holder's obligations as detailed in Section VII
have been fulfilled.

The Agency may close a DMF that does not contain an annual update of persons authorized to
incorporate information in the DMF by reference and a list of changes made since the previous
annual report. The holder will be notified of FDA's intent to close the DMF.

GENERIC DRUGs USER FEE AMMENDMENTS (GDUFA):

On July 9, 2012, GDUFA was signed into law by the President as part of the Food and Drug
Administration Safety and Innovation Act (FDASIA). GDUFA is designed to speed the delivery
of safe and effective generic drugs to the public and improve upon the predictability of the
review process. GDUFA is based on an agreement negotiated by FDA and representatives of the
generic drug industry to address a growing number of regulatory challenges.

GDUFA must be reauthorized every five years. On August 18, 2017, the President signed the bill
reauthorizing GDUFA through September 30, 2022.

GDUFA reflects input received during an open process that included regular public meetings,
posting of meeting minutes, and consideration of comments from a public docket. Agreed upon
recommendations were sent to Congress, and Congress held hearings on GDUFA that included
testimony from FDA, the generic drug industry, and other interested parties.

Introduction to New GDUFA Requirements

DMF fee when and how to pay:

 New DMF correspondences and meetings

 DMF Complete Response letter
 DMF Incomplete letter
 DMF No Further Comments letter
 DMF 10-day teleconference
 Available for Reference List

Which DMFs incur Fees:

Only DMFs that cover the manufacture of an API (Type II API DMFs) for use in a generic drug
application incur fees. Specifically, each person who owns a Type II API DMF (DMF holder)
that is referenced on or after October 1, 2012, in a generic drug submission, by any initial letter
of authorization, shall be subject to a DMF fee.

GDUFA Cover Sheet:

The GDUFA Cover Sheet is required for each of the following human generic drug user fees:

 Generic drug applicant program fee;

  Abbreviated new drug application (ANDA) or applicable amendment;
 Type II active pharmaceutical ingredient (API) drug master file (DMF) that is referenced
on or after October 1, 2012, in a generic drug submission to the FDA and for which the
DMF fee has not already been paid;
 Generic drug facility which is identified or intended to be identified in at least one
generic drug submission that is pending or approved to produce a finished dosage form
(FDF) of a human generic drug or an API contained in a human generic drug; and
 Backlog ANDA which is pending on October 1, 2012, and that has not received a
tentative approval prior to that date.
 Required upon the first reference on or after October 1,2012
 Paid only once during the DMF lifecycle

When A DMF fee is not required?

 For ANDAs that are part of the backlog For submissions not part of GDUFA (INDs,
NDAs, Changes Being Effected (CBE) 0 or 30 supplements)
 For any non-Type II DMF (Type IV DMF for an Excipient)
 For any Type II DMF that is not referenced as the API
 DMFs for API intermediates
 DMFs for drug product manufacturing intermediates
 DMFs for Drug Products
 For submissions reporting a change to the DMF that had established a relationship to the
ANDA before GDUFA
 Issuing an updated Letter of Authorization that does not establish a new relationship to
the ANDA submission
FY 2019 GDUFA Fees:

Fee Type 2018 2019

Facility Fees Domestic Foreign Domestic Foreign
Active Pharmaceutical Ingredient (API) $45,367 $60,367 $44,226 $59,226
Finished Dosage Form (FDF) $211,087 $226,087 $211,305 $226,305
Contract Manufacturing Organization (CMO) $70,362 $85,362 $70,435 $85,435

ANDA Program Fees – Based upon the number of approved ANDAs held
Large (20 or more ANDAs) $1,590,792 $1,862,167
Medium (6 – 19 ANDAs) $636,317 $744,867
Small (5 or fewer ANDAs) $159,079 $186,217
Application Fees

ANDA $171,823 $178,799

Type II DMF $47,829 $55,013

Fig. 7 FY 2019 GDUFA Fees

Under GDUFA an important goal for the DMF holder is to get the DMF to “Available for
Reference” status so referencing ANDAs can be filed

Under GDUFA, an “Available for Reference” DMF must meet two requirements:

 The DMF fee must be paid

 The DMF must pass the Completeness Assessment

DMF Fee Payment Process:

Fee collection is processed in FDA for GDUFA by OFM (Office of Financial Management),
who manage the payment infrastructure and OM (Office of Management) who manage and track
the user fee obligations. Two common cases for fee payment:
  Paying DMF fees for DMFs which are not yet filed with FDA
 Paying DMF fees for DMFs which are already filed with FDA

Case 1: Pay the DMF fee for a DMF that has not yet been filed (file and pay)

Fig. 8 DMF Fee process that has not yet been filed

Case 2: Pay the DMF fee for a DMF that has already been filed (pay only): Skip this step
since you already have a DMF

With Assigned DMF Number, DMF Holder Pays User Fee through OFM User Fee System (i-
Store)

Fig. 9 DMF Fee process that has been filed

Steps:

1. DMF Holder logs into iStore at:

https://userfees.fda.gov/OA_HTML/gdufaCAcdLogn.jsp and provides the requested

information (including the DMF#)

2. System generates the appropriate user fee cover sheet with the required fee.
3. DMF Holder pays the required fee using the cover sheet (Note that partial payment is not
acceptable).

With DMF User Fee Paid, DMF Holder Submits the DMF Document (Case 1 only)

Submitting Documentation:

Note the following for Case 1 (pay then file):

 DMF User Fee Coversheet (Form 3794) must be included in the submission.
 File in Section 1.2 under FDA Regional Information

Note the following for Case 2 (pay only):

 Submit DMF User Fee Coversheet (Form 3794) separately to the DMF as a stand-alone
amendment (not within an annual update or other amendment)
 Clearly indicate on the cover letter that the submission is the User Fee Cover Sheet.

New DMF Correspondences and Meetings:

 DMF Complete Response (CR) letter

 DMF No Further Comments letter
 DMF Incomplete Letter
 10-day teleconferences
 List of “Available for Reference” DMFs posted on FDA website

1. Basis for the DMF CR Letter:

 The GDUFA Commitment Letter, which outlines the GDUFA Performance Goals and
Procedures (link provided below) states:
 “FDA will issue a letter detailing all identified deficiencies, rather than discipline
specific letters, for all DMFs including those under review at the time of enactment of
the implementing legislation.
 The DMF deficiency letters will reflect full division-level deficiency review of
deficiencies from all relevant review disciplines, including inspections, and address
other matters relating to the DMF review such as consults with other agency
components (these will be subsumed into the DMF metrics).”

2. DMF No Further Comments Letter:

The Commitment letter states:
 “Once a DMF has undergone a complete review and the ANDA referencing same is
either approved or tentatively approved at such time there being no further outstanding
deficiencies to the DMF – FDA will issue the DMF holder a letter to indicate that the
DMF does not have any further open matters as part of the review associated with the
referencing ANDA.”
 Issued at approval of the ANDA, not when the DMF is first deemed adequate
 Not to be construed as an indication of any future status of the DMF (i.e. not
equivalent to an approval letter)
3. DMF Incomplete Letter:
Issued to communicate issues discovered during the Completeness Assessment .Comments in
the letter will describe any issues and the additional information that is needed to address the
issues
4. “10 day” Teleconferences:
 Specific type of teleconference described in the commitment letter
 30 minute t-con for first cycle deficiency letters limited to the contents of the letter
 To qualify, a written request must be received by FDA within 10 days of receiving the
letter
 Contact information for requesting these teleconferences is included in the DMF CR
letter
  Meeting timeframe is at the discretion of OGD and availability of involved parties
 There are limits of one teleconference per DMF holder per month
5. The Available for Reference List:
 Required by the GDUFA legislation
 Comprehensive list of all Type II DMFs for APIs that have paid the DMF fee and
passed a Completeness Assessment
 Updated list is posted on the FDA website on a weekly basis
 All questions regarding the contents of the list should be sent to:
DMFOGD@fda.hhs.gov

Completeness Assessment for Type II Active Pharmaceutical Ingredient Drug Master Files
to Be Referenced in ANDAs:

Scope of Completeness Assessment (CA)

Five Defining Factors:

 DMF
 Type II
 API
 ANDA, ANDA Amendment, ANDA PAS
 GDUFA

Completeness Assessment (CA) is specified in GDUFA

Section 744B (a) (2) (D)(ii) of the Federal Food, Drug, and Cosmetic Act (FD&C Act),
which was added by GDUFA, states that a Type II API DMF will be deemed available for
reference in an ANDA, ANDA amendment, or ANDA PAS, if the required fee has been paid
and if the DMF has not failed an initial completeness assessment "in accordance with criteria
to be published by" FDA.

Section 744B (a) (2)(D)(iii) of the FD&C Act requires FDA to make publicly available on its
website a list of DMF numbers that correspond to DMFs that have successfully undergone an
 initial completeness assessment, in accordance with criteria to be published by FDA, and that
are available for reference.

Completeness Assessment aims to improve submission quality and review efficiency

 A “complete” DMF contains all of the information necessary for a full scientific
review.
 A “complete” DMF is not necessarily adequate to support approval of an ANDA.

Completeness Assessment is performed by OGD/DMF Review Staff

Performed by OGD/DMF Review Staff

 A review group dedicated to drug substance review (Type II DMFs) in support of

original ANDAs

Performed by a chemist

 Leverage expertise
 Enhance efficiency

DMF Fee payment triggers Completeness Assessment

1. DMF Fee is a one-time fee

2. Not to be confused with the facility fee related to the drug substance manufacturing facility
3. Payment of the DMF fee triggers the Completeness Assessment process in OGD
4. DMF Fee is required when the referencing ANDA is submitted
5. DMF Fee may be paid independent of a referencing ANDA in order to get a completeness
assessment and be to list on the FDA’s “Available for Reference” webpage.
6. DMF Fee may be paid at the strategic timing according to the referencing ANDA
submission
 Requires proactive communication with ANDA applicant
 Risks of delaying the ANDA filling if DMF fee has not been paid
 Process Flow of Completeness Assessment:

Fig. 10 Queue generation and Project Manager (PM) processing

Process Flow of Completeness Assessment (2):

Fig. 11 Full Completeness Assessment review by the Chemist

US DMF’s – Statistics:

Fig. 12 Status of DMFs in 2018

Fig. 13 Statistical data for Types of DMFs Filings in 2018

Filings of DMFs based on type:

Description DMF No of
Type DMFs
Manufacturing site, facilities, operating procedures, and personnel I 1,826

Drug substance, drug substance intermediate, and materials used in II 15,230

the preparation, or Drug Product
Packaging Material III 4,511

Excipient, Color, Flavor, Essence or material used in their IV 1,749

preparation

FDA Accepted reference information V 355

Blanks Blanks 1,969

GRAND TOTAL 25,640

Fig. 14 Filings of DMFs based on type of DMF

MASTER FILE SYSTEM IN CANADA

Master File (MF) System

A Master File (MF) is a reference that provides information about specific processes or
components used in the manufacturing, processing, or packaging of a drug. The MF is a
useful vehicle for providing information to Health Canada, where that information is
confidential business information (CBI) and is not available to the manufacturer of the
dosage form or to the sponsors of a drug submission, DIN (Drug Identification Number)
application or clinical trial application (CTA) (hereafter referred to as the Applicants). Health
Canada must protect confidential business information in accordance with the law.

This guidance document provides MF related-definitions, information on filing

requirements, processing and assessment procedures for Type I to IV MFs, and outlines the
registration requirements for new MFs as well as other MFs transactions including
administrative changes, updates, withdrawals and closures.

 Policy objective : To provide direction on the procedures that allow MF Holders or

authorized MF Agents to file CBI directly with Health Canada to be referenced in
support of an Applicant's drug submission (including DIN applications) or CTA with
respect to quality information.
 Policy statements: For the purpose of this guidance document and in accordance with
the Guidance Document: Preparation of Drug Regulatory Activities in the Electronic
Common Technical Document (eCTD) Format, MFs are categorized as regulatory
transactions (refer to Section 1.4 for definition).

Master Files are voluntary registrations filed with Health Canada that can be referenced
by Applicants seeking drug marketing authorizations or clinical trial authorizations
involving pharmaceuticals and biologics.

It is the responsibility of the Applicants to submit non-confidential business information

provided by the MF Holder or authorized MF Agent, obtained in the public domain,
and/or developed by the Applicant in the drug submission, DIN application or CTA.
 Applicant should ensure that the information included in the MF is up-to-date and that
the MF has been received by Health Canada by contacting the MF Holder or authorized
MF Agent for confirmation before filing their submission, DIN application or CTA to
Health Canada.

The Restricted Part of MF will be held in strict confidence and will be used in support
of the drug submission or CTA only upon receipt of a written letter of access (LoA)
from the MF Holder or authorized MF Agent.

The LoA is signed by the MF Holder or authorized MF Agent and indicates to Health
Canada that the Applicant and the MF Holder have agreed that the MF can be referred
to during the assessment of the Applicant's drug submission or CTA.

 Scope and application

This guidance document applies to all MF Holders, authorized MF Agents or

Applicants using an MF to support drug submissions and DIN applications for human
use or CTAs; and, Health Canada employees involved in MF processes. Submissions
and applications include: an Extraordinary Use New Drug Submission (EUNDS), New
Drug Submission (NDS), Abbreviated New Drug Submission (ANDS), Abbreviated
EUNDS (AEUNDS), Supplements, Applications for DINs (DINA and DINB), Post-
DIN Changes for pharmaceuticals (PDC), Notifiable Changes (NC) (in the case of
biologics), Post-Authorization Division 1 Changes for biologics (PDC-B), Yearly
Biologic Product Reports (YBPR), CTAs, CTA-Notifications (CTA-N) and CTA-
Amendments (CTA-A). MFs may be referenced by more than one Applicant.

The guidance document does not apply to MFs used in support of natural health
products (NHPs) subject to the Natural Health Products Regulations. For NHP MFs,
refer to the Product Licence Application form or contact the Natural and Non-
prescription Health Products Directorate (NNHPD).

MFs are classified according to the following types:

Master file classification

Table 6: Types of master file in Canada

TYPE I ACTIVE TYPE II TYPE III TYPE IV

SUBSTANCE CONTAINER EXCIPIENT DOSAGE FORM
MASTER FILE CLOSURE MASTER FILES MASTER FILES
SYSTEM

For pharmaceuticals: Container closure All excipients Dosage forms and

Active Pharmaceutical systems (CCS) or including excipients drug product
Ingredients (API) (drug CCS of biological origin intermediates.
substances), starting components. (e.g., albumin),
materials or intermediates capsule shells, coating
used in the manufacture ingredients, colorants,
of a drug substance. flavors, and other
additives (e.g.,
For
gelatin, alum and
biologics: Drug growth media).
substances can include
bulk process
intermediates, vaccine
antigens, adjuvants
(except for alum),
albumin (except when
used as an excipients),
critical raw materials for
radiopharmaceuticals or
vectors for gene therapy.

Type I & IV have two sections:

 Sponsor's (Open)
 Restricted (Closed)
 As of January 1, 2016, Health Canada will no longer accept paper copies of DMF
transactions. Any paper received after this date will be shredded or returned at the owner's
expense.
By March 31, 2016, all existing DMFs in paper format must be replaced by a complete
DMF conversion in "non-eCTD electronic-only" format. Failure to provide the complete
electronic copy of the DMF will result in the DMF being suspended (no further access for
review will be granted and no update will be accepted for the DMF).

Table 7: Timelines for filing a DMF

PHASE ACTIVITY TIMELINES (APPROX)

Pre-Phase 1 Patent Search 30 Days
Phase - 1 Feasibility Report 60 Days
Optimization Report 130 Days
Lab Validation 50 Days
Phase - 2 Pilot Scale, Validation 70 Days
Phase – 3 Commercial, Validation, 90 Days
DMF Filing
Phase - 4 Stability Studies 90 Days

Timelines (approx.) to complete a product filing is 480 days.

Health Canada Master Files

An MF is submitted by the MF Holder or authorized MF Agent only in cases where the company
does not wish to disclose CBI to the Applicant of the drug submission, DIN application or CTA.

Type I and Type IV MFs are divided in two parts: the "Applicant's Part" and the "Restricted
Part". The Restricted Part contains the information that the MF Holder regards as confidential
and is filed by the MF Holder or authorized MF Agent to Health Canada directly. The
Applicant's Part contains the information that the MF Holder regards as non-confidential. It is
provided to the Applicant and is usually included as part of the Applicant's drug submission,
DIN application or CTA, with the accompanying LoA. The LoA is signed by the MF Holder or
authorized MF Agent and indicates to Health Canada that the MF Holder has agreed that the MF
can be referred to during the assessment of the Applicant's drug submission or CTA.

 Confidentiality

Within Health Canada, the Restricted Part of the MF is kept confidential and officials of Health
Canada must protect the information in accordance with applicable law, which includes the
Access to Information Act and the Food and Drugs Act.

The Access to Information Act applies where an access request is made under that Act for
records under the control of a government institution. Section 20 of the Act is a mandatory
exemption that protects third party information such as trade secrets; confidential financial,
commercial, scientific or technical information; information the disclosure of which could
reasonably cause financial loss or gain or prejudice to the competitive position of a third party; or
that could interfere with contractual or other negotiations.

 Registration Requirements

For New MF Registrations the following electronic documents should be included:

 One signed cover letter, stating the MF name

 MF Agent Authorization Letter from MF Holder, if applicable
 MF Application Form
 MF Application Fee Form and appropriate fees
 CEP and Attestations (for Type I MFs only), if applicable
 LoAs

Type I and Type IV MFs should include the following:

 Applicant and the Restricted Parts

 A copy of a Quality Overall Summary (QOS) in Microsoft Word format
  The Certified Product Information Document (CPID) in Microsoft Word format. The
CPID template can be adapted to provide only the sections relevant to the manufacture
and control of the drug substance.

For Type II and Type III MFs, multiple components may be included in a single MF provided
that the components are similar (e.g., a complete container closure system, different stopper
formulations, multiple flavours). A limit of 50 components will be enforced per MF. A
numbered index listing all components should be included with the MF in module 1, section
1.0.7 Note to Reviewer. Additional components should be filed in a new MF.

An MF filed in support of a CTA may include a QOS in lieu of the Applicant's Part and
Restricted Part. In addition, a single MF covering both an active substance (Type I MF) and
dosage form (Type IV MF) can be filed in support of a CTA.

 Naming a Master File

For Type I MFs, the preferred name of the MF should be the generic name (e.g., the International
Non-proprietary Name (INN) for an active pharmaceutical ingredient) followed by any
manufacturer's internal API brand names, processes or codes to identify a particular product. If
applicable, any counter ions or solvated states of the API should be clearly identified.

If the MF Holder has more than one MF for a similar product, the cover letter should state this
explicitly and provide information to distinguish the different products. Information
distinguishing the different products should be provided in a side-by-side comparison table. The
MF Holder should provide a name that distinguishes the MF from any previously registered
MFs.

 Format and structure of the Master File

As of January 1, 2016, Health Canada no longer accepts paper copies of MFs. MFs must follow
the filing and formatting requirements outlined in the Guidance Document Preparation of Drug
Regulatory Activities in the "Non-eCTD Electronic-Only" Format which includes guidance on
MF structure and content, as well as the breakdown of the MF's Applicant and Restricted Parts.
Also refer to the 2015 Notice - Re: Preparation of Drug Master File (DMF) in "Non-eCTD
Electronic-Only" Format for additional information on electronic filing of MFs.

MF Holders or authorized MF Agents may also convert their MFs from the non-eCTD format to
the eCTD format. As a baseline requirement when converting MFs from the non-eCTD format to
the eCTD format, the MF Holder or authorized MF Agent must include the entire MF in their
first eCTD transaction. It is not sufficient to convert the MF into the eCTD format by simply
submitting the next transaction in eCTD via the Common Electronic Submission Gateway
(CESG) (i.e., submitting an LOA or update in eCTD format as a subsequent transaction for an
MF currently in non-eCTD format).

Please note: once an MF has been filed in or converted into the eCTD format, all subsequent
transactions must also be filed in the eCTD format via the CESG. Any subsequent transactions
filed in the non-eCTD format for MFs already filed in eCTD format will be rejected and
shredded or returned to the sender at their expense.

Table 8: Format Comparison Table

Issue Paper format (CTD) Non-eCTD eCTD

along with electronic electronic -only electronic-only
data format format

Portion of regulatory Complete regulatory Complete regulatory Complete regulatory

activity provided activity provided in activity provided in activity provided in
electronically paper format, along “non-eCTD electronic eCTD electronic only
with partial/complete only” format. format.
electronic data.
Legal record The regulatory The regulatory The regulatory
activity in paper activity in “noneCTD activity in “noneCTD
format remains the electronic-only” electronic-only”
legal document. format is the legal format is the legal
document. document.
Signature Scanned copy of signed document (or a digital signature where
applicable) is Required

Letter of Letter of Attestation Not applicable Not applicable

Attestation stating that material in
the regulatory activity
or additional
information provided
electronically is
exactly matching the
material in paper
format

Plan for format Health Canada is This format is an Health Canada is

requirement phasing out this interim option for considering a date
format filing regulatory for mandatory filing
activities. of this format for
regulatory activities in
scope of the eCTD
guidance document.

 Official language of correspondence

An MF can be filed in either of Canada's official languages (English or French).

 Where to send Master File registrations

MF transactions in non-eCTD format should be filed to the MF Administration Unit:

Master File Administration Unit

Resource Management and Operations Directorate
Health Products and Food Branch
Health Canada
Finance Building, 2nd Floor
Address Locator: 0201A
101 promenade Tunney's Pasture Driveway
Ottawa, Ontario
K1A 0K9

Email: hc.dmf.enquiries-fmm.sc@canada.ca
Fax number: 613-941-0825

MF transactions in eCTD format must be submitted via the CESG.

A completed and signed MF Application Form must accompany the MF.

 Letters of Access (LoA)

MF Holders or authorized MF Agents file CBI directly with Health Canada. The information
may be referenced to support an Applicant's drug submission, DIN application or CTA with
respect to quality information. CBI will only be used for the purpose of the assessment of the
Applicant's drug submission, DIN application or CTA if the MF Holder or authorized MF Agent
provides a LoA on official company letter head signed by the MF Holder or Authorized MF
Agent (see Appendix 2). All LoAs remain valid throughout the life-cycle of an MF.

 Information to include in the Letter of Access

The following information should be included in the LoA:

 MF number, if assigned by Health Canada, if not yet assigned state "to be assigned"
 Name of the MF, and
 Applicant's Name and address being granted access to the MF

The following information should NOT be included in the LoA:

 Product name or line

 Submission type or number
 Filing a Letter of Access

A separate LoA is required for each Applicant who cross-references the MF in their drug
submission, DIN application or CTA. Each LoA must be accompanied by an MF application
form, an MF application fee form and is subject to the applicable fees. The LoA must be dated
and signed by the MF Holder or Authorized MF Agent. The LoA should be sent to the MF
Administration Unit in the eCTD or the non-eCTD format and to the Applicant prior to filing
their drug submission, DIN application or CTA.

For Type I and IV MFs, an LoA grants access to an MF in its entirety. The LoA is valid for all
products and submissions from the Applicant cross-referencing the MF. Therefore, only one LoA
is required per applicant for the duration of an MF's lifetime.

For Type II and III MFs, an LoA can grant access to specific components within an MF or an
MF in its entirety. When granting access to multiple components within the MF or the MF in its
entirety, only one LoA is required per Applicant for the duration of the MF's lifetime. When
granting access for an additional component, not included in the first LoA, a new LoA is
required with the applicable fee.

 Certificates of Suitability to the Monographs of the European Pharmacopeia (CEPs)

At the time of filing of a Type I MF, MF Holders or authorized MF Agents are encouraged to
include the CEP (as applicable) or confirm that no CEP is available. If a CEP is not available at
the time of filing of the MF, it should be provided as soon as the CEP becomes available. In this
case, no fees will be applied.

If the MF is revised/updated at the same time a CEP is submitted, applicable fees will apply.
Revised CEPs will be accepted with or without simultaneous updates to the MF.

 Appointment of the authorized Master File agent

When an Agent is appointed by the MF Holder they are responsible for all correspondence
related to the MF, including but not limited to the following:

 Issuing LoAs
  Handling deficiencies
 Handling the payment of fees
 Handling associated correspondence, and
 Filing updates and administrative changes

When the MF Holder is not based in North America, it is recommended that an agent be located
in North America in order to expedite communications. Once appointed, an authorized MF
Agent may perform all functions listed in this guidance document on behalf of the MF Holder.

 When to file a new Master File registration

When two (or more) MFs are being filed for similar active substances and differ only due to
additional processing steps or minor variations, cross-references to the other related MFs can be
included in the cover letters to expedite the assessment of the common information. A side-by-
side comparison table (in Module 1, Section 1.0.7 General Note to Reviewer) should also be
included.

In some cases, a new Type I MF registration is required. The examples below indicate the
criteria for new MF registrations:

 Different active substance

 Different salt of an active substance
 Different complex of an active substance
 Different co-crystal of an active substance
 Different Solvate Or Hydrate Form Of An Active Substance
 Different Isomer Or Mixture Of Isomers Of An Active Substance
 Racemate Of An Optically Pure Active Substance
 Optically Pure Enantiomer Of A Racemic Active Substance
 Enantiomer Of An Active Substance
 Introduction Of A New Substantially Different Route Of Synthesis (I.E. Resulting In A
Different Specification For The Active Substance)
 Different Polymorphic Forms (Resulting In Substantially Different
Physicochemical And/or Pharmacokinetic Properties)
  Any Other Change To The Active Substance That Results In Substantially
Different Physicochemical And/or Pharmacokinetic Properties
 Sterile Grade Of A Non-Sterile Active Substance
 Non-Sterile Grade Of A Sterile Active Substance
 Change/Addition Of Raw Materials Of Different Animal Origin (Only Where There Is
A Substantial Change In The Safety Of The Active Substance)

 Master File fees

Fees are collected for the registration and processing of each new MF, LoA and update. If a
LoA is re-filed then the fee is applicable each time it is re-filed.

Refer to the MF Application Fee Form regarding fees for the processing of new MFs, LoAs
and updates.

Fees are increased annually by 2% on the first of April each year. For further information on
how to pay fees for MFs, refer to the Guidance Document: How to Pay Fees to Health
Products and Food Branch (HPFB).

MFs are not eligible for fee mitigation.

Table 9: DMF filing fee- Type- I

Types of Submission Fees in CDN

DMF-New Registration $433 Cdn

DMF Biannual Update $196 Cdn

Number of Letters of Access $196 Cdn

(LOA)

* DMF fee will be increased by approximately by 5% in the month of April.

 Fig.15 DMF Fees in Canada, DMF fees form

Processing of Master Files

When an MF registration package is received the following activities are performed:

 assigning an MF number and a dossier ID* to the MF (only for New MF registrations),
and
 verifying that the correct information, documents and forms have been filed in the correct
format and that all submitted information, documents and forms are complete for
administrative purposes (including those related to cost-recovery)

*For MFs submitted in eCTD, the dossier ID is assigned before the submission package is
received.

Once the MF registration package is administratively complete**:

 a filing date is assigned (which is the date when the MF is considered administratively
complete), and
 an acknowledgement letter (with an MF number and dossier ID) is sent to the designated
MF contact person (MF Holder or authorized MF Agent) as listed on the MF Application
Form

If the required information, forms or fees are missing, incomplete, or are provided in the
incorrect format, the MF will be placed on Administrative Hold, in which case the MF
Administration Unit will issue an administrative process hold letter to the MF contact person
requesting the missing information.

** A file is considered administratively complete when all processing and cost recovery
requirements are met. All required information, forms and correct fees are provided in the correct
format and are complete.

 Administrative holds

At different stages during the administrative processing of MFs it may be necessary to place the
MF transaction on Administrative Hold when the MF package is incomplete (i.e., missing
required information, forms or fees). This hold will remain in place until the required
information is submitted in the appropriate format.

There are two categories of Administrative Holds:

A. Process Hold
The MF Administration Unit will place the MF on Process Hold when the MF is
considered administratively incomplete, or when the information is filed as the wrong
transaction type (i.e., new MF should have been filed as an update).
B. Cost Recovery Hold
In the event that the MF Application Fee Form or applicable fee is not provided or the
applicable fee is insufficient, the MF Administration Unit will request the fee form and
payment from the MF contact person.

 Application and File Maintenance requirements

All correspondence (e.g., cover letters or LoAs to an MF) should come from the MF Holder
or authorized MF Agent, where applicable. Any information filed by a third party will be
rejected and shredded.

All information that is included in the Applicant's Part of the MF must be provided to the
Applicant of the drug submission, DIN application or CTA referencing the MF, and is to be
included in their submission or applications to Health Canada.
 Master File performance standards

All information and material filed with an MF transaction will be processed by the MF
Administration Unit within 30 calendar days of receiving a complete package (i.e., the date
the MF is considered administratively complete).

 Assessment of Master Files

MFs are always assessed in conjunction with a drug submission, DIN application or CTA
and therefore, decisions rendered on the quality-related data in an MF pertain to the drug
seeking market authorization or clinical trial authorization.
 Clarification requests and Letters of Deficiency during MF assessment in support of a
submission

During the assessment of an MF, if further clarification of information is required, a 15

calendar day clarification request will be issued to the MF Holder by email or fax. If the
MF Holder does not respond to a clarification request within the given timeframe, or if
the MF has a significant number of deficiencies, then a Letter of Deficiency will be
issued.

The MF Holder will be required to respond to the Letter of Deficiency within the
timeframe specified in the Letter. If additional time is required, the MF Holder should
contact the Applicant for the associated submission who will contact the Director of the
relevant assessment bureau to request an extension.

 Clarifications requests during Master File assessment in support of a Clinical Trial

Application

If further information is required during the assessment of an MF in support of a CTA, a

2 calendar day clarification request will be issued to the MF Holder or authorized MF
Agent, and the Applicant will be notified in writing. The Applicant should ensure a
timely response is sent by the MF Holder or authorized MF Agent.

 Responses to clarification requests

 For MFs filed in non-eCTD format, responses to clarification requests and Letters of
Deficiencies must be sent to the MF Administration Unit in non-eCTD format as per the
Guidance Document Preparation of Drug Regulatory Activities in the "Non-eCTD
Electronic-Only" Format. Any responses to clarification requests or responses to Letters
of Deficiency received in the incorrect format will be put on administrative process hold
until the response is received in the correct non-eCTD format. For MFs filed in eCTD
format, responses must be submitted as a new sequence through the CESG.
 Updates to a registered Master File

Updates are to be filed by the MF Holder or Authorized MF Agent and should be addressed to
the MF Administration Unit.

Updates to the MF are not required on a timed basis, but are required when changes are in
accordance with the reporting categories outlined in Health Canada's Guidance Document on
Post-Drug Identification Number (DIN) Changes, Post-Notice of Compliance (NOC) Changes -
Quality Guidance Document or Guidance Document for Clinical Trial Sponsors: Clinical Trial
Applications. All updates are subject to fees and should be accompanied by the MF Application
Fee Form and appropriate fees.

A single electronic copy of the update should be filed with a signed and dated cover letter. The
cover letter should clearly indicate:

 MF number
 Dossier ID/HC file number
 Type of MF (I, II, III or IV)

Additional administrative documents include:

 A summary of changes (side by side comparison) of the affected sections of the MF

listing the level of the change and the impact of that change (in Module 1, Section 1.0.7
General Note to Reviewer).

 An up-to-date list of all Applicants authorized to access the MF.

 A revised MF Application Form.

  MF Application Fee Form and fees.

All affected data should be included in Module 3.

 Administrative changes

Administrative changes to an MF may be filed at any time throughout the life cycle of the MF.
There are no fees associated with filing administrative changes to an MF.

 Transfer of ownership and company name changes

MF Holders should advise Health Canada in writing if the company name or ownership
of the MF has changed due to the following reasons:

 Buyout

 Merger

 Corporate Restructuring

 Company Name Change, Or

 Transfer Of Ownership

All administrative changes should be filed with a signed and dated cover letter. The cover letter
should include:

 The MF Number

 The Dossier ID

 The MF Type
 The Reason For Administrative Change (I.E., Transfer Of Ownership, Company
Name Change)
 A List Of All Affected MFs
 A Confirmation That All LOAs Remain Valid
 A Confirmation That All Manufacturing Sites And Processing Remain The Same
 A Confirmation That The Previous Authorized MF Agent Is Still Valid, If

Applicable The following additional documents are also required:

  A Revised MF Application Form
 An Up-To-Date List Of All Applicants Authorized To Access The MF, Which Should
Be Provided In Module 1, Section 1.2.6 Authorization For Sharing Information For
Each MF

 Withdrawal of Letters of Access

MF Holders or authorized MF Agents who wish to withdraw an authorization to reference an

MF for a particular Applicant should advise the MF Administration Unit of the reasons for
withdrawal of access in writing (in proper non-eCTD or eCTD format). Additionally, a list of
Applicants who still have access to the MF should be provided.

The Applicant whose LoA is being withdrawn from the MF should be informed of the
withdrawal of the LoA by the MF Holder or authorized MF Agent. The letter should clearly
state the date after which the material will no longer be supplied to the Applicant. Substances
supplied prior to the date where the LoA was withdrawn due to a supply agreement
termination may still be used in authorized products according to the conditions of
authorization, but the MF may no longer be referenced in subsequent applications.

Health Canada will retain the withdrawn LoA according to appropriate procedures
established for record retention and disposal in accordance with the Library and Archives of
Canada Act. It is understood that when a LoA is withdrawn, the previously manufactured
drug substance/material will no longer be supplied to the Applicant.

 Master File closures

Health Canada will close and archive an MF that has not been assessed by Health Canada
in support of a drug submission, DIN application or CTA within 5 years following the initial
registration. If the MF Holder wishes to reactivate the MF with Health Canada, the MF should be
filed in non-eCTD format (via CD or USB key) or in eCTD format (via the CESG). A cover
letter stating the MF Holder's wish to reactivate the MF along with updates and applicable data
since the date of the MF closure should be provided. The same MF number and dossier ID will
be retained and fees for a New MF registration will be applied.
Table 10: Comparison of USDMF with Canadian Master File

DMF REGULATORY
REQUIREMENTS US CANADA

Regulatory Authority U.S Food and Drug Health Canada

Administration
Mandatory No No
Types of DMF 5 types 4 types
Format of submission The USFDA require two copies of ICH CTD Module 3-Quality
each type DMF in the CTD and QOS. DMF divided into
format, but not in CTD Module two separate parts, namely
form. FDA requires one the Applicant’s Part (AP)
continuous document in the CTD and the Restricted Part (RP)
format. QOS is also required. Electronic submission and
Electronic submission and paper paper submission
submission.

Electronic Submission eCTD eCTD

Electronic DMF The deadline for having a DMF in As of Jan 1, 2016, Health
deadline electronic format is May 5, 2017
Submissions A. Transmittal Letters
along with DMF a. Identification of Submission:
Original, The type of DMF as
classified in Section III, and
Canada will no longer accept
paper copies of DMF
transactions. Any paper
received after this date will
be shredded or returned at
the owner’s expense. Canada
mandates DMF in eCTD
format
The DMF Should include the
following information:
 The Name and Address
of the agent if applicable.
 It’s Subject.  The Name and Address
b. Identification of the of the Corporate
Application, if known, that the Headquarters (DMF
DMF is intended to support, Owner); and
including the Name and Address  The Name and Address
of each Sponsor, Applicant, or of the Manufacturing
Holder, and all relevant document Processing, and
numbers. Packaging Facilities.
c. Signature of the Holder or the
Authorized Representative.
d. Type written Name and
Title of the Signer.
B. Administrative Information
a. Names and Address of the
following:
1) DMF Holder
2) Corporate Headquarters
3) Manufacturing Processing
Facility
4) Contact for FDA
Correspondence.
5) Agent(S), If any
b. The Specific responsibilities of
each person listed in any of the
categories in Section A.

Provide Information Drug Substance Intermediate, Active Substance

Drug Products , Flavors Etc
Forms for filling of Not applicable except Type ii Not applicable
DMF DMF, Form FDA 3794
Language English English/French
Letter of Authorization Letter of Access is required Letter of access is required
Appointment Of In Applicable Applicable
Country Care Taker
Closure or withdrawal Applicable Applicable
Changes and Approved Applicable Applicable
Approved/Disapprove d Not Approved Only Accepted In Only Accepted
by Regulatory Support Of Applications
Authority
DMF number assigned Yes No
by reviewers
ICH Zone Zone II Zone I
Requirements
Forwarding Address Drug Master File Staff FDA, Health Products and Food
5901-B Amendable Rd. Beltsville, Branch, Therapeutic
Md 20705 -1266 Products Directorate, Master
File Administration Unit,
address locator 0201D,101
Tunney’s pasture Driveway,
K1A0K9 Canada
Fees for filling of DMF According to GDUFA fees will be DMF for new Registration $
taken only for type II DMF is 408 Cdn
$31,460
SUMMARY &
CONCLUSION
CHAPTER 06
CHAPTER 6 SUMMARY&CONCLUSION

SUMMARY & CONCLUSION

The study states that the DMF is filed in support of various applications. The DMF contains
complete and factual information on a drug, CMC (Chemistry Manufacturing and Control),
Stability, impurity profile and cGMP status of any human drug product. The above
mentioned DMF contents are used to obtain marketing authorization. The main objective of
the DMF is to support regulatory requirements of a medicinal product to prove its quality,
safety and efficacy. This helps to obtain a marketing authorization grant.. Beginning on May
5, 2018, new DMFs, as well as all documents submitted to existing DMFs, must be submitted
using the Electronic Common Technical Document (eCTD). DMF submissions that are not
submitted in eCTD format after this date will be rejected Electronic Common Technical
Document (eCTD) is currently FDA’s standard submission format for NDA’s,IND’s,
ANDA’s, certain BLA’s and DMFs through Electronic Submission Gateway (ESG).From the
current scenario of the regulatory requirements are important to keep in mind that FDA is
examining DMF’s more closely than ever before and also the regulatory technicalities are
keep on updating. So, it is important to visit FDA’s current guidance when preparing DMF
submissions and to adhere to FDA’s requirements for various types. Each and every country
in the world has different regulatory procedures to file DMF. In Canada DMF filing was
done through New Drug Submission (NDS) for both drugs and biologic products. By March
31, 2016, all existing DMFs in paper format must be replaced by a complete DMF
conversion in "non-eCTD electronic-only" format.
To understand the regulatory technicalities the comparison study of USDMF with
CANADIAN guidelines is mentioned in this research. With Health Canada’s mandate
already in effect and US FDA’s mandate just 17 months away, lack of knowledge on paper to
eCTD conversions and eCTD submissions may put your DMF submission compliance efforts
at risk and may prove costly too. To avoid last minute challenges, it is advised to start
working towards the compliance right now. The study concludes that the DMF to be filed in
a timely manner and that the standards used to challenge it are of the same quality as the drug
application, and also there is a need of harmonization on filing of DMF in the world in
future.

Page 86
BIBILOGRAPHY
CHAPTER 07
CHAPTER BIBLIOGRAPH
7 Y
BIBILOGRAPHY
1. Available from:
http://www.fda.gov/Drugs/DevelopmentApprovalprocess/FormsSubmissiondRequire
ments/DrugMasterFileDMFs/ucm073164.htm

2. Guidelines for drug master files, United States, Food and Drug Administration
[Internet]. USFDA; 2011 Nov 14 [cited 2015 Nov 09]. Available from:
www.FDA.gov/downloads/Drugs/.../UCM279666.pdf
3. Randeria Juhi, Ronak Dedania, Zarna Dedania, Vinnet Jain, Danej Meghna.
Regulatory requirements for Dossier Submission in African Countries (Kenya,
Uganda and Tanzania): A Review. IJDRA 15 June 2018; 6(2): 14-21
4. S. Anusha, N.V.N Mounica, V. Sharmila, S.Sravika, M.V Nagabhushanam, D.
Nagarjuna reddy. Processing and Submission of Drug Master File. Wjpps 20 Feb
2017; 6(3): 356-366
5. Available from: fda.gov/media/85079/download
6. Heal Canada NOTICE file number: 08-124317-334 dated September 05, 2008
7. Chennamsetti Srilakshmi. Regulatory Requirements for Registration of API in US and
EU. ijpacr 2017; 3(2): 2395-3411
8. Shravya K, Swathi P, Snigdha B, Rastrapal D, Suthakaran R. Regulatory Dossiers of
ASEM countries. IJPSR 2014; 5(8): 3144-31
9. Available from:
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfr/CFRSearch.cfm?fr=314.420
10. Available from: https://www.fda.gov/drugs/forms-submission-requirement/drug-
master-files-dmfs
11. Available from: https://www.freyrsolutions.com/blog/dmf-types-fdas-clarity-type-iii
12. Available from: https;//www.registrarcorp.com/fda-drugs/fda-
dmf/ectd/?utmsource=google&utmmedium=cpc&utmterm=ectd%20module&utmcont
ent=19409719740&utmcampaign=36490740&matchtype=p&device=c&gclid=cjwkC
AjwnrjrBRAMEiwAxScC43WCJ2RYnKF3xXhEKj9oDy30p-NtRcimTrBKcZxno8n
6JRSoNxKyhoCF UQAvD BwE
13. Available from: http://apic.cefic.org/pub/eCTDHowtoDo_final%20201407.pdf
14. Mithun E.G, S.B. Puranik, NareshKumar, Hasija. An overviewof registration of API
(DMF) in regulated markets (USFDA, Canada, EU & EDQM (CEP). IJPPR 2018;
8(1): 216-231.
Page 87
CHAPTER BIBLIOGRAPH
7 Y
15. http://www.hcsc.gc.ca/dhpmps/alt_formats/hpfbdgpsa/pdf/prodpharma/draft_ebauche
_dmf_fmm_guide_Id-engpdf.
16. Available from: https://www.fda.gov/media/76783
17. Available from: https://www.fda.gov/drugs/guidances-drug-master-files-guidelines
18. Albert Yehaskel. An overview of Drug Master Files. Pharm Regul Aff, open access
18-01-2017; 7(1).
19. Nupur Sunil Bhargava. Registration process of API in U.S and Europe along with
comparison of USDMF and EUDMF. IJPSR 2015; 6(3): 0975-9492
20. Indu Gurram, M.V.S. Kavitha, Nagarjuna Reddy, M V Nagabhushanam. Drug Master
Filing in US, Europe, Canada and Australia. Journal of Pharmaceutical Research 28-
06-2017; 16(2): 160-173
21. Food and Drug Administration. Center for Drug Evaluation and Research, Guideline
for Drug Master Files (DMF), [cited 1989 September]. Available from:
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidance’s/u
cm122886.htm (2 Jan2015)
22. Food and Drug Administration. Center for Drug Evaluation and Research, Guideline
for Drug Master Files (DMF) [cited 2015 Jan 05]. Available from:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirem
ents/DrugMasterFilesDMFs/default.htm
23. Gurram I, Kavitha MVS, Reddy N, Nagabhushanam MV Drug Master File filing in
US, Europe, Canada & Australia. Journal of Pharm research 2017; 16(2): 160-173
24. Guideline for Drug Master Files (DMF), Food and Drug Administration [internet].
[Cited on 2014 March 20]; Available from:
http://www.fda.gov/drugs/developmentapprovalprocess/formssubmissionrequirements
/drugmasterfilesdmfs/ucm073164.htm
25. Guidelines for drug master files, CDER FDA [Internet]. FDA; 2015 [cited 2015
Nov12]
26. Available from: www.epicsgroup.org/media/62a95afed1a0fab6ffff9129ffffe415.pdf
27. Yamini SPK, Jain Chandra A, Shukla VK, Bansal A, Kumar S. Filing of DMF in US,
Canada and Europe. Pharmaceutical Drug Regulatory Affairs Journal 29-01-2019;
2(1).
28. DMF fees in USA [Internet] Washington. DC: GPO: 2013 [cited 2015 Sept 03]
Available from: http://www.gpo.gov/fdsys/pkg/FR-2013-08-02/pdf/2013-18625.pdf.

Page 88
CHAPTER BIBLIOGRAPH
7 Y
29. Available from: http://www.FDA.gov/cder/guidance/DMF.htm
30. Danej meghna, Ronak Dedania, Sanket Gandhi, Randeria Juhi, Kankrej Gaurav.
Regulatory requirements for Drug Master File in context to Canada and Australia.
IJDRA 2018; 6(2): 41-47
31. Agarwal pooja, Badjatya J.K. DMF Filling in US, Europe and Canada. IJDRA 2018;
3(4): 9-17
32. Pankaj Kumar, Bharti Mangla, Satbir Singh and Arapna Rana. Drug Master File:
Global Regulatory Issues and Challenges. Ejbps 2018; 5(1): 623-626

Page 89
ANNEXURE
 LIST OF
ATTACHMENTS

(ATTACHMENT 01)
LETTER OF AUTHORIZATION (LOA)
Notes are in bold font. Information to be filled in italics

Date: [Enter the date of this submission]

DMF#: [Enter the DMF number]

Holder: [Enter the DMF holder’s name]

Subject (Title): [Enter the subject (title) of the DMF as it appears on the DMF List, available
on the DMF web site athttps://www.fda.gov/drugs/forms-submission-requirements/drug-
master-files-dmfs]

Submission Type: Letter of Authorization

Statement of Commitment: [The following statement of commitment, signed by the DMF

holder, should be included in this letter or separately in eCTD section 1.2. If included in
eCTD section 1.2, mention that here (e.g., “See eCTD section 1.2 for statement of
commitment”).]
Dear DM staff:
HOLDER hereby authorizes AUTHORIZED PARTY** to incorporate by reference
information regarding item in DMF NUMBER into any APPLICATION*** Filed by
AUTHORIZED PARTY
Identify specific information to be referenced or entire DMF, where applicable (Note: Do not
include the Volume number.)
Include:
Name of item
Date of Submission
Page number/sections within Submission to FDA
[DMF HOLDER] states that [DMF NUMBER] is current and [DMF HOLDER] will
comply with the statements made within it. [DMF HOLDER] will notify FDA through an
amendment to [DMF NUMBER] of any addition, change, or deletion of information in the
DMF. [DMF HOLDER] will also notify [AUTHORIZED PARTY] in writing that an
4addition, change, or deletion of information has been made to the DMF as required by 21
CFR 314.420(c).

Signature of DMF holder

Dear DMF staff:

[Provide the name of the specific products, items, or processes to be referenced by the
authorized party. Include the submission date, section numbers, and page numbers.

Provide the name of the authorized party (one party per LOA).

Page 90
 LIST OF
ATTACHMENTS

Additionally, we recommend including the type (e.g., new drug application, investigational
new drug application) and number of applications or other DMFs referencing the DMF.]

Sincerely,

[Signature of responsible official]

[Name of responsible official]

[Responsible official’s title]
[Responsible official’s company (i.e., DMF holder or agent)]
[Responsible official’s telephone number]
[Responsible official’s fax number]
[Responsible official’s email address]

Page 91
 LIST OF
ATTACHMENTS

(ATTACHMENT 02)
TRANSMITTAL (COVER) LETTER ORIGINAL DMF

Notes are in bold font. Information to be filled in is in italics

Date: Enter the date of the Original Submission
Holder: Enter the Name of Holder
Manufacturer Name (if different from holder name): Enter the Name of Manufacturer *
Subject (Title): Enter MATERIAL***
DMF Type: Enter the requested DMF Type (II, III, IV, V)
Submission Type: Original submission

Dear DMF Staff:

Information regarding submission.

Sincerely,
Signature
Signature of Responsible Official
Enter
Name of Responsible Official
Responsible Official’s Title
Responsible Official’s Company i.e. Holder or Agent ****
Responsible Official’s Telephone number
Responsible Official’s Fax number
Responsible Official’s e-mail address

Page 92
 LIST OF
ATTACHMENTS

(ATTACHMENT 03)

Withdrawal of Letter of Authorization

Date: [Enter the date of this submission]

DMF#: [Enter the DMF number]

Holder: [Enter the DMF holder’s name]

Subject (Title): [Enter the subject (title) of the DMF as it appears on the DMF List, available
on the DMF web site at https://www.fda.gov/drugs/forms-submission-requirements/drug-
master-files-dmfs]

Submission Type: Withdrawal of Letter of Authorization

Dear DMF staff:

[DMF HOLDER] hereby withdraws authorization for [AUTHORIZED PARTY] to

incorporate by reference information regarding [DMF NUMBER IN ITS ENTIRETY OR AN
ITEM IN DMF NUMBER] into any [APPLICATION] filed by [AUTHORIZED PARTY].
The original letter of authorization was submitted on [DATE OF THE LOA]. The authorized
party has been notified of this withdrawal of authorization.

Sincerely,

[Signature of responsible official]

[Name of responsible official]

[Responsible official’s title]
[Responsible official’s company (i.e., DMF holder or agent)]
[Responsible official’s telephone number]
[Responsible official’s fax number]
[Responsible official’s email address]

Page 93
 LIST OF
ATTACHMENTS

(ATTACHMENT 04)
ANNUAL REPORT
Date: [Enter the date of this submission]

DMF #: [Enter the DMF number]

Holder: [Enter the DMF holder’s name]

Subject (Title): [Enter the subject (title) of the DMF as it appears on the DMF List, available
on the DMF web site athttps://www.fda.gov/drugs/forms-submission-requirements/drug-
master-files-dmfs]

Submission Type: Annual Report

Statement of Commitment: [For agent-submitted annual reports, the following statement of

commitment, signed by the DMF holder, should be included in this letter.* For holder-
submitted annual reports, it should be included either in this letter or separately in eCTD
section 1.2. If included in eCTD section 1.2, mention that here (e.g., “See eCTD section 1.2
for statement of commitment”).]

[DMF HOLDER] states that [DMF NUMBER] is current and [DMF HOLDER] will
comply with the statements made within it. [DMF HOLDER] will notify FDA through
an amendment to [DMF NUMBER] of any addition, change, or deletion of
information in the DMF. [DMF HOLDER] will also notify [AUTHORIZED PARTY]
in writing that an addition, change, or deletion of information has been made to the
DMF as required by 21 CFR 314.420(c).

Signature of DMF holder

[* DMF holders should not delegate authority to agents to refer to the statement of
commitment in the eCTD as current when submitting annual reports. Only DMF holders may
refer to the statement of commitment in the eCTD.]

Dear DMF staff:

[Provide the following information:]

Administrative Information
[Provide a statement that the administrative information in eCTD section 1.3 is up-to-date.]

Amendments
[List the dates of any amendments submitted that report changes since the last annual report or
the original DMF filing date, whichever is most recent.
OR

Page 94
 LIST OF
ATTACHMENTS

Provide a statement that no amendments have been submitted since the last annual report or
the original DMF filing date, whichever is most recent.]

Authorized Parties
[Provide a statement that the list of authorized parties in eCTD section 1.4.3 is up-to-date.
OR
Provide a statement that there are no authorized parties for the DMF.]

Authorizations Withdrawn
[Provide a list of all parties whose authorization has been withdrawn and the dates of
withdrawal.]

Sincerely,

[Signature of responsible official]

[Name of responsible official]

[Responsible official’s title]
[Responsible official’s company (i.e., DMF holder or agent)]
[Responsible official’s telephone number]
[Responsible official’s fax number]
[Responsible official’s email address]

Page 95
 LIST OF
ATTACHMENTS

(ATTACHMENT 05)
REQUEST FOR CLOSURE

This letter should be signed by the DMF holder.

See the next page for the template. Information to be filled in, including notes about that
information, is in brackets.

Date: [Enter the date of this submission]

DMF#: [Enter the DMF number]

Holder: [Enter the DMF holder’s name]

Subject (Title): [Enter the subject (title) of the DMF as it appears on the DMF List, available
on the DMF web site at https://www.fda.gov/drugs/forms-submission-requirements/drug-
master-files-dmfs]

Submission Type: Other

Dear DMF staff:

[Include information regarding the request to close a DMF.]

The following authorized parties have been notified of our intention to close [ENTER DMF
NUMBER]:

 [Enter the list of authorized parties.]

We understand that this DMF will no longer be available for review.

[Signature of responsible official]

[Name of responsible official]

[Responsible official’s title]
[Responsible official’s company (i.e., DMF holder)]
[Responsible official’s telephone number]
[Responsible official’s fax number]
[Responsible official’s email address]

Page 96
 ERRATA

ERRATA