ejbps, 2018, Volume 5, Issue 01 623-626. Research Article SJIF Impact Factor 4.

382

Kumar et al. European Journal

Europeanof Biomedical
Journal ISSN 2349-8870
of Biomedical and Pharmaceutical Sciences
Volume: 5
AND Pharmaceutical sciences Issue: 01
623-626
http://www.ejbps.com Year: 2018

DRUG MASTER FILE: GLOBAL REGULATORY ISSUES AND CHALLENGES

Pankaj Kumar1*, Bharti Mangla2, Satbir Singh1, and Arapna Rana1

1
Department of Pharmaceutics, Advanced Institute of Pharmacy, Palwal, Haryana, India-121102.
2
Department of Pharmaceutics, Jamia Hamdard University, New Delhi, India 11062.

*Corresponding Author: Pankaj Kumar

Department of Pharmaceutics, Advanced Institute of Pharmacy, Palwal, Haryana, India-121102.

Article Received on 08/11/2017 Article Revised on 29/11/2017 Article Accepted on 19/12/2017

ABSTRACT
\
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. The pharmaceutical industry
is one of the most regulated industries; no drug would be marketed without the teams of medical researchers and
other specialists who worked to make sure it receives regulatory authority’s approval. There is no legal or
regulatory requirement to file a DMF. This 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.

KEYWORDS: DMF, intellectual property, regulatory authority, FDA, WHO.

1. INTRODUCTION The DMF is not a substitute for an INDA, NDA,

1.1 Drug master in USFDA ANDA, or export application. A DMF in support of
The drug master file is provided in 21 CFR 314.20. application for approval a new drug should provide
Drug master file (DMF) is a set of documents information about.
submitted to food drug and administration (FDA) by a 1. Drug substance.
pharmaceutical manufacture, the drug master file may 2. Intermediates.
also provide information which may be confidential for 3. Drug products.
the company may be required to regulatory authority 4. Excipients.
for complete understanding of their product, facility, 5. Packaging materials.
and the processes, systems, equipments and article 6. Flavors.
used for various of process of manufacturing and 7. Essence.
quality assurance, or storage and distribution.[1] The 8. Colorants.
drug master file is used when two or more partners are 9. Substance used to make them
engaged in developing and manufacturing of a drug 10. Stability data of drug products.[2]
product. The drug master filing allows a firm to protect
its intellectual property from its partners while FDA never approves or disapproves a DMF. The DMF
complying with regulatory requirements. staff (FDA) only checks whether it is administratively
completed or not. FDA reviews DMF in context with
The drug master file is submitted by a pharmaceutical an INDA, NDA, ANDA, or export application. These
manufacturer to support various applications. applications may reference the context of DMF
 Investigational new drug application (INDA) wherever it is applicable. The DMF is submitted in two
 New drug application (NDA) copies to FDA, one copy must be retained by the
 Abbreviated new drug application (ANDA) person or holder who is submitting DMF.[1]
 Export application
 Another DMF or amendments and supplements to
any of these application

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Kumar et al. European Journal of Biomedical and Pharmaceutical Sciences

In US FDA the drug master file is classified into to market a new product in Europe. There are for
following types. procedure as given below.
Type 1 DMF: Manufacturing facility or site, technical 1. Centralized procedure.
personnel’s working for the company and operating 2. Decentralized procedure.
procedures. 3. Mutual recognition procedure.
But type I DMF is no longer use as per federal register, 4. National authorization procedure.
January 12, 2000: volume 65 number 8. Effective date
July 10, 2000. The ASMF procedure can be used for the following
Type II DMF: Drug molecule, its intermediate and active substance, including herbal active substance
starting materials used in the manufacturing in the drug preparation i.e.
product and drug molecule. a) New active substances.
Type III DMF: Packaging material used for packaging b) Existing active substances not included in the
of drug product. European Pharmacopoeia or the pharmacopoeia of
Type IV DMF: Colorants additives, excipients and the EU member state
flavor essences or substances in their manufacturing. c) Pharmacopoeia active substances not included in
Type V DMF: It contains the information reference the European Pharmacopoeia or the
which is accepted by the FDA. which cannot be pharmacopoeia of the EU member state.[5]
submitted through type ii to type IV DMF. FDA
generally discourages the use of type v.[1] 1.3 JAPANESE MASTER FILE
Master file system in Japan is applicable for drug
1.2 EUROPE substances. The purpose of master file registration is to
The Active Substance Master File (ASMF) procedure, provide detailed manufacturing information on drug
formerly known as European Substance Master File substances to be used in review process, while
(ESMF) procedure is used when Active Substance protecting the intellectual property of the
Manufacture (ASM) is not the applicant for a product manufacturer. Both Japanese and foreign manufacturer
marketing authorization.[3] of drug substance can apply for master file registration.
They can get their drug substance etc. registered by
The main objective of ASMF procedure is to protect submitting data on manufacturing methods,
the valuable known how on manufacture the active specification and test methods. Since they are
substance, while at the same time allowing the indispensable to guarantee the quality of
applicant marketing authorization(MA) holder to take pharmaceutical preparation. The registered data is
full responsibility for the medicinal product and the called as master file. The registered data/ items will not
quality and quality control of the active substance. An be assumed as approved by pharmaceutical and
ASMF is a way of providing detailed confidential medical device agency (PDMA). This registered data
information about manufacturing of active substance to is registered is regarded as a part of information which
national competent authority (NCA), European is used in an approval application for drugs in Japan.
Medicine Agency (EMA) to demonstrate that the MF registered items are reviewed at the time of
quality of the active substance is adequately controlled approval review of the drug in which registered drug
by the specification proposed by applicant. An ASMF substance is used.
is only used the active substance to provide
confidential information on manufacture of active Foreign manufacturer can also apply for MF
substance. The CMSs information on drug product and registration, but it is necessary to obtain a foreign
excipients can be provided in dossier application. manufacturer accreditation the accreditation category,
NCA/EMA have full access to complete the accreditation number, and the date of accreditation of
information that is necessary for the evaluation of foreign manufacturing site must be entered in the MF
suitability of the use of the active substance in the registration application form. Before applying for
medicinal product. An ASMF can only be submitted to accreditation number, foreign manufacturer must have
NCA/EMA in support of a marketing authorization codes for foreign manufacturer and the manufacturing
application (MAA) or marketing authorization site is required. Thus both codes must be registered in
variation.[4] advance. An in country caretaker of drug substance
with an address with in Japan is also required to
ASMF procedure is generally used when there is a undertake the duties according to relevant MF
matter of confidential between ASM an applicant / MA registration/
holder. It is not mandatory to present information on
active substance in the form of an ASMF. The Items which can be registered in MF.
information may form part of the application for 1. Drug substance and intermediate (for medical
authorization to place a medicinal product of market.[3] use).
2. Pharmaceutical product material (with special
The applicant MAA has several options which with doses form).
ASMF procedure can be used while seeking approval

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Kumar et al. European Journal of Biomedical and Pharmaceutical Sciences

3. New excipients and pre-mix excipients with a necessary for an evaluation of the suitability of the use
different composition ratio from the existing one. of the API in the finished pharmaceutical product. It is
4. Materials for medical devices. also permissible to use the procedure when there is no
5. Contain packaging material. confidentially issue between the applicant pre
qualification dossier and the API manufacture. It is
MF for drug substance, intermediates and expected that the API manufacturer is also the holder
pharmaceutical product materials used in over the of APIMF.
counter (OTC) drugs are not appropriate for
registration in MF, as it is considered that their quality The scientific information in the APIME should be
and safety are already established even in the existing physically divided into two separate parts, one is the
specification and test methods.[6] open part a second is the restricted part. The open part
contain the information that the APIME holder regards
Japanese master file is not mandatory by law. It is as non- confidential to the applicant prequalification
optional to register drug substance in MF. The purpose dossier, where as the restricted part contain the
of master file registration is to protect the intellectual information that the APIME holder regards as the
property of manufacturer of drug substance, etc. All confidential, it is emphasizes that the open part is still a
the CMCs information on the drug substance, etc. confidential document that cannot be submitted by
which is necessary for an approval review of the drug anyone to third parties without the written consent of
product in which the drug substance is used, can be the APIME holder.[9]
provided in the application for approval of drug
product by drug substance manufacture if there is no COMPARATIVE STUDY OF DRUG MASTER
issue of confidentially between drug substance FILE IN DIFFERENT COUNTRIES
manufacture and applicant.[7] There are different rules and regulations for DMF
filling, so here is a comparison of DMF among
1.4 INDIAN DRUG MASTER FILE different countries.
There is no drug master file guidelines issued by the
Indian regulatory authorities (CDSCO) central drug
standard control organization. In Indian generally
united state format of DMF used for submission of
confidential information to drug substance and drug
product to regulatory authorities in India. A drug
master file may be filed for a bulk drug or for a
formulation. A drug master file declared by the
company provides in details the manufacturing place,
physiochemical properties, Pharmacodynamic /kinetic,
toxicological studies of bulk drug and formulation,
therapeutic classes, dosage form, strength, route of
administration, labeling and packaging etc. If any
foreign manufacturer wants to be obtain a drug
marketing license in Indian for drug product
manufactured in foreign country. In such case,
manufacturer should submit all chemistry
manufacturing and controls (CMSs) information on
drug product in Indian common technical document
(CTD) format to CDSCO. If foreign drug product,
drug substance, intermediates etc. has any accepted
DMF by USFDA, Europe or any other country should
be submitted along with the application for approval of
drug product in India.[8]

1.5 WHO
Active pharmaceutical ingredients master file (APIMF)
is a procedure to protect valuable confidential
intellectual property or know how of the manufacture
of the active pharmaceutical ingredients (API), while
at the same time allowing the applicant or holder of
prequalification dossier to take full responsibility for
the finished pharmaceutical product and the quality
and quality control of API. The regulatory authorities
thus have access to the complete information that is

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 Kumar et al. European Journal of Biomedical and Pharmaceutical Sciences

Sr.
Requirement US FDA Europe Japan India WHO
no.
Central Drug and
European Ministry Of
Food And Drug Standard Control
1 Regulatory Authority Medicine Health Labor And WHO
Administration (FDA) Organization
Agency(EMA) Welfare
(CDSCO)
Use Of DMF in Prequalification
2 Support of IND, NDA,ANDA MAA PDMA MAA Dossier
Application Application
3 Mandatory No No No No No
Drug Substance API, Drug
Active Active Substance ,
4 Provide Information Intermediate, Drug Products, Flavors, API
Substance Drug Substance
Products , Flavors Etc. Colorants, Etc.
5 Fees For Assessment ANDA Case Only No Fee No Fee No Fee No Fee
Submission In CTD Required In Indian
6 Required Required Required Required
Format CTD Format
Not Applicable Except
Forms For DMF Not Applicable Form
7 Type Ii DMF, Form Not Applicable Not Applicable
Filling Applicable No. 42
FDA 3794
English And
8 Language English English English English
Japanese
9 Electronic Submission eCTD eCTD eCTD eCTD eCTD
DMF Number Master File
10 Assigned By Yes No Registration No No
Reviewers Number
Approved/Disapprove Not Approved Only
Only
11 d by Regulatory Accepted In Support Only Accepted Only Accepted Only Accepted
Accepted
Authority Of Applications
12 Deficiency Letter Applicable Applicable Applicable Applicable Applicable
Changes And
13 Applicable Applicable Applicable Applicable Applicable
Approved
Appointment Of In-
14 Applicable Applicable Applicable Applicable Applicable
Country Care Taker
Latter Of
15 Applicable Applicable Applicable Applicable Applicable
Authorization
Closure Or
16 Applicable Applicable Applicable Applicable Applicable
Withdrawal
17 Reactivation Applicable Applicable Applicable Applicable Applicable

SUMMARY AND CONCLUSION 2. http://www.fda.gov/Drugs/DevelopmentApprovalPr

The study concludes that the drug master file is filed in ocess/FormsSubmissiondRequirements/DrugMaster
support of various applications to present drug into the FileDMFs/ucm073164.htm.
market. It is used to provide chemistry manufacturing 3. http://www.erigone.com/Vet%20folder/3aq7aen.pdf.
and controls (CMCs) on drug substance, drug product, 4. http://www.ema.europa.eu/docs/en_GB/document_li
intermediate used in their preparations etc. There is no brary/scientific_guidline/2012/07/WC500129994.pd
regulatory requirement to file the drug master file in any f.
country. Each country in the world has different rules 5. http://www.marsdd.com/dms/entrepreneurtoolkit/Re
and regulations to file the drug master file (DMF). So gulatoryPDFs/How_New_Drugs_Are_Approved_in
there is a need of harmonization on filling of DMF in the _Europe.pdf.
world in future. 6. http://www.pdma.go.jp/english/service/pdf/mf/MF.p
df.
ACKNOWLEDGEMENT 7. http://www.pdma.go.jp/english/service/pdf/mf/Drug
Authors express their sincere thanks to Advanced s_MF_QA_Part1.pdf.
Institute of Pharmacy for providing the facilities and 8. http://apps.who.int/prequal/info_applicants/Guidline
support for carrying out this work. s/APIMF_Guide.pdf.
9. http://www.cdsco.nic.in/guidance%20_percent20doc
REFERENCE ument%20_%20I%20and%20R_%20Corrected_200
1. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cf 72011.pdf.
cfr/CFRSearch.cfm?fr=314.420.

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