Indo American Journal of Pharmaceutical Research, 2019 ISSN NO: 2231-6876

A REVIEW: REGULATORY REQUIREMENTS OF DRUG MASTER FILE IN CONTEXT

TO GHANA
Rushikesh B. Katkar1*, Sunil T. Galatage2, Sandip M. Honmane3, Supriya Darandale4
1
Jr. Executive Quality Assurance Department Shri Anand Life Science Belgaum, Karnataka.
2
Sant Gajanan Maharaj College of Pharmacy Mahagaon, Kolhapur, Maharashtra.
3
Annasaheb Dange College of B. Pharmacy, Ashta. Sangli, Maharashtra.
4
LSDP College of Pharmacy Pune, Maharashtra.
ARTICLE INFO ABSTRACT
Article history Drug Master Files are required in most African countries as supporting documents for the
Received 05/09/2019 registration of drug products. Africa is world’s second fastest growing pharmaceutical
Available online market. The CGAR of African Pharmaceutical market is 11.6%. African people suffer from
30/09/2019 numerous diseases. The local pharmaceutical market is weak and insufficient to meet the
demand of such diseased condition and so Africa relies heavily on externally developed and
Keywords procured drugs. This combination of economic strength and prevalence of diseases is
DMF, already driving a demand for medicines across Africa. DMFs generally contain information
HRMs, pertaining to the chemistry, manufacturing and controls (CMC) sections of the drug
NDS, submission and reflect the drug’s identity, strength, purity and quality. Ghana and Australia
ASMFs, which are consider as highly regulated markets (HRMs). In GHANA, DMF filing was done
CCS, through New Drug Submission (NDS) for both drugs and biologic products. They use MF
EU, terminology for DMF which contain four types of MASTER FILE- ASMFs, CCS MFs,
eCTD. Excipient MFs, Drug product MFs. In AUSTRALIA different application processes and
regulatory requirements apply depending on the type of therapeutic goods that is applied.
They consist of eight phase for DMF registration. Where EU guidelines adopted in
Australia include references to EU legislation. Now from 2018 onwards most of the
regulated countries will use eCTD or their electronic format for their DMF submission.

DOI NO: 10.5281/zenodo.3463964

Corresponding author
Rushikesh B. Katkar
Jr. Executive Quality Assurance Department,
Shri Anand Life Science Belgaum,
Karnataka.

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Please cite this article in press as Rushikesh B. Katkar et al. A Review : Regulatory requirements of Drug master file in context
to Ghana. Indo American Journal of Pharmaceutical Research.2019:9(09).

Copy right © 2019 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical
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Vol 9 Issue 09, 2019. Rushikesh B. Katkar et al. ISSN NO: 2231-6876

INTRODUCTION
Drug Master File
The Drug Master File (DMF) filing allows a firm to protect its intellectual property from its partner while complying with
regulatory requirements for disclosure of processing details. DMF contain detailed facilities, processes, or articles used in the
manufacturing, processing, packaging, and storing of one or more human drugs. The submission of a DMF is not required by law or
FDA regulation. The information contained in the DMF may be used to support an IND, a NDA, an ANDA, and another DMF. DMF
is provided for in 21 CFR 314.420 1.
DMF are divided in two parts:
The Applicant’s Part: which contains all the information that the license-holder needs to assess the quality and submit a
license or amendment application.
Restricted Part: This contains confidential information that disclosed to the authorities.

Role of Drug Master File

1. Supporting documents for the registration / approval of drug products.
2. In the Chemistry, Manufacturing and Controls (CMC) sections of the drug. DMF documents the drugs identity, purity,
strength and quality.
3. Protect Proprietary and Confidential Information 2.

Types of Drug Master Files

Type I: Production Site, Facilities, Procedures, and Personnel
Type II: Drug Substance, Intermediate, and Material Used in their Preparation, Drug Product
Type III: Packaging Material
Type IV: Excipient, Colorant, Flavor, Essence, Material Used in Their Preparation
Type V: FDA Accepted Reference Information 3.

(Regulatory Guidelines in Ghana)

Health Ghana is the department of government of Ghana with responsibility for national public health.
Canadians and their health care providers use pharmaceutical drugs that have been approved by Health Ghana to treat or
prevent an array of diseases and disabling physical conditions. Enabling timely access to safe and effective drugs, and ensuring
that these products remain safe and effective is critical to improving and maintaining the health of Canadians. Drugs are regulated
under the Food and Drugs Act, which is administered by Health Ghana.
Health Ghana’s responsibilities include the following core activities
 Reviewing clinical trial applications, for clinical trials to be conducted in Ghana.
 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 (4).

Regulatory Guidelines in Australia

The TGA administers the Therapeutic Goods Act 1989 Act, applying a risk management approach designed to ensure
therapeutic goods supplied in Australia meet
Acceptable standards of quality, safety and efficacy. The work of the TGA is that benefits to customer and provides risk free
medicines and medicines devices. The TGA regulates therapeutic goods through Pre and post market monitoring and enforcement of
standards, Licensing of Australian manufacturers and verifying overseas manufacturer’s compliance with the same standards as their
Australian counter parts 5
The TGA's approach to risk management involves identifying, assessing and evaluating the risks, applying for treating the
risks posed, monitoring and reviewing risks over time, the risk-benefit approach gave confident that medicine which used by
consumers that are safe and good for health 5.

Regulatory Guidelines for DMF as per Ghana

Health Ghana 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. It also
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introduces process changes that are less cumbersome on industry and Health Ghana (6).
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Table 1 MFs are classified according to the following types (6)

Type I For pharmaceuticals

Active Substance Master Active Pharmaceutical Ingredients (API) (drug substances), starting materials or
Files (ASMFs) intermediates used in the manufacture of a drug substance.
Type II For biologics
Container Closure Drug substances can include bulk process intermediates, vaccine antigens, excipients of
System Master Files (CCS MFs) biological origin, adjutants, albumin and critical raw materials for radiopharmaceuticals
Type III or vectors for gene therapy.
Excipient Master File Packaging material, Container closure systems components Description
Type IV Suitability-protection, safety, compatibility, performance Quality control
Dosage Form Master Files Capsule shells, coating ingredients, colourants, Flavours, and other additives.
Dosage forms and drug product intermediates.

Registration Requirements for MFs (6)

 One signed cover letter.
 MF Agent Authorization Letter from MF Holder.
 MF Application Form, Master File Fee Form and appropriate fees.
 Certificates of Suitability to the Monographs of the European Pharmacopeia (CEPs) – It should be filed by the drug substance
supplier in an Active Substance Master File (ASMF) with full information on the drug substance. MF Holders are requested to
confirm at the time of filing if no CEP is available.
 Letter(s) of Access (LoA)-The information in the MF will only be used if the MF Holder provides Health Ghana have a signed
actual LoA to the MF
Applicant. LoA grants Health Ghana permission to access the information contained in the MF.
Information to include in the LoA that MF number, if assigned by Health Ghana, if not yet assigned state “to be assigned”, name of
MF manufacturer’s internal code, applicant’s name being granted access to the MF the appropriate Master File fee form and fees.
 The MF must include the Applicant and the Restricted Parts.
 The Certified Product Information Document (CPID) in Word format, if applicable. It should be completed to provide a condensed
summary of the key Quality information for New Drug Submissions (NDSs) and Abbreviated New Drug Submissions (ANDSs)
containing drug substances and their corresponding
products of synthetic or semi-synthetic origin that are filed with Health Ghana.
 A Copy of Quality Overall Summary (QOS) in Word format.

Processing of MFs
 MFs are processed in sequence according to the date of receipt. When a MF registration package received the following activities
are performed.
 Assigning an MF number and a dossier ID to the MF.
 Verifying that the correct information, documents and forms have been filed.
 Once the MF registration package is administratively complete.
 A Filing date is assigned.
 An Acknowledgement letter is sent to the designated MF contact.

MF Fees
Refer to the Master File Fee Form regarding fees for the processing of a New MF, LoA and Update. Fees are increased
annually by 2% on the first of April. The revised fee structure increases the cost of filing a new DMF to
$424 (Canadian), the cost of filing a biannual update to
$191 (Canadian), and the cost of filing a Letters of Access to $191 (Canadian).

Format and Structure of the MF

March 2016, all MFs previously registered with Health Ghana must have filed a complete conversion to replace their paper MF
with a Non-eCTD Electronic-Only (NeeS) which includes guidance on MF structure and content as well as the breakdown of the
Applicant and the Restricted Parts. The navigation through a NeeS Format dossier is based on electronic tables of contents,
bookmarks, and hypertext links. MF Holders may also file their MFs in eCTD format and. All documents should be provided in
Portable Document Format (PDF) or Microsoft Word. Documents may also be provided in Microsoft Excel where applicable. 7
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Regulatory Guidelines for DMF as Per Australia

In the case of an API used by a producer for a medicine who’s origin is a third party manufacturer, data about its fabrication, quality
control and stability can be presented by a Drug Master File (DMF) The European style relevant for the procedure of a Active
Substance Master File, adopted by Australia’s Therapeutic Goods Administration (TGA) 8.
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DMF Filing System (9, 10

An Australian DMF registration system consists of the following stages.
Phase 1: Pre Submission Phase 2: Submission
Phase 3: First Round of Assessment
Phase 4: Consolidated section 31 request response Phase 5: Second round assessment
Phase 6: Expert Advisory Review Phase 7: Decision
Phase 8: Post Decision

Phase 1: Pre Submission

The pre-submission phase uses for category 1 and category 2 applications. Pre-submission Planning Form should be lodged
at least 2 ½ months prior to the intended lodgments date for the submission. A complete PPF identifies quality, nonclinical, and
clinical evidence to be included in the dossier. TGA assign resources for the evaluation process. Within six weeks of receipt of a
PPF the TGA will send the sponsor a TGA Planning Letter that provides the expected submission date.
The PPF is divided into three parts

Part 1 - Applicant and product details

-Applicant details
-Product details
-Indications
–planning

Part 2 - Details of application

- General information
- CTD Modules 1–5
- Justifications and further information
- Summary of attachments

Part 3 – Declaration Phase 2: Submission

The TGA will send a planning letter to the sponsor, identifying whether the submission is accepted for evaluation. After
receipt of the TGA Planning Letter, lodgement of submission and supporting data is within a month. Sponsors must lodge well-
planned, high quality, complete submission dossiers.
The Application fee is non-reimbursable from the time of submission. If submissions are not accepted due to deficiencies
amount will be remaining by the TGA, covering administrative costs.
Evaluation fee ($100,000): 100% of the evaluation fee is required when the submission is lodged.

Phase 3: First Round of Assessment

All dossier data would evaluate by the evaluators. It necessary section 31 request for documentation. Report prepared by
clinical, non clinical evaluators. The period is 90 days for completion, with an additional 30 days for prepare question.

Phase 4: Consolidated section 31 request response

Prepare a response and send the response to the TGA. Documents must be provided in CTD format. Applicants need to
send both hard copy and electronic copy formats of the response to the TGA. Applicants should review the first round assessment
reports and advise the TGA for major omissions.

Phase 5: Second round assessment

Complete the evaluation of the data. Response should be send to TGA by Sponsor within 30 days.

Phase 6: Expert Advisory Review

The main advisory group is the ACPM, PSC and some ACSOM for prescription medicine. All data evaluate by advisor
and give their suggestion in different issues.

Phase 7: Decision
The TGA will decide whether the application is to be approved or rejected. In this there so many objection that related to PI,
CMI or RMP and general registration information. Sponsor prior to making a decision within 28 days.

Phase 8: Post Decision

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Time line for this phase is 90 days. All regulatory activities administrative procedure completed.
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 DMF Requirement GHANA AUSTRALIA
Health Authority Health Ghana Australian government-TGA
Vol 9 Issue 09,
Definition 2019. A DMF is a reference Rushikesh
of DMF B. Katkar
that provides et case
In the al. of an API used by a producer for
ISSN NO: 2231-6876
a medicine whose
information about specific processes or origin is a third party manufacturer, data about its fabrication,
components used in the manufacturing, quality control and stability can be presented by a Drug Master
processing, and packing of a drug File (DMF).
No type for drug master file
Types of DMF Type I-Active Substance Master Files
(ASMFs)
Type II-Container Closure System
Master Files (CCS MFs)
Type III-Excipient Master
Files(Excipient MFs)
Type IV-Dosage Form Master The currently approved form is the CTD format.
Format MFs must follow the filing and formatting
requirements outlined in the Guidance
Document Preparation of Drug Regulatory
Activities in the “Non-eCTD Electronic-Only Letter of Access is required. New
(NeeS)” Format. chemical entity is
Letter of Letter of Access is required. $46,900.
Authorization No cost for filing a letter of Access.
Fees The revised fee structure increases the cost of
filing a new DMF to $424 (Canadian), and Five years once
the cost of filing a Letters of Access to Postal add-
$191(Canadian). Prescription Medicines Authorisation Branch
Updation Bi- annually Therapeutic Goods Administration PO Box 100
Forwarding Health Ghana Woden ACT 2606 Australia
Address Health Products and Food Branch Street Add-
Therapeutic Products Directorate Therapeutic Goods Administration 136
Master File Administration Unit Narrabundah Lane
Address Locator 0201D Symonston ACT 2609 Australia
promenade Tunney's asture Driveway Email: info@tga.gov.au
Ottawa Ontario Under the registration process, applicants provide the TGA
K1A 0K9 with planning data in the Pre-submission planning form (PPF)
Ghana at the pre-submission phase. Planning data include general
Email:dmf_enquiries@hc-sc.gc.ca Fax submission information as well as information about the
number: 613-941082 proposed application type and details of the quality, non
clinical and clinical evidence that will be provided in the
Submissions The DMF Should include the followingdossier.
along with DMF information The PPF provides the TGA with the necessary information for
The Name and Address of the agent ifeffective resource planning.
applicable. The currently approved form is the CTD format.
The Name and Address of the DMF
owner. CTD Module 1-Administrative information and prescribing
The Name and Address of manufacturing information for Australia.
processing and packaging facilities. ICH M4Q - Common Technical Document for the Registration
of Pharmaceuticals for Human Use: Quality (14).
ICH M4E - Common Technical Document for the Registration
Format Difference ICH CTD Module 3-Quality and QOS. of Pharmaceuticals for Human Use: Efficacy (15).
When providing MF Types I& IV, two ICH M4S - Common Technical Document for the
separate documents should be included in the Registration of Pharmaceuticals for Human Use: Safety (16).
folder.
“Quality Overall Summary”, a “QOS
(Restricted Part RP)” and a “QOS
(Applicant’s Part AP)” files.
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Registration requirements for DMF11

 Cover letter: A description of the submission, including appropriate regulatory information, regulatory activity category and
regulatory activity types.
 Application form: It is the basis of the new/revised ARTG entry. It should enter accurately information.
 Pre–submission details: PPF is required for category 1 and 2 not for category 3 application.
 Patent certification: Forms is required to satisfy legislative requirements under section 26B of the Act when before newly
approved registration.
 Letter(s) of Access

Categories of Applications for Prescription Only Medicines 12

Category 1 applications: include applications for a new chemical entity or a new indication for a registered prescription product as
well as other major changes such as changes to product information or approval of a new generic medicine.
Category 2 applications: When an application has been previously approved in two acceptable countries these applications have a
shorter statutory time frame for evaluation. For this two independent evaluation reports from acceptable countries, where the product
is already approved, are required to be provided at the time of application.
Category 3 applications: Involve a change to a product that is already registered on the ARTG, Where the change does not require
quality data (clinical, toxicological or bioavailability data) to support the change.
Category 1 and 2 requests to vary the entry in the Australian Register of Therapeutic Goods (ARTG) of registered therapeutic goods
are made under section 9D of the Act. Section 9D requires that applications are made in a manner approved by the Secretary. The
currently approved manner is the CTD format. It is a set of specification for a dossier for the registration of medicines. It is
internationally agreed “well structured common format”.

Figure 1. ICH Common Technical Document Format (13)

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Table 2 Comparison of DMF’s of Ghana and Australia.

Closure of DMF MF withdrawn by the MF holder. The Applications that do not meet the TGA's
MF holder should advise Health Ghana in writing regulatory requirements will be considered 'not effective'.
of the reason for the closure, including a Applicants applications considered 'not effective' will be
statement that their notified in writing of the reasons the application was not
obligations have been fulfilled and accepted for evaluation.
provide a list of the Canadian Customers using If the applicant wishes to proceed with the application they
their MF.
must lodge a new PPF and potentially a new dossier.
Health Ghana will close a MF that has not been
update within a 5 years period.
Clinical and In Nees format Clinical and Non Clinical data In CTD format overview and summary of Clinical and Non
Non included in separate Clinical Trial Application Clinical included in module 2 and study report included in
Clinical data (CTA). module 4 and module 5.
ICH Zone Zone I Zone II
Requirements
Sterilization Autoclave program, Use gamma radiation, Bioburden test, Pre-use and Post-use filter integrity test,
Process Terminal sterilization, Depyrogenation of Aseptic manufacturing process, Container Closure Integrity
packaging components, Aseptic condition, Use test, Finished drug substances sterility testing.
ethylene oxide gas.

CONCLUSION
A 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. The content and the format for Drug Master File is used
to obtain marketing Authorization. In Ghana 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. In Australia there is TGA guidelines, different application processes and regulatory requirements apply
depending on the type of therapeutic goods that is applied. Under the registration process, applicants provide the TGA with planning
data in the Pre-submission planning form (PPF) at the pre- submission phase with details of the quality, non clinical and clinical
evidence that will be provided in the dossier. The European style Active Substance Master File adopted by TGA. The currently
approved form is the CTD format which contains 5 Modules.

ACKNOWLEDGEMENT
The author wishes to thank to the management of Shri Anand life sciencs for supporting this work and helping for such type
of review publication.

Conflict of interest
The authors declare no conflicts of interest.

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