DRUG MASTER FILE AND GLOBAL REGULATORY REQUIREMENTS

NAILA KANWALSr. Officer Regulatory AffairsThe SEARLE Company Limited

DRUG MASTER FILE (DMF)&

Global Regulatory Requirements

DRUG MASTER FILE (DMF)

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.

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.

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DRUG MASTER FILE (DMF) Typically, a DMF is filed when two

or more firms work in partnership on developing or manufacturing a drug product. The DMF filing allows a firm to protect its intellectual property from its partner while complying with regulatory requirements for disclosure of processing details.

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DRUG MASTER FILE (DMF) Contains :

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1.The DMF contains factual and complete information on a drug product's chemistry,

2-Manufacture

4-Purity

3-Stability

6- Packaging.

5-Impurity profile,

DRUG MASTER FILE (DMF) Consist of: :


C. CHARACTERISATION 1. Eluciation of Structure and other characteristics

A. GENERAL INFORMATION

B. 1. General properties

2. Structure 3. Nomenclature

C. CHARACTERISATION 1. Elucidation of Structure and other characteristics2. Impurities a) Sources of Potential Impurities. b) Types of impurities. c) Test Procedure for determining impurities

B. MANUFACTURE 1. Manufacture(s) 2. Description of

Manufacturing Process and Process Control a) Flow Chart of Manufacturing Process b) Synthetic Route of Manufacturing Process c) Manufacturing Method.

3. Control of Material a) List of Materials. b) Specification and routine tests of the Raw Materials.

4. Control of Critical Steps and Intermediates.

a) Critical Steps. b) Process Validation and/or evaluation.

5. Specifications and Test method for the Intermediates.

6. Manufacturing ProcessDevelopment

DRUG MASTER FILE (DMF) Consist of


E. REFERENCE STANDARDS OF MATERIAL F. CONTAINER CLOSURE SYSTEM G. STABILITY 1. Stability summary and

Conclusions 2. Post-Approval Stability

protocol and Stability Commitment.

3. Stability data a) Accelerated Stability b) Long Term Stability

Studies c) Forced Degradation

Studies

H. MATERIAL DATA SAFETY SHEET I. APPENDICES 1. FACILITIES AND

EQUIPMENTS a) Building and

Utilities2. EQUIPMENTS DESIGN ANDLOCATION a. Equipment List b. Equipment Flow Chart3. ADVENTITIOUS AGENTS SAFETY EVALUATIONS STATEMENT OF COMMENT

D. CONTROL OFDRUG

SUBSTANCES1. Specification

s2. Analytical

procedure 3. Validation of

Analytical procedure

4. Batch Analysis

a) Description of Batches

b) Certificate of Analysis

5. Justification of Specification


DMFs Globally :


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DMFs in the United States


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1-DMFs in the United States In the United States, DMFs are submitted to the

Food and Drug Administration FDA).

The Main Objective of the DMF is to support regulatory requirements and to prove the quality, safety and efficacy of the medicinal product for obtaining an Investigational New Drug Application (IND), a New Drug Application (NDA),As an Abbreviated New Drug Application (ANDA), another DMF, or an Export Application.


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A US: drug master file comprises two parts:

The Applicant’s Part 1- (USA: Open Part) Which contains all the information that the

licence-holder needs to assess the quality and submit a licence or amendment application.


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2- Restricted Part (USA: Closed Part):

Which contains confidential information about the manufacturing procedure only disclosed to the authorities.






TYPES OF DMFs The types of DMFs are: Type I : Manufacturing Site, Facilities, Operating

Procedures, and Personnel (no longer applicable).

Type II : Drug Substance, Drug Substance

Intermediate, and Material Used in Their Preparation, or Drug Product.



TYPES OF DMFs Type III : Packaging Material. Type IV : Excipient, Colorant, Flavor, Essence, or

Material Used in Their Preparation. Type V : FDA Accepted Reference Information.



2- DMFs in Europe



DMFs in Europe The content and the format for drug master

file used in United States differs from that used in European Countries to obtain market authorization (MA). The Main Objective of the EDMF is to support regulatory requirements of a medicinal product to prove its quality, safety and efficacy. This helps to obtain a Marketing authorisation grant.



The DMF contains information which includes valuable know-how which should be kept confidential and submitted to the authorities only.

Therefore, it should be divided into 2 parts – an applicant’s part and an ASM Restricted Part.

The applicant’s part of a DMF is provided by the ASM (Active Substance Manufacturer) to the applicant directly and becomes part of the application for marketing authorization. Both the applicant’s part and the ASM Restricted Part of the DMF are submitted to the authorities.



Applicant’s part of a DMF – opening part The applicant must be supplied by the ASM with

sufficient information to be able to take responsibility for an evaluation of the suitability of the active substance specification to control the quality of the substance. This normally includes a brief outline of the manufacturing method, information on potential impurities originating from the manufacturing method, from the isolation procedure (natural products) or from degradation and, where applicable, information on the toxicity of specific impurities.



ASM Restricted Part of DMF – closing part Detailed information on the individual steps of

the manufacturing method such as reaction conditions, temperature, validation and evaluation data for certain critical steps of the manufacturing method, etc. and on quality control during manufacture may contain valuable know-how. Such information may therefore be supplied to the authorities only.



Other DMF Systems:1- Canada2- Australia


3-DMFs in Canada:Canada has 4 Types of DMFs,

Type 1: Used for Active Pharmaceutical Ingredients (APIs)

Type II: used for packaging materials Type III: used for excipients Type IV: used for products


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3-DMFs in Canada: Type I & 4 have two sections

Sponsor's (Open) Restricted (Closed)


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4-DMFs in 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).


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4-DMFs in Australia: The Europena style relavent for the

procedure of a Active Substance Master File, adopted by Austrailia’s Therapeutic Goods Administration (TGA), are available on the TGA website.

A DMF format used by the US (FDA) is acceptable if the DMF is prepared according to the Common Technical Document (CTD) format or the older European format if this is not available.


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DRUG MASTER FILE (DMF)Global DMF Trends:

Not Yet Harmonized !!!!!!


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• National Regulatory Authorities

• API / Excipient Manufacturer /Packaging Supplier

• Consumer• Pharmaceutica

l Manufacturer / MAA

Safety / Efficacy / Quality

Secrecy

Cost / Results

Speed to Market



Health & Medicine

DRUG MASTER FILE AND GLOBAL REGULATORY REQUIREMENTS