What is DMF (Drug Master File)?

Drug Master File (DMF)

A 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.

Why drug master file is required?

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.

What is the difference between DMF and CEP?

Being a European certificate, the CEP is granted by the EDQM but is recognized by other countries/institutes such as the FDA in the US. Furthermore, just like the DMF, the data as submitted in the CEP is handled strictly confidential and provides a centralized system recognized by many countries.

Is DMF required for excipients?

An Excipient DMF is not required by law or FDA regulations. It is submitted solely at the discretion of the holder. It is not approved or disapproved. The DMF contains manufacturing and control information and technical data to support the safety and quality of the excipient.

What are the types of DMF?

Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel (no longer applicable).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

Type III: Packaging Material

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

Type V: FDA Accepted Reference Information

Drug Master File (DMF) contains confidential and factual information about facilities, processes (includes drug product chemistry, manufacture, stability, purity, impurity profile, etc.), or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs. DMF helps the manufacturer to keep relevant information secret and at the same time to sell the product to different customers using this drug within their final application.

The information contained in the DMF may be used to support an Investigational New Drug Application (IND), a New Drug Application (NDA), or an Abbreviated New Drug Application (ANDA).

A DMF is NOT a substitute for an IND, NDA, ANDA, or Export Application. It is not approved or disapproved. Technical contents of a DMF are reviewed only in connection with the review of an IND, NDA, ANDA, or an Export Application.

DMF contains complete information on an Active Pharmaceutical Ingredient (API) or finished drug dosage form. In Europe, it is known as the European Drug Master File (EDMF) or Active Substance Master File (ASMF), and in the US it is known as the US-Drug Master File (US-DMF).

Note: EDMF is the old name of Active Substance Master File (ASMF)

DMFs are mostly prepared following the rules of Common Technical Documentation (CTD).

Prerequisites

• The production process is well established and fixed in writing (Master production instructions).
• Specifications of raw materials as well as of the final product are defined including specification of packaging material.
• In-process controls, sampling points, and procedures are clearly outlined.
• Critical process steps are validated, and equipment is qualified.
• Analytical methods are validated.
• The impurity profile is established.
• A stability program is set up and first data are available.
• Basic GMP requirements are fulfilled.

Data required for the CTD are

1. General Information
2. Nomenclature
3. Structure Description
4. General Properties
5. Manufacture
6. Manufacturer(s)
7. Description of the manufacturing process and process controls
8. Control of materials
9. Controls of critical steps and intermediates
10. Process validation and/or evaluation
11. Manufacturing process development.
12. Characterization
13. Elucidation of the structure and other characteristics
14. Impurities
15. Control of drug substance
16. Specification
17. Analytical Procedures
18. Validation of analytical procedures
19. Batch analyses
20. Justification of Specification
21. Reference Standards or Materials
22. Container Closure System
23. Stability

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US-DMF

In the United States DMFs are submitted to the FDA. The main objective of the DMF is to support regulatory requirements and prove the quality, safety, and efficacy of the medicinal product.

In the US there are five types of DMFs.

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 the FDA in conducting on-site inspections of their manufacturing facilities. The DMF should describe the manufacturing site, equipment capabilities, and operational layout.
• The description of the site should include acreage, the 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. It Summarizes all significant steps in the manufacturing and controls of the drug intermediate or substance.

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. Data supporting the acceptability of the packaging material for its intended use should also be submitted.

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.

Type V: FDA Accepted Reference Information

• FDA discourages the use of Type V DMFs for miscellaneous information, duplicate information, or information that should be included in one of the other types of DMFs. 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 (for address, see D.5.a. of this section). FDA will then contact the holder to discuss the proposed submission.

General Requirements for Filling Type-I, II, III, IV, V DMF

• Type II, Type III, and Type IV DMF should contain a commitment by the firm that its facilities will be operated in compliance with applicable environmental laws.
• Stability study design, data, interpretation, and other information should be submitted.
• A DMF is required to contain a complete list of persons authorized to incorporate the information in the DMF by reference.

EDMF

• In Europe, DMFs are submitted to EMEA. The main objective of the Active Substance Master File (ASMF) procedure, commonly known as the European Drug Master File (EDMF), is to allow valuable confidential intellectual property or 'know-how' of the manufacturer of the active substance (ASM) to be protected, while at the same time allowing the Applicant or marketing authorization (MA) holder to take full responsibility for the medicinal product and the quality and quality control of the active substance. Competent Authorities/EMEA thus have access to the complete information that is necessary for an evaluation of the suitability of the use of the active substance in the medicinal product.
• The scientific information in the EDMF should be physically divided into two separate parts, namely the Applicants Part (AP) and the Restricted Part (RP). The AP contains the information that the EDMF holder regards as non-confidential to the Applicant/MA holder, whereas the RP contains the information that the EDMF holder regards as confidential.
• It is emphasized that the AP is still a confidential document that cannot be submitted by anyone to third parties without the written consent of the EDMF holder. In all cases, the AP should contain sufficient information to enable the Applicant/MA holder to take full responsibility for an evaluation of the suitability of the specifications for the active substance to control the quality of this active substance for use in the manufacture of a specified medicinal product. The RP may contain the remaining information, such as detailed information on the individual steps of the manufacturing method (reaction conditions, temperature, validation, and evaluation data of critical steps) and the quality control during the manufacturing method of the active substance.

The EDMF procedure can be used for the following active substances (except biological active substances)

1. New active substances
2. Existing active substances not included in the European Pharmacopoeia (Ph. Eur.) or the pharmacopeia of an EU Member State
3. Pharmacopoeial active substances included in the Ph. Eur. or in the pharmacopeia of an EU Member State

• DMF (Drug Master File), CoS (Certificate of suitability) as well as CMC (Chemical Manufacturing and Control Documentation) are used for one and the same intention – to give evidence, that the drug substance (API – Active Pharmaceutical Ingredient) is suitable for its intended use and that the manufacturing process is well established and controlled. 
• The content of DMF, CoS, and CMC are nearly equal. There are only differences in the kind of document preparation (forms to use) and the authority you have to contact (USDMF FDA; EDMF EMEA; CoS EDQM; CMC national bodies). 
• Therefore above mentioned procedure is nearly equal for all three types. Especially CoS does not replace an approval process. Approval authorities can require more information even if CoS is available.

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