Drug Master Files: All You Need to Know

• By: Staff Editor
• Date: July 20, 2017

Drug Master Files: All You Need to Know

Drug Master File (DMF) is a package of confidential, proprietary assets, detailing the formulae, processes, materials, test methods, and other information relevant to the manufacture of product used in the composition, packaging, and/or processing of pharmaceuticals and/or biologics. Though there are no regulatory requirements to file a DMF, the benefit of its use is overwhelming. A DMF filing help firms maintain confidentiality of proprietary information and yet ensure compliance with regulatory requirements for disclosure of product details.

What is DMF?

DMF is a voluntary, confidential, proprietary compilations of information submitted to FDA. It Includes information regarding formulae, processes, materials, test methods, and more. The information contained in the DMF must be relevant to the manufacture of product used in the composition, packaging, and/or processing of drugs and biologics. Thus, DMF is:

• A submission to the FDA of a drug product or a component of a drug product that permits the FDA to review this information in support of a third party submission.
• Information supplied is usually concerning the Chemistry, Manufacturing and Controls (CMC).
• Other non-CMC information may be filed in a DMF.
• Information in the DMF may be used to support:
  • An Investigational New Drug Application (IND)
  • A New Drug Application (NDA)
  • An Abbreviated New Drug Application (ANDA)
  • Another DMF
  • An export application
  • Amendments and supplements to any applications
• A DMF is not a substitute for an IND, NDA, ANDA, or export application.
• DMF’s are submitted at the discretion of the holder and are not approved or rejected.

DMFs are Important for:

• Vendors: DMFs help ensure the marketability of products in an increasingly competitive business environment, while maintaining the confidentiality of proprietary information.
• Applicants: DMFs are a necessary component of applications because FDA requires sufficient information regarding component materials for approval of applications.
• FDA: DMFs help ensure the safety and efficacy of the drug or biologic products under review. Because the information contained in DMFs is confidential, DMFs provide FDA with a source of detailed data for FDA’s safety and efficacy review and the use of DMF expedites FDA’s timely review of Applications.

Status of DMFs

Four different status exist for DMFs:

Types of DMFs

There used to be 5 types of DMFs. Now there are 4 types. Type 1 was eliminated because it had general plant and facility layout information that is now expected to be included in Type II. So currently there are 4 types:

Type II DMFs

Type II DMFs for drug substance and drug product should be separate.

For drug substance, type II DMF may be submitted in the format for “Drug Substance” in the “Guidance for Industry M4Q: The CTD – Quality. Methods Validation Package (3.2.R.3) can be excluded.

For drug product, type II DMF may be submitted in the format for “Drug Product” in the “Guidance for Industry M4Q: The CTD – Quality. It is not essential to incorporate a Methods Validation Package (3.2.R.3).

Type III DMFs

The type III DMFs contains confidential detailed packaging material information in support of an application i.e. IND, NDA, ANDA and BLA. Information is reviewed to support the approval of an application; another DMF; and a supplement or amendment to any of these.

A letter of authorization (LOA) is required for a Type III DMF.

Type IV DMFs

The type IV DMFs contains information regarding excipients, colors, flavors, essences or anything used in preparation of any of these. FDA regulations can be used as sources for release tests, specifications, and safety for the following:

• Color additives (21 CFR Parts 70 - 82)
• Direct food additives (21 CFR Parts 170 - 173)
• Indirect food additives (21 CFR Parts 174 - 178)
• Food substances (21 CFR Parts 181 - 186)

This type of DMF can be used as a reference by FDA as part of a NDA review and is not “approved” by FDA.

Type V DMFs

Type V DMF requires clearance from the FDA prior to submission. If any holder needs to submit information in a DMF that is not covered by Types I through IV, a holder must first submit a permission request letter to FDA. Permission is not required if filing a Type V DMF for the following:

• Manufacturing site, facilities, operating procedures and personnel for sterile manufacturing plants
• Contract facilities for the manufacture of biotech products.

Filing Requirements: Am I Required to File a DMF?

There is no legal or regulatory requirement to file a DMF in the United States. It is an option to file a DMF to provide the FDA with important CMC information during their review of a New Drug or Biologic application. A DMF may be submitted for specific information that is normally in scope for a CMC review

If an item is not part of a CMC review, then it does not need to have a DMF.

The following items are essential components of a DMF:

• Product Description
• Materials used in Construction
• Manufacturing Process
• Specifications
• Suitability for Intended Use
• Packaging (where applicable)
• Stability Studies and Data
• Environmental Assessment and Commitment

Format and Content Requirements

DMF’s submissions should use the Common Technical Document (CTD) format stated in the "Guidance for Industry M4Q: The CTD - Quality" (CTD-Q). However, beginning May 5, 2018, all new DMFs and submissions to existing DMFs are required to be submitted in Electronic Common Technical Document (eCTD).

In general, DMF will have the following content:

• Administrative Information
  • Manufacturing Facility & Corporate Building Info
  • Contacts for the DMF
  • US Agent Information
• Statements of Commitment
  • Manufacturing & Environmental Commitment
• Customer Lists
  • Current & Past Customers
• Process Description
  • Written Description of Process
  • Flow Charts or Diagrams
  • Molecular Drawings and Formulas
• Manufacture Details
  • FDA does not need to know how to make product at your facility
  • They want to verify that product is manufactured according to the defined procedures and intended use
• Finished Product Specifications/Release Specifications
  • Product specs compared to C of A’s and brochures
  • Internal specs compared to specs available to customers
• Test Methods
  • Monographs
  • Third-party Testing
  • Internal or Proprietary Testing

The DMF formats and submissions are not same for different countries. For instance, in Europe, DMF is commonly known as Active Substance Master File (ASMF) procedure or a European Drug Master File (EDMF). Also EU Authority (EMA) does not provide a DMF number. Similarly in Japan, DMF is defined by the Pharmaceutical Affairs Law (PAL) and Pharmaceuticals and Medical Devices Agency (PMDA) will conduct reviews of DMF’s.