Type III Drug Master File (DMF)

A Drug Master File (DMF) is a submission to the Food and Drug Administration (FDA) that may be used to provide confidential detailed information about 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. A DMF is submitted solely at the discretion of the holder. The information contained 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, or amendments and supplements to any of these.

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.

The main reasons for a DMF is to maintain confidentiality of proprietary information (e.g., Manufacturing procedure) for the holder. Furthermore it permits the review of information by reviewers at FDA to support applications submitted by one or more applicants. DMFs usually cover the Chemistry, Manufacturing and Controls (CMC) of a component of a drug product e.g. drug substance, excipient, packaging material. Drug product information or non-CMC information may be filed in a DMF.

Drug Master Files are provided for in 21 CFR 314.420. DMFs are generally created to allow a party other than the holder of the DMF to reference material without disclosing to that party the contents of the file. When an applicant references its own material, the applicant should reference the information contained in its own IND, NDA, or ANDA directly rather than establishing a new DMF.

Types of DMFs

• Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel (no longer applicable)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

Type III DMF

• 1. Location of packaging information
• 1.1 Purpose
• 1.2 Review
• 1.3 Location: DMF
• 1.4 Location: application
• 1.5 Contents of a Type III DMF
• 2. Information that should be submitted
• 3. Letters of authorisation
• 4. Obligations of a Type III DMF holder
• 5. Guidance for Type III DMF

1. Location of Packaging Information

• The container closure system should be identified and described in the application
• Information on packaging components or materials may be located either in the application or in a Type III DMF

1.1 Purpose

• Purpose of a Type III DMF: To provide confidential detailed packaging material information in support of an application (IND, NDA, ANDA, BLA) permitted under 21 CFR 314.420
• Cannot substitute for an application

1.2 Review

• Review of Type III DMFs: A letter of authorisation (LOA) is required
• Information is reviewed to support the approval of an application, another DMF or a supplement or amendment to any of these
• DMF may provide information on one or more packaging components in its entirety
• DMF deficiencies are sent to the DMF holder only*
• Applicant is notified that DMF is deficient*

1.3 Location: DMF

• Individual containers
• Pressurised containers
• Bulk containers
• Cap Closures
• Liners
• Inner seals
• Resins/elastomers
• Valve Closure System

1.4 Location: Application

Complete container closure system

1.5 Contents of a Type III DMF*

• Description of intended use
• Components/composition
• Acceptance specifications
• Release specifications for finished material or component
• The supplier’s and/or fabricator’s name & address
• Data supporting acceptability
• Toxicological data if appropriate

*CDER Guideline for Drug Master File, September 1989

2. Information that should be submitted

Information re: a Container Closure System (Guidance for Industry : Container Closure Systems for Packaging Human Drugs and Biologics, May 1999)

Information that should be submitted in an original application for any drug product

Description

Overall general description of the container closure system, plus:

For each packaging component:

• Name, product code, manufacturer, physical description
• Materials of construction (for each: name, manufacturer, product code)
• Description of any additional treatments or preparations

Suitability

Protection: (by each component and/or the container closure system, as appropriate)

• Light exposure
• Reactive gases (e.g. oxygen)
• Moisture permeation
• Solvent loss or leakage
• Microbial contamination (sterility and/or container integrity, increased bioburden, microbial limits)
• Filth
• Other

Safety: (for each material of construction, as appropriate)

• Chemical composition of all plastics, elastomers, adhesives, etc*1
• Extractables, as appropriate for the material*2
• Extraction and/or toxicological evaluation studies, as appropriate
• Appropriate USP testing
• Appropriate reference to the indirect food additive regulations (21 CFR 174-186)
• Other studies as appropriate

Compatibility: (by each component and/or the packaging system, as appropriate)

• Component and/or dosage form interaction, USP methods are typically accepted
• May also be addressed in post-approval stability studies

Perfomance: (for the assembled packaging system)

• Functionality and/or drug delivery, as appropriate.

Quality control

For each packaging component received by the applicant:

• Applicant’s test and acceptance criteria*3
• Dimensional (drawing) and performance criteria
• Methods to monitor consistency in composition, as appropriate

For each packaging component provide by the supplier:

• Manufacturer’s acceptance criteria for release, as appropriate
• Brief description of the manufacturing process

Stability

See section III.C.4

1. Including any additives used in the manufacturer of a packaging component.
2. See attachment C for further discussion of extraction studies. Testing of plastics should be performed on the packaging component, not on the uniform resin. For a blow/fill/seal product, extractables should be evaluated on the formed drug product container itself. This also applies to a container closure system that is manufactured as part of the drug product manufacturing process.
3. Note that an applicant’s acceptance test may include, among others, test parameters indicated under the description, suitability, and quality control sections of this table.

Examples of Schematics

1. Drawings of a bottle
2. Diagrams of multiple layered materials
3. Tamper- & child-resistant closures
4. Metered dose valves

Example: Relationship between Application & DMFs

NDA XX-XXX Packaging system	DMF#0001 Child-resistant closure	DMF#0002 Closure resin
Description Companents Mfgr. process Acceptance criteria Key properties Suitability Protection Safety Capability Quality control Stability	Supplier name / Adress Identification of use Composition Release controls Toxicological data	Supplier name / Adress Identification of use Composition Release controls Toxicological data
Examples of types of studies that might be provided:
Stability Torque release Water vaportransmission Weight loss	177.1520Extractions Compatibility Torque release Dimension evaluation ASTM physical test	177.1520 Extractions Melt flow Additive specifications

3. Letters of Authorization

• FDA to refer to specific DMF information in support of a third party’s application
• A copy must be provided in the application
• Duplicate copies should be included in the DMF

4. Obligations of a Type III DMF holder

• Notify applicants of any pertinent changes (21 CFR 314.420 (c))
• Annual update should contain:
  • Duplicate copies should be included in the DMF
  • List of companies and/or persons authorised reference to DMF (21CFR314.420(d))
  • All amendments incorporated since the previous update
  • Foreign DMF holders are encouraged to engage a U.S. Agent
  • Notify all transfer of ownerships

5. Guidance for Type III DMF

The applicable Guidance for Type III DMFs is the “Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Documentation” and “Questions and Answers. (Category 3)

A Manual of Policies and Procedures covering reviewer responsibilities for review of Type III DMFs has been implemented. MAPP 5015.5 CMC Reviews of Type III DMFs for Packaging Materials This MAPP instructs reviewers to look for information regarding many packaging materials in the application (IND, NDA, ANDA) for the drug product that utilises the packaging material before reviewing the DMF. Much of the information needed for review can be provided directly to the applicant for inclusion in the application, thereby avoiding the need to review the DMF.