Type III Drug Master File (DMF)

A Drug Master File (DMF) is a document submitted to the U.S. Food and Drug Administration (FDA) that may contain detailed and confidential information about the manufacturing premises, processes, and conditions/articles used in the manufacture, packaging, and storage of one or more human drug products. However, the relevant laws or FDA regulations do not mandate the submission of a DMF. The DMF holder may determine for itself whether to submit a Drug Master File to the FDA. 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, amendments to or supplements to these documents.

A DMF is NOT a substitute application for an IND, NDA, ANDA, or export application. The DMF will either be approved or rejected. The technical content of a DMF is evaluated solely in the context of processing an IND, NDA, ANDA, or export application.

The primary purpose of a DMF is to protect the confidentiality of information on which intellectual property rights are based (e.g., relating to the manufacturing process) for the benefit of the DMF holder. In addition, evaluators working at FDA can use DMFs to assess those claims that have been submitted in support of an application by one or more applicants. In general, DMFs include information on the chemistry, manufacture and controls (CMC) of a drug component, e.g., active ingredients, excipients, and packaging materials. It may also contain information on medicinal products not covered by the relevant regulations.

A designation of the Drug Master Files can be found in 21 CFR 314.420 (CRF: Code of Federal Regulations (USA)). DMFs are generally created for the purpose of allowing a party other than the DMF holder to reference the information contained in the DMF without disclosing that information to the third party. If an applicant wishes to refer to its own disclosures, it must refer directly to the disclosures contained in its own IND, NDA and ANDA and thus no longer needs to create a new DMF.

  • Type I: Production site, production facilities/plants, operating procedures and personnel (no longer valid).

  • Type II: Drug substance, active ingredient, excipients and other substances used in the manufacture of the medicinal product

  • Type III: Packaging material

  • Type IV: Excipients, colorants, flavorings, fragrances, or other substances used in the manufacture of the drug product.

  • Type V: FDA-approved reference material

1 Place of packing information

1.1 Aim

1.2 Assessment

1.3 Place: DMF

1.4 Place: Application

1.5 Table of contents of a Type III DMF

2. information to be provided

3. authorizations

4. obligations of the holder of a Type III DMF

5. guidelines for a type III DMF

  • The application must include and identify the holder's sealing system.

  • The information on the packaging components as well as the material used may be listed either in the application or in a Type III DMF.

  • The purpose of a Type III DMF is to provide detailed confidential information on the packaging material to support an application (IND, NDA, ANDA, BLA), as permitted by 21 CFR 314.420.

  • This document is not a substitute for an application.

  • Assessment of Type III DMFs: requires a Letter of Authorisation (LoA).

  • The information is used for the assessment with a view to approval of an application, another DMF, an addition or an amendment to this one.

  • The DMF may contain information on one or more components of the packaging as a whole.

  • If the DMF is insufficient, this will only be communicated to the DMF holder*.

  • The applicant shall receive this notification*.

  • Special packaging

  • Packaging under pressure

  • Packagings with larger quantities

  • Lid

  • Lining/Liner

  • Inner seals

  • Resins/elastomers

  • Closure systems with flaps

  • Complete packaging and sealing system

  • Description of the intended use

  • Components/composition

  • Acceptance standards

  • Specifications of the final product or of the ingredient placed on the market

  • Name and address of supplier and/or manufacturer

  • Information in favour of acceptance

  • Toxicological data, if applicable

*CDER Drug Master File Guideline, September 1989

Information concerning: the closure system of the packaging (Directive for the sector "Container Closure Systems for Packaging Human Drugs and Biologics", May 1999).

Information to be included in the initial application for a medicinal product
Description Complete general description of the holder's closure system, plus: For each package component:
  • Name, product code, manufacturer, physical description
  • Material used (for each material: name, manufacturer, product code)
  • Description of additional treatments or preparations
Suitability Suitability Protection: (by each component and/or the closure system of the packaging, if applicable)
  • Exposure to light
  • Reactive gases (e.g. oxygen)
  • Moisture permeability
  • Volatilization or leakage of solvents
  • Bacterial contamination (sterility and/or integrity of packaging, increased biological load, bacteriological limits)
  • Dirt
  • Other
Safety: (for each material used, if applicable)
  • Chemical composition of all plastics, elastomers, adhesives, etc. *1
  • Extractions, substances emitted by the packaging, if applicable to the material*2
    • Extraction and/or toxicology assessment tests, if applicable.
    • Applicable USP tests (United States Pharmacopoeia)
    • Relevant references to Indirect Food Additive Regulations (21 CFR 174-186)
  • Other tests, if applicable
Compatibility: (for each component and/or packaging system, as applicable)
  • Interactions between components and/or dosage form; USP methods are generally accepted for this purpose.
  • May also be addressed in stability testing conducted subsequent to approval
Benefits: (relating to the compounded packaging system)
  • Functionality and/or drug dosage form, if applicable.
Quality control Quality control For each pack component received from the applicant:
  • Applicant's testing and acceptance criteria*3.
  • Criteria relating to sizes (drawing) and performances
  • Control methods related to consistency of composition, if applicable.
For each packaged component supplied by the supplier:
  • The manufacturer's pre-marketing acceptance criteria, if applicable.
  • Brief description of the manufacturing process
Stability
  • See paragraph III.C.4

  1. Include additives used in the manufacture of the packaging components.

  2. For a more detailed discussion of extraction tests, see Appendix C. Plastic material tests should be performed on the resin generally used, but on the pack components. In the case of a blow/fill/seal product, the substances (extractions) emitted by the manufactured drug package are to be tested. This also applies to the packaging closure system manufactured as part of the drug manufacturing process.

  3. Note that the acceptance test performed by an applicant may include, but is not limited to, the following: The test parameters listed in the description, the suitability, and the quality control selection listed in the chart.

Examples of schematics:

 

  • Drawing of a bottle

  • Diagram of multilayer material

  • Sealed and child-resistant closures

  • Dosing flaps

Example: Relationship between application and DMF

 
NDA XX-XXX DMF#0001 DMF#0002
Packing system Child resistant closure Resins used
  • Description:
    • Components
    • Manufacturing process
    • Acceptance criteria
    • Most important properties
  • Suitability:
    • Protection
  • Safety
    • Capacity
    • Quality control
  • Stability
  • Supplier name and/or address
  • Usage
  • Composition
  • Checks carried out before marketing the product
  • Toxicological information
  • Name and/or address of supplier
  • Use
  • Composition
  • Checks carried out before marketing the product
  • Toxicological information
Examples of test results, if any
  • Stability
  • Torque required to open the holder
  • WWater vapour permeability
  • Weight loss
  • 177.1520 Extractions
  • Compatibility
  • Torque necessary for opening the holder
  • Evaluation of sizes
  • ASTM physical test
  • 177.1520 Extractions
  • Melting range
  • Specification list

  • FDA refers to specific information in the DMFs that is intended to support third party applications

  • Appropriate copies must be attached to the application

  • Appropriate copies must be included with the DMF

  • Inform applicant of relevant changes (21 CFR 314.420 (c)).

  • An update to be submitted annually and to include the following items:

  • A list of entities and/or individuals approved to refer to the DMF (21 CFR 314.420 (d)).

  • Any changes identified in the previous update.

  • Foreign DMF holders are advised to consult with an agency established in the U.S.

  • Report all transfers of ownership

Applicable guidance documents for Type III DMFs are "Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Documentation" and "Questions and Answers. (Category 3)"

"MAPP 5015.5 CMC Reviews of Type III DMFs for Packaging Materials" implements a manual of policies and procedures that addresses the responsibilities based on assessors of Type III DMFs. According to this manual, prior to the actual assessment of the DMF, assessors must research information on the packaging material used with the drug product and listed in the application (IND, NDA, ANDA). Much of the information required for the assessment can be provided directly to the applicant so that they can include it in their application, thereby avoiding the need to subject the DMF to an assessment.

Source: APG Europe GmbH

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