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.
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Type I: Production site, production facilities/plants, operating procedures and personnel (no longer valid).
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Type II: Drug substance, active ingredient, excipients and other substances used in the manufacture of the medicinal product
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Type III: Packaging material
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Type IV: Excipients, colorants, flavorings, fragrances, or other substances used in the manufacture of the drug product.
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Type V: FDA-approved reference material
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Assessment of Type III DMFs: requires a Letter of Authorisation (LoA).
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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.
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The DMF may contain information on one or more components of the packaging as a whole.
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If the DMF is insufficient, this will only be communicated to the DMF holder*.
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The applicant shall receive this notification*.
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Description of the intended use
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Components/composition
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Acceptance standards
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Specifications of the final product or of the ingredient placed on the market
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Name and address of supplier and/or manufacturer
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Information in favour of acceptance
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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:
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| Suitability | Suitability Protection: (by each component and/or the closure system of the packaging, if applicable)
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| Quality control | Quality control For each pack component received from the applicant:
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| Stability |
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Include additives used in the manufacture of the packaging components.
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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.
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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:
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Drawing of a bottle
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Diagram of multilayer material
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Sealed and child-resistant closures
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Dosing flaps
Example: Relationship between application and DMF
| NDA XX-XXX | DMF#0001 | DMF#0002 |
| Packing system | Child resistant closure | Resins used |
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| Examples of test results, if any | ||
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Inform applicant of relevant changes (21 CFR 314.420 (c)).
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An update to be submitted annually and to include the following items:
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A list of entities and/or individuals approved to refer to the DMF (21 CFR 314.420 (d)).
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Any changes identified in the previous update.
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Foreign DMF holders are advised to consult with an agency established in the U.S.
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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.
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