Drug Master Files (DMF) Pharmaceutical Regulatory Science Notes
Definition Drug master files:
Drug master files (DMFs) are submissions to FDA used to provide confidential, detailed information about facilities, processes or articles used in the manufacturing, processing, Packaging and storing of human drug products.
They allow parties to reference material without disclosing DMF contents to those parties. Are not required by regulation. Are neither approved nor disapproved. Instead, FDA reviews the technical contents of DMFs in connection with the review of applications that reference them (e.g., NDAs, ANDAs, INDs, BLAs).
Drug master files are provided for in 21 CFR 314.420
This guideline is intended to provide DMF holders with procedures acceptable to the agency for preparing and submitting a DMF. The guideline discusses types of DMFs, the information needed in each type, the format of submission to a DMF, the administrative procedures governing review of DMFs and the obligations of the DMF holder
Types of Drug master files
Manufacturing site, facilities, operating procedures and personnel (no longer accepted by FDA).
Drug substances, drug substance intermediates and material used in their preparation, or drug product. 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. Summarize all significant steps in the manufacturing and controls of the drug intermediates or substances. Manufacturing procedures and controls for finished dosage forms should ordinarily be submitted in an IND, NDA, ANDA, or Export Application. If this information cannot be submitted in an IND, NDA, ANDA, or Export application, it should be submitted in a DMF.
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 the preparing the packaging material and the acceptance specifications should also be given
Excipient, colorant, flavour, 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.
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 II to IV a holder must first submit a letter of intent to the Drug Master File Staff. FDA will then contact the holder to discuss the proposed submission.
Contents of a DMF Submission
Requirements for each DMF submission:
- Transmittal latter administrative information about the submission and the specific information to be included in the DMF all of which must be written in English.
- Aside from the user’s fee form, no other forms should be filled out or submitted along with a DMF submission.
- Each page of each copy of the DMF should be dated and consecutively numbered and any updates should include an updated table of contents.
- The transmittal letter for an original DMF should cover the following: Identification of submission: Original, the type of DMF, and its subject. Identification of the applications, if known, that the DMF is intended to support, including the name and address of each sponsor, applicant or holder and all relevant document numbers.
- Signature of the holder, authorized representative or agent. Name and title of the signer.
The Administrative information required is as follows:
- The names and the address of the following must be provided: DMF holder. Corporate headquarters. Manufacturing/processing facility. Contact for FDA correspondence. Agent, if any.
- The specific responsibility of each person.
- A statement of commitment.
- A signed statement by the holder certifying that the DMF is current and that the DMF holder will comply with the statements made in it.
A DMF is never approved or disapproved.
The agency will review the information in a DMF only when an IND sponsor, an applicant for an NDA, ANDA, or Export application or another DMF holder incorporates material in the DMF by reference.
As noted, the incorporation by reference must be accompanied by a copy of the DMF holder’s letter of authorization.
If FDA reviewers find deficiencies in the information provided in a DMF, a letter describing the deficiencies is sent to DMF holder.
At the same time, FDA will notify the person who relies on the information in the deficient DMF that additional information is needed in the supporting DMF.
The details of the deficiencies are only disclosed to the holder. During the submission of the requested information by FDA, the holder should also send a copy of the accompanying transmittal letter, which will provide a notice that the deficiencies have been addressed.
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