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Drug Master Files: Highlights of the Updated FDA Guidance

On October 18, 2019, FDA released an updated draft Guidance regarding Drug Master Files (DMFs) titled “Drug Master Files Guidance for Industry”. This is the first formal to revision to this guidance that was originally published in September of 1989. Drug Master Files are a submission pathway for a sponsor to allow others to reference data related to facilities, processes, or articles used in the manufacturing, packaging, or storage of human drug products, while keeping the information confidential. These submission types are not an alternate to an NDA, IND, ANDA or BLA, but are rather a resource that can be used to support them. All parts of a DMF are open to the FDA only to review and cannot be accessed by the referencing party.

A DMF is neither approved nor denied. In fact, it is not reviewed by the agency until the DMF holder submits a Letter of Authorization citing that the information may be reviewed for the specific application (IND, NDA, BLA, ANDA) that the authorized party is using to cite this information. The sponsor must also provide a copy of this LOA in their original application. DMFs are categorized into the four following types:

The review process for all DMF types, whether for products submitted to CDER or CBER is the same. However, there is one major difference: BLAs that are evaluated by CBER under section 351 of the PHS act, the BLA holder is expected to submit information about drug substance, drug substance intermediate, or drug product directly to the BLA, rather than by reference to a DMF.

DMFs are registered and routed to one division – either CDER or CBER. Per the guidance, sponsors who wish for information to be available for review by both divisions should contact CDER and CBER to determine the best suitable path for the specific DMF.

As of 5 May 2018, any new DMFs, excluding Type III, must be submitted in eCTD format. Type III will be required to be submitted in eCTD on 8 May 2020.

DMFs must be updated annually in order to remain active – if an annual report is not submitted for 3 years, the DMF will be considered terminated.

Overall, this new draft guidance retains most of the original information contained in the 1989 guidance, but has been re-organized and modernized, with extensive details on how to author and organize documents in the current eCTD standard.

A few notable highlights of the new information included in this update:

  1. While DMFs are currently submitted without forms, Footnote 12 on page 5 of the guidance notes that the FDA is currently working on a form to replace the cover letter and anticipate it will be ready when the guidance is finalized.

  2. Section C.4 notes that there is no requirement to re-submit legacy information for DMFs that are being converted to eCTD format, but gives recommendations on how sponsors wishing to do so can proceed.

  3. Section D.1 notes that Type II DMFs that are being submitted to support ANDA submissions should follow the guidance for industry Completeness Assessments for Type II API DMFs Under GDUFA, which was finalized in October 2017.

Comments can be made by the public for 60 days (Ending 20 Dec 2019) at under docket number FDA-2019-D-3989.

The WAYS team has a strong background in all DMF submission types, both to CDER and CBER. We have helped several sponsors in the eCTD conversion process, and are happy to provide assistance to anyone looking for assistance in this process.

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