What is a drug master file (DMF)?

1What a DMF is, and what it is not.

FDA describes drug master files as “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 let other parties reference material without the contents being disclosed to them. DMFs are not required by statute or regulation, and they are “neither approved nor disapproved”: FDA reviews their technical content in connection with the applications that reference them, such as NDAs, ANDAs, INDs and BLAs.¹

The regulation is 21 CFR 314.420. A holder files a DMF either to incorporate the information by reference in its own IND or application, or to let other persons rely on it “without the holder having to disclose the information to the person”.² A DMF is not a substitute for an IND, NDA or ANDA.³ An applicant referencing its own material need not create a DMF and can put the information straight into its application.⁴

For example, a maker of an active pharmaceutical ingredient (API) can authorise several applicants to reference its Type II DMF. FDA reviews the confidential manufacturing information in the DMF, and the applicants do not receive it.¹⁴

2The four types of DMF.

Section 314.420(a) lists what a DMF may cover, and FDA numbers the types to match.²⁵

The table’s notes come from FDA’s draft DMF guidance and its DMF types page.⁴⁵ Type I DMFs, which covered manufacturing sites, facilities, operating procedures and personnel, were discontinued in 2000, but the other types kept their numbers.⁴³ Information on sterile manufacturing plants can now be filed as a Type V DMF without a letter of intent.⁴

3How a letter of authorization works.

An application may incorporate all or part of a DMF by reference “if the holder authorizes the incorporation in writing”, and must identify the material by name, reference number, volume and page.² That written authorisation is the letter of authorization (LOA).

FDA’s November 2019 draft guidance sets out how LOAs are used. FDA will not review a DMF until the holder has submitted an LOA for a specific application or other DMF. The holder sends a copy to the authorised party, which includes it in its application. An LOA “does not give an authorized party permission to view or access a DMF”, and each authorised party should have its own LOA.⁴

The DMF must keep a complete list of everyone currently authorised to reference it, with what each may reference. If the holder adds, changes or deletes any information, it must notify each authorised person in writing.² A holder withdraws an authorisation with a “Withdrawal of Authorization” letter to the DMF, and a primary DMF can itself reference a secondary DMF under that holder’s LOA.⁴

4How FDA reviews a DMF.

When an original DMF’s administrative information is acceptable, FDA sends an acknowledgment letter with the DMF number. It is not available for technical review until it is referenced in an application or another DMF.⁴

FDA then reviews the referenced technical information for the particular use, for example a drug substance used in a solid oral dosage form. Whether a DMF is acceptable depends on that use. If reviewers need more information, or find the DMF cannot support approval or let a clinical trial proceed, FDA contacts the holder.⁴

Type II API DMFs referenced in ANDAs have extra rules under the Generic Drug User Fee Amendments (GDUFA): a fee, a completeness assessment and communications with the holder. The completeness assessment is a set of questions a DMF must satisfy to be listed publicly as available for reference; it does not replace the full scientific review. These provisions do not apply to other types, or to Type II DMFs used only for NDAs or INDs.⁵ Under GDUFA III, and in circumstances a draft guidance describes, FDA can begin assessing a Type II API DMF 6 months before an ANDA or prior approval supplement that references it is submitted.⁶

5How to keep a DMF current.

DMFs are subject to FDA’s electronic submission requirements, and must be submitted in eCTD format; for Type III DMFs it is optional but encouraged.⁷ Before an original eCTD submission, the holder must obtain a pre-assigned number.⁴

The draft guidance asks for an annual report with a signed statement of commitment that the DMF is current and that the holder will comply with it, plus the dates of amendments since the last report and the lists of authorised and withdrawn parties. Changes go in amendments, not the annual report. If FDA cannot be assured a DMF is current and the holder does not respond, FDA could close it, and a closed DMF cannot be reviewed in support of a new or amended application.⁴

The 2019 draft revises FDA’s September 1989 guideline, keeping most of its content. It is not final, and like all FDA guidance it is a recommendation, not a requirement.⁴

6DMFs for biologics, and the EU’s ASMF.

For biological products under a BLA, FDA has generally not let applicants incorporate drug substance, intermediate or drug product information by reference to a master file. A BLA holder is expected to know and control its manufacturing process, so that information goes into the BLA itself.⁴

The EU equivalent is the Active Substance Master File (ASMF), formerly the European Drug Master File. It covers active substances only and is split into an Applicant’s Part, which the applicant sees, and a Restricted Part, which holds confidential detail such as individual manufacturing steps. The holder grants access by a letter of access, and an applicant generally may not refer to both an ASMF and an EDQM Certificate of Suitability for one active substance in the same application. Its Annex 5 says the ASMF concept “cannot be applied in the context of biological medicinal products”. Revision 4 took effect on 17 June 2019.⁸

7How it runs in Seal.

A DMF is only as current as the manufacturing record behind it. In Seal’s API manufacturing workflow, every step in the genealogy carries the operation, equipment, quantities, conditions, samples, results and approval that produced the next state, and a revised route, limit or yield rule becomes a new recipe version for the lots that follow while earlier lots keep the one they were made under.

For the dossier itself, Seal’s regulatory submissions workflow keeps each section with the studies, batches and results it rests on, so a corrected or new result creates review work on the content it affects instead of silently changing approved text. Regulatory information management connects each submission to its authority exchanges and recorded outcome, and keeps commitments with their owners, due dates and evidence.