USFDA Guidance: Cross-Center Master Files: Understanding FDA’s New Submission Expectations

The U.S. FDA has released a draft guidance titled Cross-Center Master Files: Where to Submit, issued in November 2025 addressing a longstanding challenge in regulatory operations: determining which FDA center should host a master file (MF) when the file must support multiple regulatory submissions across different FDA centers. This guidance aims to reduce industry confusion, avoid duplicate submissions, and streamline review processes when MFs are used across drugs, biologics, devices, veterinary products, or more complex combination products.

A Master File (MF) is a voluntary and confidential submission to the FDA that contains detailed proprietary information about the facilities, processes, components, manufacturing methods, formulation technologies, or other technical elements used in an FDA-regulated product. The MF mechanism allows manufacturers or component suppliers to share sensitive information directly with the FDA without disclosing it to sponsors or partners.

Key features of MFs include:

• They are not approved or rejected by FDA but are reviewed only when referenced by a regulatory submission.

• An MF is typically referenced via a Letter of Authorization (LOA), which allows FDA to use the MF to support a submission.

• They support regulatory submissions such as INDs, NDAs, BLAs, ANDAs, PMAs, IDEs, 510(k)s, and veterinary submissions.

• MFs ensure that proprietary technologies—like container closures, excipients, device components, manufacturing know-how—can be protected while still enabling efficient regulatory review.

A “cross‑center” master file is an MF that will be accessed and reviewed by staff from more than one FDA center, for example when it is used to support both human and animal drugs or multiple combination products with different lead centers. The draft guidance covers such MFs submitted to CBER, CDER, CDRH and CVM, but explicitly excludes certain CVM VMF types VI–VIII, their public master files, and master files submitted to the Human Foods Program or Center for Tobacco Products.

Once an MF is submitted and hosted in one center, reviewers in other centers can still access it for referencing submissions, so duplication is not technically necessary. FDA therefore discourages submitting duplicate or “convenience copy” MFs to multiple centers, because that complicates version control and may introduce inconsistencies between files.​

The guidance aims to standardise how industry decides where to submit cross‑center MFs so that similar situations are handled consistently and both MF holders and FDA reviewers know where to find core information. Importantly, the document focuses only on which center should host an MF; it does not change center‑specific content, formatting, or review expectations, which remain covered in existing MF and DMF guidance and web resources

When deciding where to submit an MF, the guidance recommends that holders consider three core questions: the purpose of the MF information, which center will receive the referencing submission, and whether the MF will support a combination product. These factors determine whether the MF should follow the rules for combination‑product‑related files or for non‑combination products.​

If, after assessing these points, the MF holder still cannot determine the appropriate hosting center, they are encouraged to engage FDA for case‑specific advice. The guidance recognises that exceptions may arise and states that unusual scenarios will be handled on a case‑by‑case basis.

A hosting center is the FDA center where the MF resides, while the lead center is the center with primary review responsibility for a regulatory submission that references the MF.

The central purpose of the guidance is to help MF holders determine where to submit their MF based on who needs to use it.

FDA provides two broad categories:

1. Master files supporting combination product submissions

2. Master files supporting non-combination product submissions

This blog is based on FDA’s draft guidance Cross‑Center Master Files: Where to Submit (Docket FDA‑2025‑D‑5715, November 2025), which should be consulted as the authoritative source for definitions, recommendations and examples on hosting cross‑center master files.