Drug Master Files and letters of authorization: what FDA expects

A Drug Master File (DMF) is one of the more misunderstood constructs in U.S. drug regulation. It is not an application, it is never approved, and yet it sits behind a large share of the INDs, NDAs, and ANDAs that FDA reviews every year. This overview sets out what a DMF is, how a supplier grants another party the right to reference it, and what FDA guidance actually says about DMF content, holder obligations, review, and the letter of authorization (LOA).

What a Drug Master File is

FDA defines a DMF as "a submission to the Food and Drug Administration (FDA) that may be used to provide confidential detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs" ¹⁸. The purpose is to let FDA review proprietary, manufacturing-related information confidentially so it can support another party's application without disclosing that information to the party relying on it.

The information in a DMF can 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, or amendments and supplements to any of these" ¹⁸.

Two points define the DMF's legal character:

It is voluntary. "The submission of a DMF is not required by law or FDA regulation. A DMF is submitted solely at the discretion of the holder" ¹⁸.
It is never acted on as an application in its own right. "A DMF is NOT a substitute for an IND, NDA, ANDA, or Export Application. It is not approved or disapproved" ¹⁸. FDA states the point in the strongest terms: "A DMF IS NEVER APPROVED OR DISAPPROVED" ⁷.

That distinction matters for regulatory strategy. Because a DMF carries no approval status of its own, an API or component supplier cannot point to a "DMF approval" as evidence of acceptability. The DMF is only ever evaluated in the context of an application that references it.

The DMF types

FDA guidance organizes DMFs by type, according to the article or information they cover ¹⁸²⁰. Based on the guidance rows reviewed:

Type II: drug substance, drug substance intermediate, and material used in their preparation, or drug product ⁸³. A 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" ⁸³. For substances and intermediates, the holder should "summarize all significant steps in the manufacturing and controls of the drug intermediate or substance" ⁸³. For finished dosage forms, manufacturing procedures and controls "should ordinarily be submitted in an IND, NDA, ANDA, or Export Application"; where they are not, "it should be submitted in a DMF" ⁸³. Type II API DMFs are the most common type and the ones that carry a user fee under GDUFA (below).
Type III: packaging material ⁸²⁸⁵. Each packaging material "should be identified by the intended use, components, composition, and controls for its release," together with the names of the suppliers or fabricators of the components and the acceptance specifications ⁸². "Data supporting the acceptability of the packaging material for its intended use should also be submitted" ⁸².
Type IV: excipient, colorant, flavor, essence, or material used in their preparation ⁸²⁸⁵. "Each additive should be identified and characterized by its method of manufacture, release specifications, and testing methods" ⁸², and toxicological data on these materials would be included under this type where not otherwise available ⁸².
Type V: FDA-accepted reference information ⁸²⁸⁵. FDA discourages using Type V DMFs "for miscellaneous information, duplicate information, or information that should be included in one of the other types of DMF's" ²⁰. One recognized Type V use: manufacturers of automated synthesis equipment for PET drugs may submit a Type V DMF covering items such as equipment description and principle of operation, equipment specifications, and quality system information ⁷⁴.

(A former Type I, for manufacturing site and facilities information, is not described in the guidance rows reviewed here.)

How a supplier authorizes a client to reference the DMF

A DMF holder does not "share" the file with its customer. Instead, the holder authorizes FDA to review the confidential contents on the customer's behalf. That authorization is a written letter of authorization (LOA). The holder provides the LOA to the authorized party, who includes it with their own submission; the LOA permits FDA to review the referenced DMF information in support of that submission ³⁶⁷⁴¹⁵⁷.

Based on the guidance, an LOA should identify:

The DMF number / reference number of the master file ²⁹⁶⁶⁷⁴⁷⁷
The specific information or sections of the DMF authorized for reference, particularly where only part of the file is covered ²⁹³⁶⁴⁴
The date ²⁹⁷⁴³⁹
The name of the authorized party ²⁹⁷⁷
The name of the DMF holder / owner ²⁹⁷⁴³⁹
The name of the product or subject of the DMF, where identified ⁷⁴⁷⁷
The nature of the material to be referenced ⁷⁷
Where applicable, the volume and page number where the information can be found ⁶⁶⁴⁴⁷⁷
Any limitations on the authorization, such as only certain sections being referenced ²⁹³⁹

FDA also expects the LOA to be on the DMF holder's letterhead and signed; one guidance row specifies it should be dated and signed with an original signature ³⁶⁷⁴. The LOA should describe the specific sections of the master file to which the right of reference is granted ³⁶³⁹.

Authorization is not a one-way, permanent grant. The DMF itself must contain a complete, current list of the persons authorized to incorporate information by reference, and the holder maintains that list through annual updates (below) ¹.

What a DMF must contain

FDA guidance describes the master file submission as containing "a transmittal letter, administrative information about the submission, and the specific information to be included in the file" ⁶². General content and format expectations drawn from the guidance include:

The file should be in English; non-English material should be accompanied by "an accurate certified English translation" ⁶².
Each page should be consecutively numbered ⁶².
An updated table of contents should be included with each submission ⁶².

For a Type II DMF specifically, the guidance directs the holder to summarize all significant manufacturing and control steps for the intermediate or substance ⁸³; Type III, IV, and V content expectations follow the type descriptions above ⁸²⁸⁵.

On electronic format, the guidance rows reviewed here do not state a clean, DMF-specific mandate to submit in eCTD. What the guidance does establish is that Type II DMFs are among the submissions for which the date of submission is determined by completion of transmission to the FDA Electronic Submissions Gateway (ESG) under GDUFA ⁷⁰, and that eCTD submissions must include the required index.xml and us-regional.xml files and must not reuse a previously submitted sequence number ⁷⁰. A footnote points to the eCTD Technical Conformance Guide without adding DMF-specific requirements ⁷². Readers planning a submission should confirm the current electronic submission requirement directly, as the rows here do not resolve exemptions or the precise scope of any eCTD obligation for each DMF type ⁷⁰⁷².

The holder's ongoing obligations

A DMF is a living file. The guidance places several continuing obligations on the holder:

Notify affected applicants of pertinent changes. The holder must notify each affected applicant or sponsor who has referenced the DMF of any pertinent change, and should do so well before making the change so the sponsor or applicant can supplement or amend affected applications ¹.
Submit changes and amendments properly. Any change or addition, including a change in authorization tied to specific customers, should be submitted in duplicate and adequately cross-referenced to previous submissions, including affected dates, volumes, sections, and/or page numbers ⁷.
File an annual report. The holder should provide an annual report on the anniversary date of the original submission, including the authorized-persons list and identifying all changes and additional information incorporated since the previous annual report. If nothing has changed, the holder should state that the DMF is current ².
Keep the authorized-persons list current. The DMF must contain a complete list of persons authorized to incorporate information by reference. The updated list should include the holder's name, DMF number, date of update, and identify what each person is authorized to incorporate and where that information is located; withdrawn authorizations should be identified ¹.
Maintain currency to avoid delay. Failure to update, or to annually assure FDA that previously submitted material and lists remain current, can delay FDA review of a pending IND, NDA, ANDA, Export Application, or amendment/supplement, and FDA can initiate closure of the DMF ².
Appoint a U.S. agent if foreign. When an agent is appointed, the holder should submit a signed letter of appointment giving the agent's name, address, and scope of responsibility. Domestic holders do not need an agent, although foreign DMF holders are encouraged to engage a U.S. agent ².

How FDA reviews a DMF

FDA does not independently approve, disapprove, or clear a DMF. It reviews DMF information "only when the DMF is incorporated by reference in a supporting application," for example by an IND sponsor, NDA applicant, ANDA applicant, Export Application applicant, or another DMF holder ⁷.

If FDA finds deficiencies, it sends a deficiency letter to the DMF holder and, at the same time, notifies the person relying on the DMF that additional information is needed. FDA identifies the general subject of the deficiency to the relying party but discloses the details only to the DMF holder, preserving confidentiality ⁷. When the holder responds, the holder should also send a copy of the transmittal letter to the affected relying persons and to the FDA reviewing division; that transmittal letter serves as notice that the deficiencies have been addressed ⁷.

Type II API DMFs under GDUFA

For generic drug supply chains, the Generic Drug User Fee Amendments (GDUFA) added a fee and an assessment step for Type II API DMFs. A Type II API DMF referenced on or after October 1, 2012, in a generic drug submission by an initial letter of authorization is subject to a one-time DMF fee ⁴³. The fee is due on the earlier of the date the first generic drug submission referencing the DMF by initial LOA is submitted, or the date the DMF holder requests the initial completeness assessment ⁴³.

Holders do not have to wait for an ANDA applicant to request an LOA before the DMF is assessed as available for reference; the holder can pay the fee before any LOA is requested ⁴³. FDA strongly encourages holders to submit a complete DMF and pay the fee at least six months before submission of an ANDA or prior approval supplement (PAS) that will rely on the DMF ⁴³. In practice this is why suppliers try to get their Type II DMF fee-paid and onto the available-for-reference list ahead of a customer's ANDA timeline.

Closing a DMF

A holder who wants to close a DMF should submit a request to the Drug Master File Staff stating the reason for closure, including a statement that the holder's obligations have been fulfilled ⁵. (For veterinary master files, the parallel step is a request to the Center citing the reason for closure, stating that the holder's obligations have been fulfilled and all users have been notified ⁴.)

On FDA-initiated action, the guidance rows reviewed do not set out a general standard for FDA closing a DMF beyond the holder-requested route and the currency point above ². FDA will return an original DMF submission that is administratively incomplete or inadequate and will not assign a DMF number in that situation ⁷. Consistent with its overall character, a DMF is never approved or disapproved ⁷¹⁸. The rows reviewed do not address DMF inactivation, reactivation, or a formal refuse-to-receive action for DMFs.

Practical takeaways for regulatory teams

Treat the DMF as a confidentiality vehicle, not an approval. There is nothing to "clear"; the file only gains regulatory meaning when an application references it and FDA reviews it in that context ⁷¹⁸.
Build the LOA carefully. A vague LOA is a common cause of review friction. Include the DMF number, the specific sections authorized, the authorized party, the holder, the date, and any limitations, on signed letterhead ²⁹³⁶⁷⁴³⁹.
Keep the file and the authorized-persons list current through annual reports; stale files delay the customer's application and can trigger closure ¹².
For Type II API DMFs supporting generics, resolve the GDUFA fee and completeness assessment early, ideally at least six months before the customer's ANDA or PAS ⁴³.

For a supplier or applicant working a specific program, the natural follow-ups are the current eCTD submission requirement and file structure for each DMF type, the completeness-assessment criteria FDA applies to Type II API DMFs, and how deficiency correspondence is sequenced against the referencing ANDA review clock. Those are worth confirming against the latest FDA guidance for the specific DMF type at issue.

Drug Master Files and Letters of Authorization: What FDA Expects