Guidance Breakdown: Review of Drug Master Files in Advance of Certain ANDA Submissions Under GDUFA
The agency explains when a DMF prior assessment can be requested and the conditions that must be met. We break it down.
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Earlier this month, the FDA finalized a guidance outlining a significant program enhancement under GDUFA III that allows for early assessment of certain Drug Master Files (DMFs).
The guidance specifically targets holders of Type II active pharmaceutical ingredient (API) DMFs that will be referenced in Abbreviated New Drug Applications (ANDAs) or Prior Approval Supplements (PAS).
This guidance expands on the information in the "GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 2023-2027" (GDUFA III commitment letter). Specifically, it provides information and recommendations on when a DMF early assessment, also referred to as a DMF prior assessment, could be requested and the conditions that must be met for FDA to commence such an assessment of Type II API DMFs six months before the submission of an ANDA or PAS referencing the DMF. For example, FDA states the following information must be provided when requesting an early assessment:
at least one Letter of Authorization with one pre-assigned ANDA number;
documentation that the DMF holder has paid a GDUFA DMF fee; and
when the request is to support an original ANDA, reference to the corresponding reference listed drug listed in FDA's Approved Drug Products With Therapeutic Equivalence Evaluations (the Orange Book).
The guidance also provides a checklist containing elements the FDA recommends be included in the cover letter of the early assessment request and recommends that the DMF holder clearly state the basis on which it believes the request qualifies for such early assessment.
It is important to note that the FDA clarified that these requests should be limited to one DMF per API for each application. If the drug product has multiple APIs, and the DMF holder wishes for multiple early assessments, then a separate request must be submitted for each API. Notably, this guidance does not apply to DMFs supporting NDAs or other types of DMFs beyond Type II API DMFs. It applies to electronic systems in clinical investigations of medical products, foods, tobacco products, and new animal drugs.
Background
The guidance emerges from the Generic Drug User Fee Amendments of 2022 (GDUFA III) reauthorization, representing the program's third iteration since its 2012 inception.
This enhancement aims to maximize assessment cycle efficiency and potentially reduce the number of assessment cycles for ANDAs. The program allows for DMF assessment six months before certain ANDA or PAS submissions, marking a significant shift in the review timeline process.
Core requirements for DMF prior assessment
For DMF holders to request early assessment, three fundamental requirements must be met:
The submission must include at least one Letter of Authorization (LOA) with a pre-assigned ANDA number.
For original ANDA submissions, a reference to the corresponding Reference Listed Drug (RLD) from the FDA's Orange Book must be included.
Documentation confirming payment of the GDUFA DMF fee must be provided.
Qualifying conditions for early assessment
The guidance outlines five specific scenarios where DMF holders may request early assessment for ANDA submissions:
When all patents and exclusivities will expire within 12 months of the planned submission date.
For products with no more than three approved drug products in the Orange Book, no blocking patents or unexpired exclusivities, and no planned "carve-outs."
For products that could help mitigate or resolve drug shortages.
For products addressing declared or anticipated public health emergencies.
For products with specific Orange Book status conditions, including only one approved ANDA product in the Active Section.
PAS-related submissions
For Prior Approval Supplements adding new API sources, qualification is limited to two scenarios:
Products that could help mitigate or resolve drug shortages.
Products addressing declared or anticipated public health emergencies.
Important implementation details
The guidance provides several crucial operational details for implementation. Only one DMF per API can be submitted for prior assessment, though multiple APIs in a fixed-combination product may each have a DMF submission. Secondary DMFs referenced by a primary DMF under review will be assessed during the prior assessment period.
The FDA will evaluate each request and issue either a grant or denial letter. For granted requests, the DMF staff will conduct the review to meet the date indicated in the grant letter, though unsolicited amendments may extend the target date. Communication regarding needed clarifications will occur through Information Requests to the DMF holder.
Submission requirements and best practices
The guidance provides detailed recommendations for submission content, emphasizing the importance of clear communication and proper documentation.
Key elements include:
Clear identification as a "GDUFA DMF Prior Assessment Request"
Explicit permission for FDA to perform substantive scientific review
Specification of the ANDA submission type being supported