Early DMF Review: A Key to Efficient Generic Drug Approval

The review of Drug Master Files (DMFs) plays a critical role in context of Abbreviated New Drug Applications (ANDAs) under the Generic Drug User Fee Amendments (GDUFA). As regulatory requirements evolve, it becomes imperative for applicants to understand the implications of DMF submissions on their ANDA processes.

A DMF serves as a confidential document submitted to the U.S. Food and Drug Administration (FDA) that provides comprehensive details on manufacturing, processing, and packaging of drug substances or excipients. Prior to submitting certain ANDAs, applicants must ensure that relevant DMFs are current and accurately referenced in their applications.

The FDA’s review process for DMFs enables timely access to quality generic drugs while ensuring compliance with the established safety and efficacy standards. Any deficiencies identified during the review of a DMF can delay the approval of associated ANDAs. Therefore, proactive communication with the FDA regarding any changes or updates to DMFs can significantly enhance the efficiency of both filing processes.

Scope and Applicability:

This guideline applies to:

• Type II active pharmaceutical ingredient (API) DMFs.
• DMF holders intending to reference their DMFs in ANDA or Prior Approval Supplement (PAS) submissions.

DMF Prior Assessment:

The FDA conducts an early assessment of Type II API DMFs, 6 months prior to ANDA or PAS submission referencing the DMF. This assessment evaluates:

1. DMF completeness
2. API manufacturing process
3. Control strategies
4. Quality attributes

Notably, the sterility assurance information, of sterile drug substance, is not reviewed as part of this assessment as it is reviewed with the drug product submission.

Prior assessment can be done only for one API at a time unless the ANDA submission type involves a fixed combination of multiple APIs.

Conditions for Requesting a DMF Prior Assessment:

To qualify for DMF Prior Assessment, one of the following conditions should be met:

For original ANDAs (including amendments):

• Validity of all patents/exclusivities
  • no more than 12 months
• Less than four therapeutically equivalent drug products, including Reference Listed Drug (RLD)
  • no valid patents/unexpired exclusivities
  • no “carving out” of conditions of use
• Drug product for which –
  • only one approved drug product ANDA is listed in the “Active Section” of the Orange Book and RLD for which it is in the “Discontinued Section”
  • the ANDA was not approved via suitability petition
  • no valid patents/unexpired exclusivities are there
  • the submission does not meet any other condition to qualify for ANDA priority review

For original ANDAs (including amendments) and PAS:

• Drug product helps mitigate/prevent an existing or future drug shortage
• Drug product helps address a public health emergency

Requesting Early Assessment:

DMF holders can request early assessment by submitting a formal request comprising a cover letter and including:

• Statement requesting the FDA for substantive DMF review
• ANDA submission type – original, amendment, or a PAS
• Confirmation of the GDUFA fee payment
• Accompanying Letter of Authorization intended for the support of appropriate ANDA submission type
• Mention of the RLD in case of original ANDA application
• Planned submission date of ANDA submission type (at least 6 months from the date of DMF review request)
• Applicable justification to demonstrate that the applicable conditions are met for this review request

In conclusion, thorough preparation and an understanding of how DMFs interconnect with ANDA submissions are vital for stakeholders in the pharmaceutical industry seeking compliance under GDUFA regulations. Through this guideline, the FDA intends to streamline the DMF review process while enhancing efficiency and communication. This diligence not only aids in expediting approvals but also contributes in maintaining high standards within drug development practices. By following early DMF assessment approach, applicants can ensure timely and successful ANDA submissions, ultimately facilitating access to affordable generic drugs.

For further details, refer to the U.S. FDA’s Final guidance document, “Review of Drug Master Files in Advance of Certain ANDA Submissions Under GDUFA (October 2024),” available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/review-drug-master-files-advance-certain-anda-submissions-under-gdufa