Overview
Review of Drug Master Files in Advance of Certain ANDA Submissions Under GDUFA. The Generic Drug User Fee Amendments (GDUFA) provides a framework for improving the efficiency and transparency of the review process for generic drug applications, known as Abbreviated New Drug Applications (ANDAs). One key aspect of this framework is the review of Drug Master Files (DMFs), which are critical for ANDA submissions involving drug substances, intermediates, or excipients that are not fully described in the ANDA itself.
Introduction
In October 2024 the FDA released a guidance document for the review of drug master files prior to certain ANDA submissions under GDUFA. This guidance is directed at holders of Type II Active Pharmaceutical Ingredient (API) Drug Master Files (DMFs) that will be referenced in an Abbreviated New Drug Application (ANDA) or a Prior Approval Supplement (PAS) to an ANDA. The document aims to clarify how the Food and Drug Administration (FDA) implements improvements agreed between the Agency and the pharmaceutical industry during negotiations for the reauthorization of the Generic Drug User Fee Amendments (GDUFA), as outlined in the “GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 2023-2027,” also known as the GDUFA III Commitment Letter.
GDUFA III introduced several measures to increase efficiency and predictability in the generic drug review process, especially with regard to the use of DMFs in ANDAs. One of the program’s main enhancements is the possibility of a “prior evaluation” of Type II API DMFs, which can help identify and resolve any deficiencies before the file is formally referenced in an ANDA or PAS submission. This speeds up the approval process, benefiting both DMF holders and companies seeking generic approval.
What is a Drug Master File (DMF)?
A DMF is a confidential document submitted to the Food and Drug Administration (FDA) by a manufacturer that provides detailed information about the facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of a drug substance or drug product. DMFs are often referenced in ANDAs to support the approval of generic drugs. However, the information contained in a DMF is proprietary to the DMF holder and is not typically disclosed to the ANDA applicant.
GDUFA and DMF Review
Under GDUFA, the FDA commits to reviewing DMFs in advance of ANDA submissions to enhance the overall approval timeline. The early review of DMFs helps identify any deficiencies or issues before they impact the approval process for the generic drug. To facilitate this, DMF holders are encouraged to pay the required DMF fee under GDUFA, which allows the FDA to begin its evaluation.
The DMF fee ensures that the file will be placed in the queue for review. Once the DMF is found acceptable, it can be referenced by multiple ANDAs, streamlining the review process for generic drug manufacturers.
Key Aspects of DMF Review Under GDUFA:
- Advance Review: The FDA aims to review DMFs well in advance of the submission of ANDAs to prevent delays.
- DMF Fee: DMF holders must pay a user fee to the FDA for the review process to begin. This fee is critical for the FDA’s commitment to a more predictable and timely review.
- Transparency and Communication: GDUFA facilitates better communication between the FDA and DMF holders, allowing for quicker resolution of any issues that may arise during the review process.
- Reference in ANDAs: Once the DMF is reviewed and found to be acceptable, it can be referenced by any ANDA, helping to expedite the approval of generic drugs.
- Deficiency Letters: If any issues are found during the DMF review, the FDA will issue a deficiency letter to the DMF holder, outlining the problems that need to be addressed before the DMF can be referenced in an ANDA.
Benefits of Early DMF Review:
- Details the circumstances in which DMF holders can request early evaluation and the conditions under which the FDA can begin reviewing the DMF six months prior to submission of the ANDA or PAS that references it.
- Early evaluation allows for greater transparency and collaboration between the FDA and DMF holders, resulting in a more streamlined and efficient approval process.
- The guidance offers recommendations for DMF holders on how to proceed when making a request for early assessment.
- It highlights the need to ensure that the DMF is complete and up-to-date, as well as clear communication between the DMF holder and the FDA throughout the submission process.
- This improvement reflects the FDA’s and industry’s commitment to optimizing the generic drug approval process, promoting greater access to safe and effective drugs on the market, while minimizing possible delays and increasing regulatory predictability for all involved.
Conclusion
The review of DMFs in advance of certain ANDA submissions is a crucial element of the GDUFA program. It ensures that potential issues are addressed early in the process, reducing the likelihood of delays and improving the efficiency of the FDA’s review of generic drug applications. By paying the DMF fee and engaging in early communication with the FDA, DMF holders and ANDA applicants can significantly benefit from a more streamlined approval pathway.
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