On Day 2 of the Generic Drugs Forum (GDF), there were a couple of sessions on Drug Master Files (DMFs) that provided some helpful information. The first presentation, from Dr. Jayani Perera, Senior Chemist in the Division of Product Quality Assessment (DPQA) XIX, provided some insight into the GDUFA III impact on DMF Assessments and DMF Prior Assessments (watch it here: GDF 2025 DMFs at approximately 4:27 of the recording) and it is the topic of this blog. (For those very interested in this topic, consider reviewing the additional presentation by Mr. David Green, Senior Pharmaceutical Quality Assessor in the DPQA XVII, on common deficiencies in DMFs; it can be found at the link above, right after Dr. Perera’s presentation, at approximately 4:48 of the recording.)
Under GDUFA III, and as described in MaPP 5015.14 Prioritization of Solicited DMF Amendments Associated With ANDAs or PASs not Concurrently Under Assessment, “the Office of Pharmaceutical Quality (OPQ) intends to prioritize assessments of CDER solicited Type II Drug Master File (DMF) amendments that are submitted to the Agency prior to the submission of a referencing off-cycle abbreviated new drug application (ANDA).” The MaPP goes on to define the applicable “referencing ANDA” to which this applies, which could include an original ANDA, a response to an ANDA Complete Response Letter (CRL, either major or minor), or a PAS to an ANDA. These DMF-solicited amendments will be evaluated and prioritized for review, even if the referencing ANDA in which the DMF is referenced has not been submitted for review. Priority is given to ANDAs for which acceptability of the DMF assessment may result in a final approval during the subsequent assessment cycle. As this is a GDUFA policy, this does not apply to NDAs. MaPP 5015.14 discusses how the Office of Pharmaceutical Quality (OPQ) is enacting and prioritizing the DMF assessments.
This GDUFA III enhancement is specific to Type II DMFs. So, you may be asking, what qualifies as a solicited DMF amendment under this assessment? Solicited DMF amendments are responses from a DMF holder to a DMF CRL or DMF deficiency letter; however, responses to DMF Information Requests (IRs) and DMF Additional Comment Letters are excluded. Off-cycle amendments refer to an assessment of a DMF when there is no referencing ANDA with an open assessment cycle.
Dr. Perera shared the flow chart shown below, which provides an overview of the process that comes from Attachment 1 of MaPP 5015.14. The opportunity to have an early “off-cycle” assessment could aid applicants by enabling the DMF to get to an adequate status more quickly; anyone who has had their approvals held up due to a DMF issue knows how important this is! Though not every off-cycle solicited DMF amendment will be reviewed through this enhancement, the FDA estimates that between 75 and 100 solicited off-cycle amendments will be prioritized and reviewed annually under this GDUFA III provision. Dr. Perera stated that any time you submit an amendment, you should email the inbox DMFOGD@FDA.HHS.GOV to alert the FDA to the submission as this will trigger the Agency to pick up the amendment to triage; this mailbox is regularly monitored. It should be noted that the recommendation to email this inbox is not in the MaPP but was mentioned multiple times by Dr. Perera during the presentation as an important step. These DMF Assessments have a DMF review target date (DTD) of 120 days for standard assessment. NOTE: No email is sent from the FDA to the DMF holder unless the solicited amendment is prioritized; however, you can reach out via the inbox listed above for a status update.
In the second part of Dr. Perera’s presentation, she discussed DMF Review Prior to ANDA or PAS submission (DMF Prior Assessments) as discussed in the FDA Guidance for Industry Review of Drug Master Files in Advance of Certain ANDA Submissions Under GDUFA (October 2024). This starts with a submission by the DMF holder, for either a new DMF or a previously unreviewed DMF, and should be submitted six months prior to the planned ANDA or PAS submission date. As discussed in the GDUFA III Commitment Letter and guidance document (Review of Drug Master Files in Advance of Certain ANDA Submissions Under GDUFA), there are conditions that should be met regarding the ANDA or PAS. Specifically, for an ANDA application: patents and exclusivities should be expiring within twelve months; there should be no more than three approved applications; it should be for a drug shortage, public health emergency, or sole source products; and for a PAS to add a new API source, the PAS must be for a drug product that could help mitigate or resolve a drug shortage or help address a public health emergency. The high-level process is shown in the following slide from Dr. Perera’s presentation:
The benefits of the DMF Prior Assessment are obvious; the longer review clock allows multiple DMF assessment cycles before the end of a GDUFA clock for a better opportunity to reduce your ANDA or PAS assessment cycles and obtain approval more quickly. The FDA estimates that about eighty original DMFs might qualify under this enhancement each year; however, the FDA has not received the numbers expected. Dr. Perera emphasized that industry needs to take advantage of this prior assessment. As shown in the graphic below, the FDA has a > 60% grant rate over the last three years (from Dr. Perera’s presentation, Slide 13). Dr. Perera also again emphasized the importance of emailing the inbox to notify the FDA that a prior assessment has been submitted so that the Agency can triage it.
Other items of note from the presentation: the grant or deny letter will be issued within two weeks; if denied, a reason for denial will be provided; and, when granted, a DTD is communicated back to Industry. Also, in the case of drug shortage or public-health-emergency products, DMF holders can include a request to waive the condition to submit at six months prior to ANDA/PAS submission when unable to submit the request six months in advance. The FDA points out the importance of DMF holders communicating with their customers (the ANDA/PAS applicants) before submitting a prior assessment request.
Dr. Perera referenced the SBIA DMF workshop from November 30, 2022 (see DMF Workshop: GDUFA III Enhancements and Structured Data Submissions – Session 2), which speaks directly to the topics in her presentation. She also recommends emailing the inbox DMFOGD@FDA.HHS.GOV with questions. Additional information about the GDUFA III DMF enhancements may be found on the FDA webpage at GDUFA III Drug Master File (DMF) Review Enhancements.
If you need assistance in working with your DMF holder or your ANDA applicant on either of the above topics, Lachman Consultants can help. Reach out to us at lcs@lachmanconsultants.com for a consultation.
