FDA Reveals More Info on API File Submissions

By Zachary Brennan

- Last updated on GMT

FDA Reveals More Info on API File Submissions
Drug Master File (DMF) completeness reviews required under GDUFA could take three months and should be sought before ANDA submission according to the US Food and Drug Administration (FDA).

The completeness assessment reviews, in addition to a one-time fee of $21,340, are new for all DMFs submitted after Oct. 1, 2012. They will only be required when a Type II DMF is referenced in an abbreviated new drug application (ANDA) submission for a generic drug, at which point the holder will have to pay the fee, FDA officials said in a webinar on Monday​. 

The agency recommends Type II DMFs for active pharmaceutical ingredients (APIs) to be submitted at least three months prior to an ANDA submission in order for the fee to be processed and the completeness assessment to be conducted. DMFs submitted for excipients, submissions related INDs, NDAs, or for non-Type II DMFs will not require the fee.

Under the new requirements set out in the Generic Drug User Fee Act, a Type II DMF applicant may also now receive a complete response letter for DMFs that are not approved in the completeness assessment.

Response Letter

The letter has distinct sections for chemistry and microbiology deficiencies, as well as for information on manufacturing facilities and testing sites. Letters will reflect the compliance status of facilities and deficiencies from any issues related to consult reviews, like toxicology consults.

Type II DMFs should be updated with annual reports. If a report is delayed more than three years, the FDA will issue an overdue notice letter, after which the DMF holder can only keep its DMF active by resubmitting. If a response is not completed, the FDA can close the status of the DMF until it is re-activated by the holder.

The FDA can also issue an incomplete letter if additional issues are discovered during the completeness assessment. Type II DMF holders can then request teleconferences with FDA staff, though a written request for a teleconference must be obtained within the first 10 days of receiving the letter, officials said. In October, the FDA released draft guidance on requirements for the completeness assessments​.

The agency also has begun posting a list of all Type II DMFs for APIs cleared for use​ in ANDAs, which is updated on a weekly basis. Having a DMF on the public list is the only official guarantee that there will be less risk when submitting an ANDA.

Type II DMFs can be submitted by paper or electronically through the electronic common technical document, though no waivers will be granted forDMFs that do not use the eCTD format. About 12 percent of Type II DMFs submitted since 2001 are electronic and that number is increasing, Arthur Shaw, the Center for Drug Evaluation and Research’s (CDER’s) DMF expert said in the webinar.

Questions and concerns on DMFs can be submitted to dmfquestion@cder.fda.gov​.

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