FDA has been published their guidance of ANDA Submissions – Prior Approval Supplements Under GDUFA, 2nd Revision on 14 October, 2022.
This guidance is intended to assist applicants preparing to submit to FDA prior approval supplements (PASs) and amendments to PASs for abbreviated new drug applications (ANDAs) under section 505(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(j)). The guidance explains how the Generic Drug User Fee Amendments (GDUFA) relates to PAS submissions.
Specifically, this guidance describes how the GDUFA performance goals apply to:
- A PAS subject to the refuse-to-receive (RTR) standards
- A PAS that requires an inspection
- A PAS for which an inspection is not required.
- An amendment to a PAS
- Other PAS-related matters
A. Changes to an Approved Application:
Specifically, section 506A of the FD&C Act and § 314.70 of FDA regulations provide for the following reporting categories of changes to an approved application:
1. Major Change: a change that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product. A major change requires the submission of a PAS and approval by FDA before distribution of the drug product made using the change.
2. Moderate Change: a change that has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product. Depending on the nature of the change, one of the following two types of supplements must be submitted to FDA for a moderate change:
a. Supplement – Changes Being Effected in 30 Days (CBE-30 supplement): A CBE-30 supplement involves certain moderate changes that require the submission of the supplement to FDA at least 30 days before the distribution of the drug product made using the change.
b. Supplement – Changes Being Effected (CBE-0 supplement): A CBE-0 supplement involves certain moderate changes that allow distribution to occur as soon as FDA receives the supplement.
3. Minor Change: a change that has minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product. The applicant must describe minor changes in its next annual report.
B. GDUFA Performance Goals for PAS Submissions:
Under the GDUFA III commitment letter, the 8-month goal date is available to priority PASs requiring an inspection when the applicant submits a complete and accurate Pre-Submission Facility Correspondence (PFC) no later than 60 days prior to the date of the PAS submission and the PFC is found to be complete, accurate, and remain unchanged at the time of the PAS submission.
Under the GDUFA III commitment letter, the 10-month goal date is available to priority PASs requiring an inspection when the applicant submits a PFC later than 60 days prior to the date of the PAS submission or does not submit a PFC, or when the PFC is found to be incomplete or inaccurate or the information submitted in the PFC differs significantly from the PAS submission.
C. Inspections for PAS Submissions
If a PAS does not require an inspection, the goal date is either 4 or 6 months from the date of submission; but if a PAS requires an inspection, the goal date is either 8 or 10 months from the date of submission.
However, the GDUFA goal date can be revised to 4 or 6 months if it is later determined that an actual inspection is not required for that PAS. Conversely, an initial goal date of 6 months occasionally may change to a 10-month goal date if, during the assessment, FDA determines an inspection is necessary.
D. Submission of Supplements
Any PAS to an approved ANDA should identify on the first page of the submission that it is a PAS. To facilitate processing, FDA recommends that the applicant provide the following information on the first page of the submission:
1. A statement indicating whether the PAS is for a new-strength product
2. A statement indicating whether the PAS is for a request for proprietary name assessment
3. A statement indicating whether the PAS is for a Risk Evaluation and Mitigation Strategy (REMS) or a REMS modification
4. A statement indicating whether the submission is an amendment to a PAS, and if so, whether it is a major or minor amendment
5. A statement indicating whether the PAS contains any manufacturing or facilities changes
6. A list of the specific assessment disciplines to assess the PAS (Chemistry, Biopharmaceutics, Labeling, DMF, Bioequivalence, Microbiology, or Clinical)
7. If expedited assessment is requested, the label Expedited Review Request should be placed prominently at the top of the submission. The submission should include a basis for the expedited assessment request
8. If the submission is part of a grouped supplement (see section III.E.1 below),
a statement identifying the additional submissions for the same/identical proposed change(s)” should be added. This request would greatly facilitate OPQ’s identification of grouped supplements).
E. Other Matters
Grouped supplements are multiple supplements submitted to ANDAs by a single applicant for the same chemistry, manufacturing, and controls (CMC) change to each application.
In addition to grouped supplements, there are alternative ways of submitting multiple PASs for the same change. For example, for some changes (e.g., widening of an approved specification or introduction of a new API supplier), once a PAS is submitted and approved for the lead ANDA, subsequent supplements for the same change to other ANDAs may be classified as CBE-30s. The Agency recommends that applicants contact the appropriate assessment division beforehand to ensure the change is appropriate for a PAS followed by a CBE-30, or if there are specific questions regarding this alternative.
If FDA finds that a supplement submitted as a CBE supplement should have been submitted as a PAS, it will notify the applicant. The applicant is not required to withdraw the CBE supplement because when FDA sends a letter explaining that the applicant’s submission is not accepted as a CBE supplement, The applicant may resubmit the supplement as a PAS and the GDUFA performance goals will apply to that PAS.
Prior Approval Supplement Review Time
