FDA officials address common pitfalls affecting post-approval change applications

Regulatory NewsRegulatory News | 15 November 2021 |  By 

The US Food and Drug Administration (FDA) offered some advice to help ensure smoother reviews of abbreviated new drug application (ANDA) post-approval supplements and addressed how certain changes should be categorized at the 10 November meeting of the Association for Accessible Medicines” (AAM) GRx+Biosim conference.
Officials were asked to address common issues affecting ANDA post-approval chemistry, manufacturing and controls (CMC) submissions. Agency officials discussed some of the documents that should accompany ANDA post-approval submissions, such as cover letters and the Form FDA 356h, and addressed whether nitrosamine risk assessment reports should be included in supplement requests.
The agency said that some of the more common post-approval change requests are for manufacturing site changes, manufacturing process changes, revising specifications, instituting container/closure changes, and changing stability protocols.
Cover letters need some improvement
Olugbenga Okubadejo, division director of post-marketing activities for FDA’s Office of Program and Regulatory Operations in the Office of Pharmaceutical Quality (OPQ), told industry that “a lot of you do a great job with your cover letter so I am going to express that up front. We do see some cover letters that need improvement, to be frank about it.”
He said that cover letters should “clearly identify” the overall proposed change classification. FDA differentiates post-approval changes into four categories: major changes requiring a prior approval supplement (PAS); moderate changes requiring the filing of a changes being effected-30 (CBE-30) supplement or a CBE-0 supplement; or minor changes necessitating only the filing of an annual report. Annual reports do not need to be submitted as supplements.
For multiple changes, applicants should have a summary table listing each change,the classification for the change and the justification for each classification.
The cover letter should also include any referenced drug master file (DMF) and address whether the submission is based on a DMF amendment. If so, the DMF amendment letter should be referenced.
Some confusion on filing categories 
Kylie Grainger, a chemist with the division of post-marketing activities II in the Office of Lifecycle Drug Products in OPQ, said that while overall industry is doing a “great job” in selecting the correct filing categories, there is room for improvement.
She noted that only a “small fraction,” or 1.3% of CBE-0 and 2.9% of CBE-30 classifications, are rejected for being in the wrong category. To help industry, Grainger offered some examples of changes that should be submitted in an annual report category:
  • Extending drug product expiration dating based on an approved stability protocol
  • Deleting the heavy metal testing to comply with the United States Pharmacopoeia (USP) and the International Council on Harmonization’s (ICH) Q3D guidelines
  • Proposing to add testing or tighten acceptance criteria to comply with the official compendia
Sponsors should submit a PAS for the following changes:
  • Adding a new active pharmaceutical ingredient (API) supplier
  • Moving to a different manufacturing site when that site does not have a satisfactory Good Manufacturing Practice (GMP) inspection for the type of operation being moved
  • Deleting microbial enumeration testing for a drug product based on a risk assessment
  • Deleting in-process blend uniformity testing
  • Relaxing acceptance criteria and deleting tests from release and stability specifications
  • Reducing long-term stability time points
  • Changing the adhesive composition for transdermal products
  • Adding a blister pack or unit dose cup when the currently approved packaging configuration is a high-density polyethylene (HDPE) bottle
Grainger also addressed how many stability batches should be included with post-approval change applications. For drug product manufacturing process changes, drug product manufacturing site changes, adding a new API source and adding a new strength, sponsors should submit between one to three batches of post-change drug product and three months of accelerated and long-term stability data. Sponsors should also agree to submit long-term stability data in annual reports.
Nitrosamine risk assessment need not be submitted
In other areas, Okubadejo clarified that nitrosamine risk assessment reports do not have to be included in supplement requests. Instead, these reports should be retained at manufacturing sites and made available upon request.
FDA issued a guidance in September 2020 to help manufacturers detect and prevent nitrosamines in products. The guidance was revised in February 2021 to give manufacturers more time to conduct nitrosamine risk assessment to ensure that these impurities do not exceed certain thresholds. (RELATED:  N-Nitrosamine impurities: FDA issues detection, prevention guidance, Regulatory Focus 1 September 2020)
AAM GRX Biosims meeting


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