As we’re on the topic of Form FDA 483s, it’s also important to understand that there are actually 3 different types of inspections, and the expectations are somewhat different. When I recently asked a director of quality and compliance at a large biopharma company, she described it very succinctly. Here’s what she said:
- Pre-Approval Inspections (PAI): The purpose of a PAI is to verify existence of the raw data included in the submission (often the focus here will be on laboratory results for both lot release and stability as well as validation) and confirm that the facility is capable of manufacture (correct scale qualified equipment, process validation, etc). Yes, there will be an overall GMP evaluation but the stated purpose of the PAI (in response to the generics scandal of the 80s) is focus on those two items. The outcome is a recommendation for approval or not. If the site has no approved products, FDA cannot issue a warning letter but they will block approval of the product until such time as remediation occurs and has been confirmed by a re-inspection.
- Routine GMP inspections are simply that. Periodically ( every 2-3 years generally) the FDA will perform an unannounced (for the US and PR, those conducted outside the US are scheduled in advance so companies know they are coming) GMP inspection for manufacturers who make commercial products. They generally do not inspect clinical manufacturing sites unless there are known issues, such as unexpected deaths in a clinical trial that may be linked to method of manufacture. This can cover all GMP systems or can be a more limited inspection. I’ve seen a PAI that went perfectly well, but the next GMP inspection found serious flaws in the GMP systems.
- “For-cause” inspections are based on a FAR/BPD report to the agency, a recall, adverse event cluster (think heparin) or other “event” the FDA will conduct a focused inspection on that particular event. Yes, they can migrate elsewhere during that inspection if they find other problems, but generally the focus is on the specific event and the company response to same.
At the end of the day, when the FDA shows up at your doorstep, everything is fair game. The different types of inspections can all lead to Form FDA 483s.
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