12/05/2022
Photo by Fulvio Ciccolo on Unsplash
The US Food and Drug Administration (FDA) released an updated Compliance Program Guidance Manual (CPGM) for PAI in October 2022. The CPGM guides the Agency in an inspection. Preapproval facility evaluations and Pre-Approval Inspections (PAIs) support the Agency in evaluating if a drug manufacturer that is listed in the Chemistry, Manufacturing, and Controls (CMC) section of a NDA follows clinical Good Manufacturing Practice (CGMP) requirements and that data in the NDA are accurate and complete.
Preapproval facility evaluations are conducted by a CDER integrated quality assessment (IQA) team to evaluate if a PAI is needed from a quality perspective before a NDA can be approved. A risk based approach is used with a focus on facility, product, and process. The IQA team consists of an application technical lead, a regulatory business project manager, a drug substance assessor, drug product assessor, OPMA manufacturing assessor, and ORA representative(s).
PAIs gather the information needed to assess if the data submitted in the NDA are accurate and complete and evaluate manufacturing processes and control strategies in place to ensure quality product in compliance with CGMP requirements. The PAI inspection outcome is one aspect that goes into the determination whether to approve the NDA. The PAI team includes a field investigator and specialists such as chemistry, process, facility, formulation, or microbiology experts.
The FDA uses a risk-based approach in determining if an inspection is needed. Information provided to the FDA on the facility and from the NDA are also considered. Triggers for PAI are:
Risk in facility, product, or process
First application or multiple simultaneous applications
Breakthrough treatment
High risk active pharmaceutical ingredients (API)
Narrow therapeutic range
Primary packaging and labeling site or finished dosage manufacturer
Complicated process or substantially different process than previously used at the facility
No recent inspection history, or history of official action indicated 483 (OAI)
PAI IQA teams are looking for:
Conformity to the CMC section of the NDA
Scalable operations
Quality, accurate data
Full CGMP compliance
Manufacturing reliability
Batch records, procedures, and equipment are inspected to determine that manufacture is the same process that was used during the studies that are included in the NDA. Raw data is reviewed to verify integrity, authenticity, and accuracy of data submitted in the CMC section of the NDA.
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- The Clinical Pathways Team
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