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Prepare for Risk-focused Pre-Approval Inspections

Since the issue of its cGMP Initiative in 2002, FDA has concentrated on applying risk-evaluation techniques to the various procedures involved in new drug approval. Following this trend, the agency recently issued a completely revised Compliance Guidance Manual on Pre-Approval Inspections for use by field staff.

The new Manual (effective December 5, 2010 and scheduled for completion by November 5, 2012) requires a scientific, risk-based approach to PAI inspections focusing on three critical factors:

1. The firm’s ability and readiness to manufacture the product on a commercial scale, based upon the firm’s understanding and control of the product, the manufacturing processes and analytical procedures;

2. Conformance of the actual plant operations to descriptions in the CMC section of the application;

3. The accuracy and completeness of the data submitted in the application.

This approach is in marked contrast to the previous guidance, which concentrated on cGMP compliance and process validation, and required an overall inspection of all aspects of the manufacturer’s operations, based upon the “six-system” classification. Inspectors were instructed to “assure cGMP compliance, verify the authenticity and accuracy of the data contained in these applications, and report any other data which may impact on the firm’s ability to manufacture the product in compliance with GMP’s.”

Inspectors are advised to discuss the NDA CMC section with the CDER/CBER reviewers to highlight those areas of operation within the three main factors which should specifically be examined. Looking at each of these factors in more detail, the first requirement falls in line with the approach recommended in FDA’s guidance on process validation (final guidance issued January, 2011), namely that knowledge and understanding of the processes gained throughout the product’s life cycle should be applied to ensure that manufacture can be routinely controlled and the product will consistently meet its designed specifications. The Manual emphasizes the need for an adequate quality management function, appropriate QA and QC groups and procedures for change control, investigations of deviations, and CAPA.

The new guidance stresses the need to confirm that actual full-scale production conditions match those defined in the application and that manufacturing conditions for clinical trial batches and others referred to in the NDA are comparable to those proposed for full-scale operations. The Manual also recommends that Inspectors confirm the validation of critical analytical methods and audit laboratory notebooks. While the requirement for data auditing is not new, critical data types are identified for spot checks, including product stability, content uniformity and API impurities. The new guidance also requires that, if a data integrity discrepancy is observed, the personnel responsible for application submissions and any decision to include or exclude data from the application should be identified.

Companies expecting pre-approval inspections should carefully study the new guidance and perform a thorough risk analysis to identify those areas where inspectors may be likely to concentrate their efforts. Fore-warned is fore-armed.


Blog article by: Alex Kanarek and Howard Levine