Process validation preapproval inspections

The formal validation is often completed after the PAI, where three-batch process validation will be conducted in accordance with the protocol approved during the preapproval inspection. The primary objective of the formal process validation exercise is to establish process reproducibility and consistency. Such validation must be completed before entering the market. The formal validation studies continue through packaging and labeling operations (in whole or in part), so that machinability and stability of the finished product can be established and documented in the primary container-closure system. 

Provided that all transdermal process validations have been successfully completed, the focus shifts to the preapproval inspection (PAI). A target date for the PAI is typically known months in advance of the actual FDA visit. It is a good idea to finalize as many of the supporting protocols as possible during this time. If a company is fortunate enough to actually execute protocols and complete the summaries before the PAI, it is recommended that representative copies of the... 

Eventually the point will be reached at which the development of a product is complete the formulation is finalized, the equipment has been selected, the analytical methods are validated, the development transfer report has been issued, and the Preapproval Inspection (PAI) is anticipated. Now is the time to consider validation of both the manufacturing and cleaning processes. Although some process validation may have also been completed or a process validation protocol may have been prepared and approved, it is likely that very little has been finished that would enable us to state that the cleaning process is fully validated. 

In 1990, when FDA launched its preapproval inspections (PAI) program, the three-lot issue again arose. The PAI s chief architects (Richard Davis and Joseph Phillips, FDA Newark district directors) announced they would require evidence of three consecutive successful lots of commercial size prior to shipment of a new product across state lines as final evidence of process validation, even when the firm had already received its NDA approvable letter. 

In a well-designed validation program, most of the effort should be spent on facilities, equipment, components, methods, and process qualification. In such a program, the formalized, final three-batch validation sequence provides only the necessary process validation documentation required by the FDA to show product reproducibility and a manufacturing process in a state of control. Such a strategy is consistent with the FDA preapproval inspection program directive. ... 

During preapproval inspection, the FDA accepts a process-validation protocol based on the company s commitment to complete successfully three production-size validation batches prior to product launch. In some situations a prevalidation (process demonstration qualification) production-size batch is completed before the entire formal three-batch program is carried out. 

Complete preapproval inspection requirements conduct three-batch formal process validation, establish reproducibility for mixing, blending, and compression or encapsulation operations... 

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