Revalidation - the FDA Perspective

With the FDA Process Validation Guidance for Industry coming into effect, stage 3 in the process validation life cycle ('Continued Process Verification') replaced regular revalidation in the non-sterile area. However, revalidations may of course be conducted on an ad hoc basis. What does the FDA expect in such cases? A recent Warning Letter provides some guidance.

What happened?

The FDA criticised a manufacturer of sterile ophthalmic medicines for having a manufacturing process that was not reproducible. Furthermore, there was a lack of 'continued process verification'. As an example, the FDA cites the high susceptibility of the process to producing a large number of defective units. Many batches could not be released because they contained visible particles. Nevertheless, some of these batches were placed on the market. In this context, particle control was also criticised in general.

The lack of classification with regard to the severity of the defects (e.g. critical defect, major defect, minor defect) and the limit for the number of defects was explicitly addressed. In this regard, the last requalification study was also criticised because it did not take into account potential changes resulting from previous requalifications and the original validation.

The maximum holding times in the process were also not validated.

Interestingly, the FDA criticised the fact that the manufacturer's response did not address the lack of process capability and that there had been 'blind reliance' on visual inspection to remove defective units from the batch.

The FDA still lacks a root cause analysis of where these particles are coming from in such high numbers. There is also a lack of immediate measures to prevent processes with low capability from continuing to produce products while the defects are being rectified. The handling of potentially contaminated products on the market is also being called into question. The particle control programme should be comprehensively reassessed and the holding times validated, with timelines specified for completion of the validation.

A list of plans, assessments and summaries to be provided to the FDA concludes the description of the findings on process validation in this Warning Letter.

Conclusion: What is interesting about this Warning Letter is, firstly, that there should be rationales for requalification and/or revalidation (the terms are somewhat confused here) and, secondly, that process capability can be a good indicator of the validity of a process.

As always, you can find the entire Warning Letter on the FDA website.