CAPAs after Validation Deficiencies

The FDA Warning Letters are a very good source to learn how the FDA reacts to GMP deficiencies. In a current Warning Letter, the FDA comments on deficiencies in the context of process validation, among other things. What "CAPA" measures did it demand?

With reference to 21 CFR 211.100, the FDA criticised an inadequate process validation. None of the initial process validation studies (e.g. the Process Performance Qualification, PPQ) were complete. The conclusion the FDA drew from this: the company cannot be sure that it consistently manufactures medicines with a defined quality.

The manufacturer's response to "review" all studies was not sufficient for the FDA. The authority demands a precise specification of how the collected information will be evaluated. It also wants this information to be compared with appropriate, predefined acceptance criteria in protocols. The goal should be to be able to show that the process is reproducible and the products therefore suitable. And this should be done with the current premises, utilities, equipment, personnel, controls and with the variables that the manufacturing activities foresee.  

Furthermore, in the sense of a CAPA measure, a risk assessment is required with regard to the products that are already manufactured and on the market. Moreover, a continued process verification is required. In validation reports, content limits for the end products should be specified (in future). The many out-of-specification results during validation should be investigated.

Specifically, the FDA requires the manufacturer to:

  • A detailed summary of the validation programme with respect to the product life cycle with the corresponding written requirements. 
  • Timelines for the PPQ of the respective products 
  • Process performance protocols and written procedures for qualification of premises and equipment 
  • Detailed description of the continued process verification, including intra- and inter-batch variability. 
  • A qualification programme for the premises and equipment.

Due to the large number of additional deficiencies, the FDA recommends the involvement of a GMP consultant, as is more common in such cases.

For more detailed information please see the FDA's entire Warning Letter on the website.

In the Live Online Training Process Validation, on 30/31 October 2023, you will gain the tools to defend a process validation in a GMP inspection.

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