Process Validation covers the entire Manufacturing Process

The latest interpretations of regulatory GMP requirements often result from inspection findings. The FDA Warning Letters are very openly accessible in this regard. Following you can read about an example for the interpretation of CGMP in the context of process validation.

The deficiency point with reference to 21 CFR 211.100 (a) was 'Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess'.

What had happened?

The FDA criticised a drug manufacturer's inadequate process validation with regard to the consideration of the entire process. The company had not included filling and packaging in the validation. The data was from 2017. Although the company agreed to prepare a retrospective validation report, the FDA criticised the fact that there was no documented assessment showing the equivalence between the 2017 validation data and the current process. This also applies to the different batch sizes.

In its response, the company undertook to retrospectively re-evaluate the 2017 data in terms of its comparability with the current process and to carry out prospective validation for each over-the-counter medicine.

These statements were not sufficient for the FDA. It criticised the fact that the absence of the filling and packaging process steps in the original validation had not been addressed and that it lacked details on the validation plan for the prospective validations.

FDA requests

The FDA therefore requires:

• A detailed summary of the validation programme and the associated procedures, showing how the validated status is maintained throughout the product life cycle as part of a monitoring process. This includes a description of the Process Performance Qualification (PPQ) procedures and Continued Process Verification, with an emphasis on considering variability within and between batches
• A timetable for performing appropriate PPQ for each marketed medicinal product.
• PPQ plans
• A risk assessment and the resulting follow-up measures to be taken for marketed medicinal products manufactured without process validation.
• A programme for the qualification of equipment and facilities, including their procedural descriptions.

The FDA also notes in the Warning Letter that many deficiencies had already been found in a previous FDA inspection. It concludes from this that there is a lack of oversight by senior management.

Conclusion

This Warning Letter clearly shows that process validation must cover the entire manufacturing process and that senior management is also responsible for implementing GMP within their company.

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