Statistical Sampling: an Underestimated Element of Process Validation?

In a recent FDA Warning Letter, the FDA criticized inadequate process validation for a semi-solid dosage form.  What exactly did the FDA find inadequate?

The validation studies were criticized for not reflecting inter- and intra-batch variability. In particular, there was criticism that the sampling was random. The viscosity sampling scheme does not lead to statistical confidence in process performance.

 In a second Process Performance Qualification (PPQ) study, the influence of a critical excipient on viscosity was to be shown. Again, the FDA criticized that no inter-batch variability was demonstrated. This is not surprising, since only one run was performed.  

As measures, the FDA requires:

  • a validation programme, starting with product development, the validation itself and the control/monitoring of the processes with regard to intra- and inter-batch variability
  • an equipment and premises qualification programme
  • a programme for Process Performance Qualification and Continued Process Verification measures.

You can find the entire Warning Letter on the FDA website.

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