The Influence of Process Changes on Process Validation

What influence can process changes have on process validation? A current FDA Warning Letter gives information on this.

What was it about? To save production time, an API manufacturer had carried out a process change on 3 strengths of two APIs. After the process change, Process Performance Qualification (PPQ) batches were also produced. However, some of these batches did not meet the specification regarding mixing uniformity. The other batches were released.

The FDA commented in the Warning Letter that the manufacturer lacked data showing that the process was in "state of control" before batch release.

The assessment of the manufacturer after the process change showed that the new process led to deficiencies in mixing uniformity. The "old" process was more consistent and robust. In this respect, the unreleased batches should continue to be withheld during the discussion on how to proceed with the process change. After 8 months, the "old" process was returned to. However, the manufacturer decided that the retained batches could be distributed. This was criticised by the FDA. The manufacturer replied that it would "review" these batches and recall them if necessary. In its reply it also wrote that only the first consecutively "successfully" produced batches are eligible for market release and that non-compliant PPQ batches are considered beforehand. If an error is observed in the PPQ batches and there is no clear "root cause" for the cause, these batches should not receive market release.

Despite this response from the manufacturer, the FDA considers the manufacturer's validation strategy to be insufficient. This is because the validation strategy does not ensure that PPQ batches are properly evaluated to indicate that the process is "state of control".

The FDA also notes that it is informed that the manufacturer has recently made the decision to recall all PPQ batches produced with the new process. Nevertheless, the FDA wishes to

  • see a detailed overview of the validation programme that ensures that the state of control is maintained throughout the product lifecycle
  • accompanying work instructions
  • a description of the Process Performance Qualification and further monitoring of intra-batch and inter-batch variability
  • a description of whether a PPQ has been properly carried out for each product marketed with the appropriate criteria

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

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