Process Validation Deficits in API Manufacturing

Interpretations of legally binding requirements in the GMP environment are provided by guidelines, guidance documents, etc. (soft law) or inspection results. The following are excerpts from a Warning Letter from the FDA to an API manufacturer regarding process validation deficiencies. What did the FDA criticize?

Among other things, the FDA discovered during the inspection that a written instruction, referred to as a "pre-job briefing" document, was used by the personnel, which described itself as "not a GMP document/process". However, this document was used to enable a deviation from the validated API process.

In the response letter to the FDA's deficiency report, the company admitted that the "pre-job briefing" document was incorrectly used to implement a change to the validated manufacturing process. However, the manufacturer committed to identifying and correcting any other manufacturing instructions that relied on a pre-job briefing document to deviate from a validated manufacturing process.

However, the FDA found that no investigation into the deviation from the validated process was conducted. There was also no risk-based, retrospective review of batches within the expiry to identify other deviations. There was no rationale for terminating the process change as previously implemented. Further, there is no CAPA measure that considers the role of the quality unit in these deviations from the validated manufacturing processes.

Consequently, the FDA has requested, among other things:

• An evaluation of each manufacturing process to ensure that there is a data-driven and science-based program that identifies and controls all sources of variability. This is to ensure that the manufacturing processes consistently meet the appropriate specifications and manufacturing standards. This includes:
  - assessing the suitability of the equipment for its intended use
  - the adequacy of the detectbility of monitoring and testing systems
  - the quality of the raw materials
  - the reliability of the individual manufacturing steps and the controls of the manufacturing process
• A detailed summary of the validation program and the corresponding procedures to ensure that processes remain in a state of control during the life cycle. 
• Program for Stage 2.2 of Process Performance Qualification (PPQ) and for Stage 3 (Continued Process Verification) to monitor intra-batch and inter-batch variations.
• Schedules for the completion of further PPQ runs for adapted processes for marketed medicinal products where a state of control is not yet appropriate or fully established. 
• PPQ protocols and written procedures for the qualification of equipment and premises.
• A detailed process validation life cycle program (development, validation, maintenance, control and monitoring of a process) for each manufacturing process for state of control compliance.
• A program for the qualification of equipment and premises.

Conclusion: the FDA takes a very critical view of any deviation from a validated process without a regulated procedure. Therefore, it requires extensive documentation that shows how the process validation life cycle as well as the qualification of equipment and premises are ensured. Furthermore, a retrospective review of the deviating processes is necessary.

The entire Warning Letter is available on the FDA website.