In a recently posted FDA Warning Letter, USFDA provided a clear expectation concerning the purpose of validation:

The purpose of validation is to determine whether your processes can operate within established parameters to assure consistent batch uniformity, integrity, and drug quality. Reliable and well-documented batch operations are essential to ensuring process control and drug quality.

The firm that received the warning letter was cited for 21 CFR 100(a) – and could not provide process qualification batch records and quality control documentation.  According to the warning letter, the firm was only provided a protocol and summary report with insufficient data.

As part of the warning letter, FDA requested:

  • A data-driven and scientifically sound program that identifies and controls all known sources of variability, such that your production and packaging processes will consistently meet appropriate parameters. This includes, but is not limited to, evaluating suitability of equipment for its intended use, assuring quality of input materials, and determining the capability and reliability of each manufacturing process step and control.
  • Revised procedures that establish an ongoing program for monitoring process control and detecting variation throughout the product lifecycle.
  • An updated master batch record for manufacturing sterile [redacted] that requires specific processing details in order to fully document each significant manufacturing step.

This is a good warning letter to learn from as the above items relate back to each of the 3 stages of process validation.

In Stage 1 – Process Design is based on building and capturing process knowledge and understanding (identification of the Critical Quality Attributes and Critical Process Parameters (CQA/CPP), which leads to the establishment of a strategy for process control.

In Stage 2 – Process Qualification  is based on design of the facility and qualification of the equipment and utilities.  Completion of this phase leads to process performance qualification where the facility demonstrates that operators, equipment, procedures, and systems work together to produce compliant product.

And finally in Stage 3, Continued Process Verification where routine monitoring of the process using statistical tools can verify the manufacturing process is operating in a state of control.