FDA Warning Letter Defines Minimum Criteria for Process Validation

In addition to 21 CFR 210/211 and the related Guides to Inspection of as well as Guidelines/Guidances for Industry, Warning Letters are another way of interpreting the US cGMP regulations. The following is FDA's response to a pharmaceutical manufacturer's reference to not being aware of having to perform process validation.

A Canadian manufacturer of medicinal products was criticized for a lack of process validation. During an FDA inspection, the manufacturer mentioned that it was not aware of having to perform process validation. In the response letter to the deficiency report, the manufacturer committed to perform process validation for a product, to stop using an equipment and to stop manufacturing handmade products.

In the Warning Letter, the FDA, with reference to its process validation guidance, insists on process validation to ensure that the products have quality, identity, strength and purity. According to the FDA, manual activities lead to a variable process. In addition, the FDA expects a retrospective assessment of the potential impact on product quality and a corrective action plan to ensure that better management oversight is consistently available throughout the manufacturing life cycle of all products.

Furthermore, the following is required:

• A data-based and science-driven program that identifies sources of process variability and ensures that manufacturing activities meet appropriate quality standards (adequacy of equipment, quality of raw materials, reliability of each manufacturing step and its controls, monitoring program of process performance and product quality)
• A detailed program describing the development, validation, maintenance, control and monitoring of each manufacturing process. The program shall include the monitoring of intra- and inter-batch variability.
• A program for equipment and room qualification
• A detailed overview of the company's internal validation program including associated procedures. In particular, "PPQ" and "Continued Process Verification" should be described.
• PPQ protocols and work instructions for equipment and room qualification

In addition, it is pointed out that a subcontractor is also responsible for the quality of the products it manufactures for others. The Warning Letter also points out that similar violations had already been discovered in past FDA inspections and that a GMP consultant should therefore be engaged. Interestingly, this GMP consultant should also carry out a six-system audit of all the company's GMP activities and the CAPA system. Reference is then made to an old FDA Quality System Approach guideline in which the system is described. This passage was recently mentioned in a Warning Letter.

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

Conclusion: Ignorance is no defense against punishment (or, in this case, a Warning Letter).