Responsibilities of Quality Assurance - FDA Perspective

 Warning Letters from US FDA provide an interesting guide to interpreting the FDA's CGMP regulations. A current Warning Letter shows interesting considerations of FDA regarding the tasks of quality assurance. What does the FDA mean?

Normally, the Warning Letters list the individual deficiencies according to the paragraphs in 21 CFR 210/211. One exception is a Warning Letter to a manufacturer of over-the-counter (OTC) drugs. In this case, 21 CFR 211.22 was cited, which describes the tasks of the quality unit. A short statement criticizes the non-compliance with CGMP rules in the production of the drugs.

Criticism of the process validation

With reference to 21 CFR 211.100, the FDA also criticizes the inadequate validation of the water system under this point. It is repeatedly stated that there is no quality overview by the quality assurance department.

Although the lack of validation of the water system has been criticized, the FDA is expanding its requirements with regard to process validation and making specific demands:

• A detailed summary of the validation program ensuring that a "state of control" occurs throughout the product life cycle, along with associated procedures
• A description of the Process Performance Qualification (PPQ) program
• A description of the monitoring activities to assess intra-batch and inter-batch variability to ensure state of control
• A schedule for the implementation of PPQ for each of the marketed medicinal products
• PPQ plans and written instructions for the qualification of equipment and premises
• A detailed program for the development, validation, maintenance, control and monitoring of each manufacturing process, with regard to variations within and between batches, with the aim of achieving a state of control
• A program for the qualification of equipment and premises
• A detailed and independent assessment of the design, control and maintenance of the water system
• A detailed plan showing how a water system will be adequately installed, operated, monitored and maintained
• A detailed risk assessment of the effects of the defective water system on the products that are on the market or within the expiration date.
• Information to customers and recalls should also be taken into account

Criticism of cleaning validation

Again, under the point of deficiency for 21 CFR 211.22, the lack of cleaning verification and validation studies was criticized with reference to 21 CFR 211.67. The FDA calls for improvements to the cleaning validation program with particular emphasis on "worst-case" scenarios for drug manufacturing. "Acceptable" sanitation facilities are also required. Directly addressed is the identification and evaluation of worst-case scenarios with regard to

• Medicinal products with higher toxicities
• Medicinal products with higher levels of active ingredients
• Medicinal products with low solubility in the cleaning agent
• Pharmaceuticals with properties that make them difficult to purify
• Swab sampling points at locations that are most difficult to purify
• Maximum holding time before cleaning
• An overview of updated standard operation procedures to ensure that an appropriate cleaning process verification and validation program is in place for products, processes and equipment

Critique of stability studies

The third citation of a CFR deficiency is in reference to 21 CFR 211.137 regarding the lack of stability studies to determine expiration dates and the labeling of those expiration dates on products. This includes a detailed and independent review and CAPA plan demonstrating that the stability program is adequate. The remediation shall include, but not be limited to:

• Stability methods used
• Stability studies prior to distribution
• an ongoing stability program
• detailed identification of the specific attributes and how and when they are tested  
• All descriptions that describe the above-mentioned defect corrections

Conclusion

In this Warning Letter, the FDA lists various deficiencies under the tasks of quality assurance. It also sees quality assurance as relevant when it comes to the overview of the validation of a water system, the cleaning validation, the maintenance of the systems and the performance of shelf life studies and the affixing of shelf life information to the products. In the meantime, there are also newer Warning Letters in which other deficiencies are also listed under the actual deficiency point for quality assurance 21 CFR 211.22. Please also see "FDA Warning Letter to pharmaceutical Manufacturer in Puerto Rico" and "FDA Issues Warning Letter to Vietnamese Drug Manufacturer for CGMP Violations" when evaluating Wrning Letters.

As always, you can find the entire warning letter on the FDA website.