Documented Evidence - a fundamental Principle at the FDA

Documented evidence is a fundamental principle of the FDA in the GMP environment. A recent Warning Letter illustrates this with the example of a lack of cleaning validation. What does the FDA expect?

During an FDA inspection, deficiencies in process validation and cleaning validation were discovered. Cleaning validation was completely lacking. Interestingly, the company had already identified this itself in an internal deviation report. In addition, equipment labelled as cleaned was found to be filled.

In response, the company reports that it plans to carry out cleaning validations for the medicinal products and also to conduct hold time studies.

The FDA lacked supporting documentation in this regard. It explicitly points out the risk of cross-contamination and also recommends considering dedicated areas. The FDA expects:

• An overview of the validation programme with the associated procedures
• Schedules for when PPQ runs take place, including the corresponding protocols and instructions for the qualification of equipment and premises
• An overview of the updated work procedures for the validation and verification of cleaning procedures
• A retrospective review with regard to possible cross-contamination due to inadequate cleaning procedures for each piece of equipment that comes into contact with multiple products
• A CAPA plan based on the above retrospective review with regard to cross-contamination 

And worst case approaches to:

• Medicines with higher toxicities
• Medicines with higher active ingredient content
• Medicines with low solubility in the cleaning agent
• Medicines with properties that make them difficult to clean
• Swab sampling points at locations that are most difficult to clean
• Standing time before cleaning

Conclusion: Responses to Warning Letters must always include documents describing the measures to be taken to remedy the deficiencies identified in the Warning Letter.

The full Warning Letter can be found on the FDA website.