Risk Analyses do not always help - Example of Cross-Contamination

Recommendation

2/3 May 2024

Process Validation - Live Online Training

With ICH Q9 Quality Risk Management becoming effective, risk analyses have become the "magic word" in the GMP environment. But risk analyses do not always help. An example of this can be found in an FDA Warning Letter on the subject of cross-contamination.

Despite several risk analyses with the aim of showing that current cleaning procedures in "multi-purpose" facilities can clean off genotoxic contamination to a sufficient level, the FDA did not accept them.

The authority criticised the fact that residues close to the limit were found in the test runs and that no further investigations followed these findings. The FDA also criticised the changing of equipment without it being specified. It was also noted that cross-contamination from indirect sources, e.g. non-dedicated equipment used for solvent recovery, was not considered in the runs. Analytical results were disregarded without scientific justification.

The FDA did not accept the company's proposal to switch to dedicated solvent recovery equipment. Their argument was that the solvent tanks in which recovered solvents are stored are not themselves dedicated.

The FDA required a retrospective consideration of cleaning effectiveness in terms of cross-contamination risks. Based on this retrospective review, a CAPA plan should then be developed regarding cleaning processes and activities. The cleaning validation programme is to be improved so that worst case scenarios are considered. The following are to be considered:

• Medicinal products with higher toxicities
• Medicinal products with higher active ingredient contents 
• Medicinal products with low solubility in the purification reagent 
• Medicinal products with properties that make them difficult to purify 
• Swab sampling sites at locations that are most difficult to purify 
• Standing time before cleaning 
• Adjustments to the change management system when new equipment or products are introduced 
• Overview of updated SOPs to ensure that an adequate cleaning process verification and validation programme is in place for products, processes and the equipment.

This mention of the above items occurs very frequently in FDA Warning Letters on cleaning validation.

Conclusion: Risk analysis is useful in the GMP environment, but it must be scientifically based and not simply explain away results.

For more datailed information please see the entire FDA Warning Letter issued to Lupin Limited.