What does the FDA expect from Cleaning Validation today?

FDA's regulations regarding cleaning validation are now relatively old. A GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSES dates back to the early 90s. In this context, Warning Letters show the "current thinking" of the FDA.

An example of this is a current Warning Letter from Anicare. What has been criticised?

With reference to 21 CFR 211.67 (b), the FDA criticised that the cleaning validation report confirmed that the acceptance criteria for the residues had been met, although there were values that exceeded the limit. In addition, an exceeded limit was found in the routine production, which has not been investigated. The limit excess was identified by the FDA as critical with regard to cross-contamination for the corresponding tank.

Anicare replied that they would validate a new cleaning procedure.

This simple answer was not enough for the FDA. The FDA expects a broader consideration, also with regard to other cleaning validation processes and a timetable for the completion of cleaning validation runs. It is explicitly required to provide:

  • A plan showing how the cleaning processes, practices and validation study results are evaluated for each piece of multipurpose manufacturing equipment.
  • A scientific rationale for the cleaning validation strategy that shows that the cleaning processes are effective.
  • A summary about updating the cleaning validation protocol with - at least - the worst case scenarios:
    - Evaluation of the medicinal products with the highest toxicity
    - Evaluation of medicinal products with regard to the lowest solubility in their cleaning agents
    - Evaluation of the characteristics of the medicinal products that are difficult to clean
    - Swab sampling points of the locations that are most difficult to clean.

The FDA also requires an overview of the updated SOPs to ensure that an appropriate programme is in place to verify and validate cleaning processes for new products, processes and equipment.

Retrospectively, the company should provide the FDA with a risk assessment of the medicinal products affected by the inadequate cleaning programme and still on the US market within the expiration date.

Regardless of the deficits in cleaning validation, insufficient process validation with regard to homogeneity within a batch was also criticised. As a corrective measure, the FDA requires a data-based, scientifically founded validation programme that identifies the sources of variability and also demonstrates their control. This applies to both manufacturing and packaging processes. This includes demonstrating the suitability of equipment, the consistent quality of raw materials and the determination of capabilities and reliability of each manufacturing step.

You can find the complete Warning Letter on FDA's website.

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