Dedicated Equipment Should also be Included in Cleaning Validation

In a recent Warning Letter, the U.S. Food and Drug Administration (FDA) criticised inadequate cleaning of non-dedicated equipment, citing a violation of 21 CFR 211.67, which addresses the cleaning and maintenance of equipment under U.S. GMP regulations During the inspection, the FDA observed product residues and oxidised metal surfaces on a tablet press, despite the equipment having been assessed as clean and released by Quality Assurance.

Similar deficiencies were also identified on dedicated equipment, where product residues, oxidised metal surfaces and foreign material were present, even though the equipment had likewise been approved by Quality Assurance.

In response, the company proposed corrective actions limited to the implementation of a new visual inspection procedure using enhanced lighting to better identify residues, accompanied by personnel training.

However, the FDA concluded that this approach lacked a holistic assessment demonstrating that the cleaning procedures were suitable and effective, i.e. supported by cleaning validation. Furthermore, it lacks an assessment of the impact of previous cleaning procedures on medicinal products currently on the market within their expiry date.

FDA requirements

In this context, the FDA specifically requires:

• A comprehensive, retrospective assessment of the effectiveness of previous cleaning procedures in order to evaluate the extent of the risks posed by cross-contamination.
• A comprehensive identification of residues at other potentially improperly cleaned manufacturing equipment and an assessment of whether cross-contaminated products may have been released for distribution.
• An assessment that identifies any deficiencies in cleaning procedures and practices, and that covers all production equipment used to manufacture more than one product.
• A CAPA plan based on retrospective assessments of previous cleaning operations with corresponding conclusions on corrective measures, including timelines.
• A vulnerability analysis of the cleaning life cycle for the equipment.
• A description of improvements to the cleaning programme, including cleaning effectiveness and verification of correct cleaning performance.

Additional FDA requirements

Further FDA expectations include:

Improvements to the cleaning validation programme with a particular emphasis on worst-case scenarios for drug manufacturing. This includes, among other things, the identification and evaluation of the worst-case scenario for

• Drugs with higher toxicities
• Drugs with higher drug potencies
• Drugs of lower solubility in their cleaning solvents
• Drugs with characteristics that make them difficult to clean
• Swabbing locations representing the hardest-to-clean areas
• Maximum hold times before cleaning
• Description of change management steps required before introducing new equipment or products
• An overview of updated work instructions ensuring appropriate verification and validation of cleaning procedures for products, processes and equipment
• Written procedures for qualification of equipment and premises, including the associated qualification programme

Conclusion

Dedicated equipment should also be included in the scope of cleaning validation. The full Warning Letter is available on the FDA website.