Even Non-Reactive Residues Are Considered Cross-Contamination and Require Validation

In a recent Warning Letter, the FDA outlined its view on the topic of cleaning validation. What is it about?

An API manufacturer from India has been criticized for lacking procedures on the topics of cleaning and equipment maintenance. During their inspection, FDA investigators found "spalling" of the inner surface and incrustations on equipment components. Furthermore, residues were also found on an inner surface of one piece of equipment.

Responses to the 483

The manufacturer stated that the residues remaining were non-significant and non-reactive. Furthermore, the manufacturer wanted to implement preventive measures regarding the update of a work instruction and regarding the handling of the "spalled" material. Additionally, a verification checkpoint is to be established.

FDA's responses in the Warning Letter to the inspected company's replies

This is not sufficient for the FDA! The FDA demands an evaluation of the potential risk of "spalling" for all APIs that are manufactured there.
It also criticizes the inspected company for not providing evidence that the retained material does not react with other APIs. Additionally, a gap analysis on the cause of the cleaning deficiencies is requested.

Specifically, the FDA is asking for:

A summary, retrospective review of cleaning effectiveness with respect to cross-contamination risks. The identities of residues, equipment other than those previously considered that may also have been inadequately cleaned, and a consideration of whether cross-contaminated products may have been released are to be included. The consideration should include any inadequate cleaning procedures and practices and any equipment item in which more than one product is manufactured.

Based on this retrospective review, a CAPA plan shall then be developed regarding the cleaning programme. This should identify corrective actions to the cleaning process and activities and provide timelines to implementation. Furthermore, the FDA would like to see a summary of weaknesses in the life cycle management of cleaning. Improvements to the cleaning programme, including improvements to cleaning efficiency and improved continued verification of cleaning execution of all products and equipment, should be described.

The cleaning validation programme should be improved to consider worst case scenarios, regarding:

  • Medicinal products with higher toxicities
  • Medicinal products with higher API contents
  • Medicinal products with low solubility in the cleaning reagent
  • Medicinal products with properties that make them difficult to clean
  • Swab sampling sites to locations that are most difficult to clean
  • Standing time before cleaning
  • Adjustments to the change management system when new equipment or products are introduced
  • Overview of updated standard operating procedures (SOPs) to ensure that an adequate cleaning process verification and validation programme is in place for products, processes, and the equipment.
  • A holistic review of cleaning operations and associated cleaning validation strategy for each piece of equipment to determine if similar deficiencies exist.

Conclusion: "Simple responses" to inspection deficiencies to the FDA are often inadequate. FDA typically wants to see that the deficiencies found are evaluated retrospectively and described proactively as to what corrective actions will prevent the deficiencies in the future (CAPA).

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

PS. Current cleaning validation issues will be covered intensively at the ECA Course Cleaning Validation with Pre-Course : Impact of Annex 1 Revision on Cleaning Validation on 08-10 November 2023.

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