Are Placebo Batches Allowed in Cleaning Validation?

In our News dated 16 August 2023, we referred to a Warning Letter issued to an Indian API manufacturer. Among other things, the FDA criticized the company for residues on internal surfaces of equipment parts. The deviations were found during an FDA inspection conducted in November 2022. In late January/early February 2023, the FDA was back at another site of this company for inspection. What did the FDA find this time?

As in the November 2022 inspection, the issue of cross-contamination was addressed again, this time also mentioning the relevant passage from the Code of Federal Regulations (CFR), 21 CFR 211.67 (a). Residues were once more found on interior surfaces, but this time turned out to contain APIs. The company admitted that some areas had not been cleaned or inspected for contaminants since installation 14 years ago. A placebo batch produced during the inspection also showed contamination with API.

Immediate consequences of the inspection

The API manufacturer contacted the customer to whom it supplied APIs. The customer in turn initiated recalls of various batches of tablets containing benzodiazepam. The API manufacturer itself also recalled batches of tablets it had manufactured from the market. Furthermore, equipment was taken out of service. Cleaning instructions were updated and cleaning verification was introduced. The latter are comparable procedures to the Warning Letter issued after the November inspection at the other site. In addition, placebo batches were carried out again, which no longer showed any contamination. The conclusion from this from the manufacturer's point of view: there is no risk to patient health and safety, and no likelihood of contamination of materials.

Consequences of the inspection

In its response to the actions listed above, the FDA first and foremost criticized the company's conclusions about the placebo batches with no detectable contamination. The reason: cross-contamination is not "equally distributed." And citing non-contaminated placebo batches as justification for appropriate cleaning of visibly contaminated equipment is unscientific. In addition, recovery rates after performing the placebo batches mostly occurred on surfaces not in contact with the product.

Besides to the placebo batches, of course, the FDA then criticized the fact that recovery rates were taken at locations that did not necessarily contain the highest levels of contamination and the sampling method itself. The same more extensive measures were called for as were named in the Warning Letter following the 2022 inspection at the other site.

Conclusion: the FDA urges a scientific approach to cleaning validation here. Their Guide to Inspection Validation of Cleaning explicitly mentions "swab" and "rinse" as sampling techniques, not placebo batches.

You can find the entire Warning Letter, as always, on the FDA website.