Inadequate CAPAs once more in the Focus of FDA Warning Letters

Recommendation

7/8 May 2024

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As in the previous years, appropriate handling of deviations, investigations and CAPA still causes a lot of concerns in GMP inspections. Over the years, observations made in inspections reveal inadequate implementation of the respective systems. On 17 December 2019, five Warning Letters related to cGMP/Finished Pharmaceuticals were issued. Four of those also broached the issue of deviation handling and appropriate CAPA.

Taking a closer view at the examples of the findings, it becomes obvious that root cause analysis, impact assessment and associated actions are still a challenge for many companies.

The U.S. based company Dercher Enterprises, Inc. manufacturers Tri-Chlor and Silver Nitrate solutions. During a 2018 inspection, FDA collected samples which were tested and showed exceeding iron assay specifications. The products were recalled, but the company "failed to conduct an adequate investigation, including determining the root cause of the failures, investigating other potentially impacted batches/lots, and implementing effective corrective actions and preventive actions (CAPA)". In the follow-up inspection 2019, the same issues were observed. It seems that the company had revised an SOP on analytical testing of "retained lots" and a "new batch" of affected solutions but "did not adequately address the underlying issue of inadequate investigations and root cause determinations".  A potential impact on other lots of drug product(s) was not assessed.
As a result, the Quality Control Unit was found to have inadequate quality oversight of the manufacturing operations in several respects including failure to follow their "Problem Analysis and Corrective Action" SOP and failure to implement effective CAPA in accordance with previous inspections.

LNK International, Inc. released four lots of Diphenhydramine 50 mg Berry Syrup although microbial specifications were not met. In this context, it was also criticised that an "adequate justification that the potential cause of the microbial contamination only affected the four lots" was not provided.

"Excessive Levels of Microbial Contamination" were found in drug products from Pharmalab Enterprises, Inc., based in Florida. Here, the company "failed to perform adequate investigations concerning high microbial counts". A root cause for the high microbial counts was not identified and evidence that investigations were extended to other related batches couldn't be provided.

Wild Child WA Pty Ltd. from Australia released finished over-the-counter (OTC) drug products to the U.S. market "without adequately testing the identity and strength of the active ingredient". This seems to be compliant to Australian GMP as the company responded, however the response also included a commitment "to revise specifications to include the quantitative titration method for content and minimum fill testing". FDA wasn't completely satisfied with this response and criticised that the "corrective actions only apply to future batches and do not include a commitment to evaluate or test retain samples for batches already distributed to the U.S. market".