Four Warning Letter concerning CAPA and Root Cause Analysis published

We are seeing more and more frequently that inadequate root cause analysis and CAPA management in the event of deviations and OOS results is leading to observations during inspections. This has been a recurring theme in FDA Warning Letters, for example.

Now, four more FDA Warning Letters have been published, criticising not only inadequate quality oversight but also the root cause analysis and the CAPA measures implemented. One company in India and three in the USA were affected.

A Warning Letter to Hikal Limited (India) states, among other things, the following:

Over the years, the company had failed to adequately investigate the cause of approximately 22 complaints related to metal contamination in active ingredients. The company stated that "no exact root cause" could be identified. In addition, according to the FDA, the metal detector was not adequately qualified. In its investigation, the company referred to an industry standard for technically unavoidable particles in excipients. However, this standard is not applicable to active ingredient manufacturing at all. The investigation did not adequately assess whether the design and materials of the manufacturing equipment were suitable for API production without posing contamination risks. Furthermore, there was no adequate assessment of the cleaning procedures and in-process controls.
It is therefore not surprising that no effective CAPAs were implemented, despite numerous complaints about contamination. According to the FDA, "inadequate investigations can result in unidentified root causes, ineffective CAPAs, and recurring problems". The FDA is therefore now calling for a comprehensive action plan, including a comprehensive and independent assessment of the overall system for investigating deviations, discrepancies, complaints, out-of-specification (OOS) results and failures.

According to a Warning Letter sent to Wisconsin Pharmacal Company (USA), their quality unit (QU) did not adequately monitor the manufacture and release of drug products. For example, the QU rejected filled drug product units because they did not meet release specification. Nevertheless, the affected product units were released. According to the FDA, the QU failed to fulfil its responsibility by not withholding all affected units from distribution, but instead allowing the distribution of approximately "half of the rejected drug product".
The cause was probably that the rejected drug product was not sufficiently identified and recorded due to an improper scanning process. Corrective measures included revising the procedure and retraining employees. However, this was not sufficient for the FDA. It was not clearly explained how these corrections and corrective measures would prevent rejected drug product from being sent to customers again. The manufacturer did not address the fundamental deficiencies within the QU that led to these errors. The corrective and preventive action plan (CAPA) was therefore not comprehensive enough and the authority lacked a systematic approach to remedying these deficiencies.

Furthermore, several microbial deviations were not adequately investigated. Despite evidence of the undesirable microorganism Staphylococcus Aureus in a cream, the batch was released for commercial distribution. This decision was based on a retest without conducting a thorough investigation into the cause of the contamination. When S. Aureus was found again in another cream, drug products units from the affected vessels were rejected after a retest. Those from unaffected vessel were released. These decisions were also not based on a thorough investigation to determine the cause.
The FDA considers the manufacturer responsible for fully investigating results of microbial contamination that may affect the quality of medicinal products. Measures such as additional disinfection and cleaning measures were also not sufficient for the FDA in this case.

Somerset Therapeutics also "failed to thoroughly investigate any unexplained discrepancy or failure" according to their Warning Letter. Their "investigations lacked data supporting the assigned root cause(s), were not adequately expanded to include all potentially affected drug products, or were not formally documented in the deviation system."

Columbia Cosmetics failed to conduct adequate investigations into out-of-specification (OOS) results. They corrected n subpotency OOS with reprocessing the drug product "by adding additional API" without the review and approval of the Quality Unit (QU). FDA points out that the company "did not thoroughly investigate these unexplained discrepancies or identify failures", that the investigation started after batch release "was inadequate" and that they "failed to address the improper release of subpotent finished product" and "implement appropriate corrective action and preventive action (CAPA)".