Root Cause Investigations criticised at EU Company

The US FDA is still conducting GMP inspections in the EU despite the MRA. In October 2024 a facility in the Netherlands was inspected. Now a Warning Letter was issued summarising significant violations of Current Good Manufacturing Practice (21 CFR parts 210 and 211).
The first observation written down states that the "firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components".

What happened?

The company experienced seven out-of-limit (OOL) events for microbial content in a system used to generate a major component of drug products. Notably, at least two events showed microbial levels as high as 10,000 colony-forming units (CFU) per milliliter, far exceeding acceptable limits.

Despite the severity and frequency of these events, the company's investigations were deemed inadequate. The findings raise concerns about the company's ability to consistently produce components suitable for pharmaceutical use, with particular focus on "root cause determinations, corrective actions and preventive actions (CAPAs), and assessment of all potentially affected batches". Instead, the company limited its response to a narrow review of system test results from the day before and after each OOL event and relied on finished product test results to justify continued production-without demonstrating control over the system itself.

In the response to the observations, the company then indicated that "individual investigations with impact assessments will be created" for OOL results. Additionally, it was decided that the "quality lead will review and document results" on a defined basis. Furthermore, the company committed to train the quality team accordingly.

However, the FDA rates this response as "inadequate". The authority misses a "comprehensive retrospective risk assessment" and an evaluation of "the full scope and impact of OOL results". Also supporting documentation about the CAPAs was missing.

The FDA is now looking for an "independent assessment of the overall system for investigating deviations, discrepancies, complaints, out-of-specification results, and failures" plus a "detailed action plan to remediate this system". The action plan should also include, "significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality assurance oversight, and written procedures".

This case underscores the importance of a thorough root cause determination and CAPAs, particularly when dealing with repeated events.