Root Cause Analysis and CAPA: Two more Warning Letters issued to Companies in Europe

Despite the Mutual Recognition Agreement (MRA), the U.S. FDA continues to carry out inspections in the EU. Once again, two Warning Letters have been issued, containing observations on topics including CAPA and quality oversight.

The main observation in the Warning Letter to Excelvision-Fareva in France refers to 21 CFR 211.192 'Production Record Review', but primarily concerns the handling of customer complaints and a lack of root cause analysis.

According to the FDA, Excelvision-Fareva failed to adequately investigate customer complaints regarding various sterile medicinal products. Furthermore, it failed to identify and implement appropriate and timely corrective and preventive actions (CAPAs).

The company received a significant number of complaints regarding the presence of contamination. These included "mould, black specks and discolouration on the tips and inner caps of the containers". Several complaint samples subsequently failed the sterility test.

However, the causes of these critical, repeated contamination incidents were not identified. Furthermore, the company failed to adequately assess potential sources of contamination within the manufacturing process.
Instead, the company attributed most of the causes to improper handling by customers and concluded that no further action was required.

Possible root causes had already been observed and identified by the FDA during the inspection:

• Staff wearing gloves blocked the unidirectional airflow during installation work
• An employee leaned his head and upper body into the filling area
• Equipment was poorly designed
• Floors, walls and ceilings are not made of smooth, hard surfaces that are easy to clean
• Numerous instances of water ingress
• Damage to floors, ceilings and walls in classified areas
• Rust and corrosion

These are entirely plausible root causes which the company itself could have identified.

In a Warning Letter addressed to the Genzyme site in Ireland, 21 CFR 211.22 'Responsibilities of the Quality Control Unit' is cited first. The letter criticised the 'Quality Unit' for failing to fulfil its responsibilities.
For example, several particulate excursions and test failures across multiple batches were documented in equipment logs but not in the laboratory records and were therefore not investigated. Quality control personnel used uncontrolled checklists to review laboratory records, which were subsequently disposed of.

Ultimately, there was a failure to thoroughly investigate unexplained discrepancies or instances of non-compliance with specifications. During the inspection, numerous deviations were cancelled "without investigating the root cause or assessing product impact".

According to the FDA, these failures demonstrate a pattern whereby the quality unit failed to exercise proper oversight, including data integrity.