GMP Deficiencies at French Sterile Manufacturer

In November 2024, the US FDA inspected a French sterile manufacturer of prescription and OTC drugs. The inspectors found significant GMP violations. The inspectors cited deficiencies in the handling of complaints, the microbiological control of aseptic processes and the cleaning and maintenance of production equipment.

Insufficient handling of customer complaints and microbiological deviations

Between January 2023 and November 2024, the manufacturer received numerous complaints about mould, black particles and discolouration on containers or in the product. According to the FDA, the investigations remained superficial, were not extended to other batches and did not lead to robust root cause analyses or effective corrective actions (CAPAs). Retained samples of the affected batches were also not analysed. Instead, the causes were attributed to alleged improper use by customers without any supporting evidence.

During the same period, several types of mould such as Penicillium citrinum, Fusarium oxysporum and Aspergillus were detected during environmental monitoring in various cleanroom areas. A production employee also tested positive for Penicillium citrinum during microbiological testing. Water damage was detected under a tank floor in a production room. Mould had already occurred several times in the aseptic production area in 2022 and 2023. However, these findings were not included in the current investigations.

The manufacturer had revised its SOP for handling complaints in response to these defects. A new "questionnaire" was introduced, which is to be completed by customers in the event of microbial complaints. In addition, the processing of retained samples was optimised and a genetic identification of the moulds and a comparison with the retained samples was initiated.

The FDA considers the manufacturer's response to be inadequate. A comprehensive investigation into the causes of microbiological deviations and complaints as well as an extension to other batches was not carried out. Furthermore, the CAPAs were not effective in permanently eliminating mould from the manufacturing area.

Inadequate aseptic operation and airflow

According to the FDA, the smoke studies in the ISO 5 area of the aseptic filling line did not show a unidirectional air flow. Some of the air flowed sideways or upwards towards the vent opening in the ceiling and therefore did not ensure product protection. The FDA inspectors also observed improper behaviour by employees, such as blocking the "first air" and working with non-disinfected forearms near open containers.

The FDA requires new smoke studies to be conducted "in operation" and a comprehensive risk analysis of all contamination risks in aseptic manufacturing. The FDA considers the manufacturer's submitted response to be inadequate, as neither measures to improve airflow nor sustainable control of aseptic working were clearly described.

Deficiencies in the cleaning and maintenance of aseptic systems

The ISO 5 filling line is cleaned with disinfectants without central components being sterilised prior to assembly. The assessment of the cleaning is based solely on swab samples. In addition, scratches and cracks were documented on the line that had already been identified during previous inspections but were only dealt with after the current inspection.

The FDA criticised the fact that no risk analysis was carried out to assess possible effects on product sterility. The preventive maintenance programme was also not suitable for rectifying documented defects in a timely manner.

Consequences

According to the FDA, the manufacturer has stopped production on its aseptic line. It is currently not known if and when production will be resumed. The FDA requires the complete elimination of all deficiencies and may conduct a re-inspection to verify the implementation of corrective actions. Products from this site are currently subject to an import ban into the USA.

The detailed Warning Letter to the French sterile manufacturer can be found on the FDA website.