Deficiencies in Equipment Design lead to Warning Letter

During the inspection of a US site belonging to a French pharmaceutical manufacturer, the FDA identified serious deficiencies, including in a process system for the manufacture of OTC drugs. The deficiencies relate to both the equipment design and its qualification. Although the FDA only refers to a system for supplying a medium used in production in its warning letter, it can be assumed from context that this very likely refers to the manufacturer's water system.

In the FDA's opinion, the system is neither structurally nor operationally capable of reliably maintaining the required chemical and microbiological quality parameters. Extensive sampling was already carried out during performance qualification (PQ), with the majority of samples failing to meet the relevant USP specifications. Despite these repeated negative results, the qualification report was approved. In the following two years, the monitoring data continued to show almost continuous deviations from the USP requirements. Nevertheless the system continued to be used in the manufacture of drugs.

The FDA is particularly critical of the equipment's inadequate design. The process system has numerous design flaws, including several so-called dead legs and stagnant locations. According to the FDA, such areas are critical because they can lead to the development of biofilm.  Furthermore, the company was already aware of the existence of these design flaws.

Microbiological testing confirmed this problem. Gram-negative bacteria, including Pseudomonas aeruginosa and Serratia marcescens, which are considered typical waterborne germs and indicate the presence of biofilms, were repeatedly detected in samples.

In its statement, the company announced that it would fundamentally overhaul the process system. Among other things, it planned to remove dead legs, install additional system components, and requalify the system. However, the FDA considers this response to be inadequate, as the company had repeatedly documented deviations over a long period of time without responding appropriately.

The manufacturer also stated that it would temporarily stop using the medium from this system for drug manufacturing and instead use externally sourced material until the system has been completely refurbished.

The FDA is requesting a comprehensive technical assessment of the system design and operational controls. This assessment should identify all design and operational weaknesses. In particular, fundamental system parameters that are critical to hygienic design and safe operation should be reviewed. These include, among other things, the temperature in the system, the materials used, the slope of the piping, identified dead legs and other stagnant locations, unsanitary fittings or connections, and the flow velocity within the system. In addition, maintenance and monitoring procedures are to be revised and the system re-qualified. Furthermore, the agency has requested a detailed risk assessment regarding the possible impact on drug batches that have already been manufactured and are currently available on the US market.

The detailed warning letter can be found on the FDA website.