Deficiencies in the Water System: Warning Letter to US Manufacturers of OTC Products

The FDA inspection of the US manufacturer of OTC products already took place in January 2025. The FDA criticized laboratory tests, missing microbiological specifications and process validation. The water system in particular also showed serious deficiencies.

The FDA describes the validation of the water system as inadequate. The validation did not relate to either chemical or microbiological parameters as required for the manufacture of oral and topical medicinal products. Furthermore, the water system had technical deficiencies that increased the risk of biofilm formation. For instance, there are dead legs in the system that can contain stagnant water. In addition, the system was not operated continuously, which may be one of the main reasons for biofilm formation. Also, the sanitization measures were not sufficiently considered in the validation and the monitoring could not prove that the required water quality parameters were met. The FDA emphasizes that regular microbiological testing, including bacterial count and identification, is mandatory to maintain the suitability of the water system.

The FDA requires a comprehensive package of measures that includes the following points:

• Redesign of the water system from a GMP perspective
• Validation of the water system
• Implementation of monitoring of chemical and microbiological parameters
• Retrospective risk assessment of all affected batches of medicinal products.

Another serious deficiency is the lack of process validation for OTC products. According to the FDA, there is a lack of control over critical process parameters. For example, mixing times, mixing speeds and temperatures were not documented or monitored. Furthermore, there are no specifications for controlling and monitoring these critical parameters, even though they have a direct impact on product quality. The qualification of the manufacturer's equipment was criticized as well. Production scales were used without qualification and without calibration, making it unclear whether dosages and compositions were correctly adhered to during the manufacture of the medicinal products.

The Warning Letter to the US manufacturer can be found on the FDA website.