Deficient Water System: Warning Letter from the FDA

During an inspection in spring 2025, the FDA identified serious violations of GMP requirements at a US manufacturing facility for topical OTC medicines. The FDA deemed the response letter submitted to be insufficient, as it did not provide any reliable evidence or specific corrective measures.

A key point of criticism was the lack of validation of the water system. The company uses this water to manufacture skin protection products and other products that are applied to sensitive or damaged skin. According to the FDA, the system, which operates at ambient temperature, was neither validated nor regularly sanitised or microbiologically monitored. This meant that there was no evidence that the system delivered water of the required microbiological and chemical quality. The response letter of the manufacturer also did not include an assessment of the possible effects on batches already delivered and the associated risk to patients. The announcement that an external laboratory would be commissioned to carry out conductivity and TOC tests in future was also deemed insufficient, as neither microbiological tests nor a timetable for their implementation were specified.

In addition, the FDA criticised the inadequate handling of several microbiological out-of-limit results in the water system. Between May 2024 and April 2025, 'objectionable microorganisms' were detected at several sampling points, including Enterobacter cloacae (typical faecal contamination), Burkholderia cepacia and various Pseudomonas species. The investigations carried out did not result in any effective measures that could have prevented microbial contamination from entering the manufacturing process. Instead, the decision to release the affected end products was based on a mixing/temperature step that was supposed to be above the temperatures that Gram-negative bacteria can tolerate. In its written response, the manufacturer also maintained this step as a key measure without addressing fundamental deficiencies in the design, control and maintenance of the water system as a possible cause of the microbiological findings. In the FDA's view, this approach is insufficient as a CAPA.

In addition, the FDA criticised the lack of process validation for the manufacture of topical products. Critical parameters such as mixing times, speeds, temperatures and batch sizes were not specified or documented, which led to significant variations within individual batches. An underdosed lotion was released after re-testing without evaluation of the original non-compliant result. An overdosed lotion that repeatedly failed in-process and final product release tests was released after reprocessing attempts, including the addition of additional components. Here, too, it remained unclear what measures should be taken until complete process validation and how products that had already been released should be evaluated with regard to a possible risk to patients.

The FDA is calling for a comprehensive, independent assessment of the water system, including its design, monitoring and maintenance, as well as complete sanitisation and validation in accordance with USP guidelines. In addition, the manufacturer is to conduct a risk analysis of the possible effects on batches already on the market and, if necessary, initiate recalls or customer information campaigns. The authority also requires a robust validation programme and a defined timetable for implementation.

Please see the FDA website for the detailed Warning Letter.