Deficient Water System: Warning Letter to US Manufacturer

The FDA inspected a US manufacturer of OTC products and found the water system to be deficient. Along with other observations, this has now led to a Warning Letter.

Serious deficiencies in the water system

During the inspection, which took place in March 2025, the FDA identified serious deficiencies in the US manufacturer's water system. According to the FDA, the water system was not designed and operated in such a way as to provide water of suitable quality for the manufacture of medicinal products. The 'objectionable' bacterium Burkholderia cepacia was repeatedly detected in both the storage tank and at sampling points. Despite regular sanitisation following the relevant findings, B. cepacia reappeared shortly afterwards; in addition, microbiological monitoring at several points in the system yielded 'too numerous to count' results, indicating the presence of biofilm. The FDA objects that the microbiological out-of-limit results were not investigated promptly and comprehensively, including a lack of root cause analysis and a lack of assessment of possible effects on the manufacturer's products.

The manufacturer had meanwhile installed a new water system which, according to information provided during the inspection, is designed as an on-demand system without continuous circulation. In its response to the Form 483 report, the company denied that there was a safety risk to consumers and referred to low levels of bacteria found in samples of manufactured batches and to the antimicrobial effect of the active ingredient for its non-sterile products. The FDA rejects this argument: antimicrobial formulations are no substitute for GMP-compliant manufacturing. Furthermore, microbial contamination is not evenly distributed, meaning that samples cannot reliably reflect the actual contamination level in a system. The FDA also sees conceptual weaknesses in the new water system that jeopardise reliability and water quality. Stagnation in non-recirculating on-demand systems promotes the formation of biofilms.

FDA requests

As a consequence, the FDA requires a comprehensive assessment of the design, control and maintenance of the water system, including the extent to which continuous circulation of water occurs in the system and the extent to which heat is used to control bacterial counts.

Furthermore, the FDA expects a risk assessment of the possible effects of the water system deficiencies on all batches currently on the market in the US, with clearly defined follow-up measures, including batch recalls. In addition, an action plan with a timetable for complete microbiological testing of retained samples of non-sterile finished medicinal products is to be submitted to assess the quality of all batches still within their shelf life. In addition, the FDA is requesting a complete overview of stability data from the last five years, a compilation of all individual microbiological results from the new water system, including physicochemical data (e.g. TOC, conductivity), and a retrospective assessment of all invalidated OOL water findings with an investigation of possible causes based on the manufacturer's documentation. In addition, the FDA requires a fundamental revision of the OOS/OOL system.

Serious deficiencies in process validation & sterile manufacture

The FDA also criticised serious deficiencies in process validation and sterile manufacturing in general. The qualification of the production equipment used was also inadequate. In addition, there were no validated procedures in place to prevent microbial contamination in products marketed as sterile. In particular, no regular dosage tests were carried out to monitor the effectiveness of the sterilisation procedures.

Further deficiencies in the quality system

The FDA found further deficiencies in quality control. For example, the FDA determined that several batches of supposedly sterile finished medicinal products had been released for the US market without being tested for sterility or other relevant quality characteristics. In addition, there was no evidence of the suitability of the test methods used by the contracted testing laboratory. It also remained unclear whether reserve samples were available for all delivered batches in order to be able to carry out subsequent sterility tests.

The FDA considers the company's quality system to be inadequate and unsuitable for ensuring control over manufacturing, testing and decision-making processes.

Please see the FDA website for the detailed Warning Letter to the US OTC manufacturer.