Warning Letter for US Manufacturer: Issues in the Water System

In November 2019, a US-American pharmaceutical manufacturer received a Warning Letter from the FDA due to microbial issues in the water system, deficiencies in qualification/validation and insufficient stability data.

The pharmaceutical company uses the water for the production of OTC products, such as saline solutions for nasal administration for children. Several batches were released despite an adverse trend of objectionable microorgansism Burkholderia cepacia. Some water samples showed microorganisms that can contribute to the formation of a biofilm in water systems. Although an investigation of the microbial contamination was started, the qualification of the water system, which was ongoing at the same time, was nevertheless completed. Despite corrective measures,  the microorganisms mentioned above were still found in the pretreatment and (due to overgrowth of the agar plates) uncountable values in the total microbial count (TNTC = too numerous to count). Following the inspection, the manufacturer placed the water system in quarantine status and recalled all affected batches from the market. In addition, the manufacturer claimed to have identified weaknesses in sanitization, errors in sampling and preventive maintenance. This response was not sufficient for the FDA, which led to the issuance of the Warning Letter. Here, the FDA demands:

  • An independent evaluation of the overall system to handle deviations, complaints, OOS results, etc. and a CAPA plan to correct this system.
  • An independent assessment of the laboratory processes, including test procedures, equipment, documentation, competence of laboratory personnel, etc.
  • An independent assessment of the water system, including design, control and maintenance.
  • A comprehensive remediation plan to ensure the required status and functioning of the water system.
  • A validation report for the water system.

The pharmaceutical company also failed in the area of qualification/validation for the manufacture of OTC products. The FDA warns about the missing "Process Qualification" for all OTC products. The manufacturer had carried out process qualification, but without defining suitable acceptance criteria. Cpk values for e.g. the filling weight were also defined, but the results showed that the process was not reproducible or under control. The manufacturer then stated that validation plans should be drawn up and specific CPPs (critical process parameters) should be defined. However, the FDA would have expected detailed plans in a response and criticized this in the Warning Letter.

Deficiencies were also found concerning stability. For example, the manufacturer indicates a two-year expiry period for its products without having any substantiating data. Besides, non-compliant values were found in the test point 'content' under accelerated conditions, whereas the long-term studies were not yet completed.

The FDA recommends engaging an independent consultant to remedy the deficiencies. You can find the Warning Letter for the US-American manufacturer on FDA's website.

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