The US Food and Drug Administration (FDA) has issued a Warning Letter (dated December 18, 2017) for cGMP violations for finished pharmaceuticals to Fresenius Kabi, a Lake Zurich, Illinois-headquartered specialty and generic pharmaceuticals company and a subsidiary of Fresenius KGaA, a Bad Homburg, Germany-headquartered healthcare group, for its drug- manufacturing facility in Kishanpura Village, Baddi, Gurumajra, Himachal Pradesh, India. The Warning Letter was issued in response to an FDA inspection from April 6 to 14, 2017.

The agency cited the firm for failing to adequately investigate a sterility failure citing that the company did not sufficiently address certain factors relating to the failure and did not thoroughly investigate potential manufacturing root causes. The agency said that the company’s environmental data was insufficient as it only addressed near-term data trends and relied too heavily on cumulative contamination rates in assessing the potential routes of contamination in its manufacturing operation.

In response, the FDA said the firm must provide an assessment of its overall system for investigations of deviations, atypical events, complaints, out-of-specification results, and batch failures. The FDA advised the company that its future sterility failure investigations include: a more thorough review of long-term trends; sufficient investigation of potential vulnerabilities in its manufacturing operations; potential correlations with past incidents (e.g., extensive history of attributing sterility positives to poor material disinfection; gram negatives detected in the ISO 5 or other clean areas). The FDA said the company’s corrective action and preventive action (CAPA) plan should include, but not be limited to, improved rigor in reviewing the sources of variation in its operation that may cause deviations, failures, or defects. The agency requested a formal assessment of microbiological contamination risks in the company’s current process, equipment, and facility, and a CAPA plan to address identified hazards.

The agency also noted a similar cGMP observation from an inspection in 2015 in which the company invalidated sterility test failures without adequately investigating the root causes and failed to take timely and appropriate corrective actions. The agency noted that remediation plans discussed with the agency in 2016, but said that its current inspection found that the facility’s oversight and control over the manufacture of drugs remains deficient. The agency noted further inadequate investigations into out-of-specification results resulted in a Warning Letter issued December 4, 2017.

In the December 18 Warning Letter, the FDA noted that executive management remains responsible for fully resolving all deficiencies, and ensuring ongoing cGMP compliance. The agency recommended to the company to engage a consultant qualified to comprehensively assess risks in the company’s manufacturing operations, retrospectively review all sterility failure investigations since 2014, retrospectively evaluate chemistry out-of-specification investigations to determine their adequacy, and assist with improvements to the firm’s investigation systems.

Source: FDA