Patients had adverse events after receiving a Fresenius Kabi medicine that experienced manufacturing deviations.
The FDA has accused Fresenius Kabi of failing to sufficiently investigate a critical manufacturing deviation linked to reports of adverse events.
FDA inspectors spent three weeks at Fresenius Kabi’s manufacturing facility in Melrose Park, Illinois, earlier this year. The investigators found fault with Fresenius Kabi’s response to reports of adverse events in patients injected with famotidine, an H2 blocker used to treat heartburn and stomach ulcers, the FDA explained in a warning letter published Tuesday.
The reports included apparent pyrogenic reactions, a medical term for fever. Pyrogen contamination to injectable drug products can lead to significant adverse events such as fever, hypotension, inflammatory reactions, anaphylactic shock or death, the FDA told Fresenius Kabi.
The company’s famotidine injection manufacturing surpassed multiple bioburden action limits, the FDA said. The agency found Fresenius Kabi “failed to sufficiently investigate this critical deviation and permitted batch release following passing finished drug product test results.” Subsequent testing in response to the adverse events revealed an endotoxin failure and triggered a recall of three famotidine batches.
No patient safety concerns have been identified, a Fresenius Kabi spokesperson told BioSpace via email. The spokesperson said the facility “remains operational, and at this time we do not anticipate significant disruptions to the supply of products currently on the market,” adding that the company “is taking the necessary actions to address [the FDA’s observations] thoroughly and responsibly.”
The FDA deemed Fresenius Kabi’s initial response inadequate. Replying in March to the FDA’s Form 483, the company acknowledged that bioburden samples showed Gram-negative confluent growth, indicating that a lawn of bacteria covered the surface of the test medium. Fresenius Kabi did not consider the excessive bioburden, meaning the number of bacteria, an elevated endotoxin risk, the FDA said. Endotoxins are parts of bacteria that can activate the immune system, causing adverse events.
While Fresenius Kabi vowed to enhance endotoxin sampling and testing, the FDA called out the company for failing to commit to a comprehensive review of its complaint system to increase vigilance. The FDA wants Fresenius Kabi to maintain ongoing, robust upstream control, adding that “any batch testing that reveals atypical bioburden levels is a signal that necessitates prompt attention.”
The FDA also criticized Fresenius Kabi’s handling of media fill failures and the discovery of hair in drug products. Fresenius Kabi determined that operators’ deficient aseptic techniques could have contributed to media fill failures. The company’s investigations “did not consider how the poor aseptic practices went undetected by your firm’s aseptic observer program during commercial operations,” the FDA said.
Starting in May 2022, Fresenius Kabi documented at least nine cases of extrinsic contamination during its visible particulate inspection. The FDA named hair as an example of an extrinsic contaminant.
“This contamination was described as free-floating and in direct contact with the drug product,” the FDA said. “Drug products contaminated with hair can have microbial contamination and are generally considered adulterated. You did not initiate timely investigations in response to this contamination.”
The FDA, which sent the warning letter on Sept. 22, gave Fresenius Kabi 15 business days to respond. Remediations are underway at the site, the spokesperson said.
