Findings from sterile drug manufacturing sites emphasise the agency’s expectation for companies to provide tangible evidence showing reduced quality and microbial risk and maintenance of control.
The US Food and Drug Administration (FDA) published three enforcement letters on 14 July citing contamination control, environmental monitoring and facility maintenance failures that closely mirror requirements under EU GMP Annex 1.
The issues were found at manufacturing sites in the US and Puerto Rico, including one operated by a subsidiary of Germany’s Fresenius Kabi.
In a warning letter dated 2 July, the FDA’s Center for Drug Evaluation and Research (CDER) told International Medication Systems Limited, a South El Monte, California manufacturer of sterile injectables and active pharmaceutical ingredients, that an environmental monitoring plate beside an ISO 5 filling area had returned a “too-numerous-to-count” result with confluent bacterial growth and insect larvae. Personnel monitoring plates in an adjacent ISO 7 area returned similar results.
The company attributed the findings to insects entering sealed plates after sampling, an explanation FDA dismissed as an “unsubstantiated hypothesis.” The agency said “the presence of insect larvae and gross microbial contamination in your aseptic processing area demonstrates a critical failure of your contamination control programme,” and noted the batch was released on the basis of a passing sterility test despite the environmental monitoring results.
The FDA also found that restricted access barrier systems (RABS) at the site lacked basic design features, with operators manually cutting open stopper bags and transferring stoppers by scoop within the ISO 5 area. The company recalled epinephrine injection USP lot EA038A5 on 1 April over lack of sterility assurance.
A separate warning letter, dated 8 July, was sent to Spa De Soleil, Inc., an over-the-counter drug manufacturer based in Sun Valley, California. The FDA said the company had failed to investigate 51 out-of-limit or out-of-specification water system results recorded between May 2024 and July 2025, instead resampling and retesting until passing results were obtained. Inspectors also identified dead legs and other components capable of supporting biofilm formation.
The FDA’s Center for Biologics Evaluation and Research (CBER) issued an untitled letter, dated 7 July, to Fenwal International, a Fresenius Kabi subsidiary manufacturing blood-pack units and component solutions at a facility in Maricao, Puerto Rico. Investigators found corroded and residue-covered equipment, black material on ceiling-mounted HEPA filters and apparently biological residue and standing water around the air handling unit supplying a filling room. The FDA noted that a previous warning letter was issued to the same facility in September 2023.
these cases demonstrate that passing finished product or sterility tests cannot compensate for evidence that the manufacturing environment is out of control”
Annex 1 requires contamination control strategies to encompass premises, equipment, utilities, personnel, environmental monitoring and investigation of deviations. For European manufacturers and quality professionals, these cases demonstrate that passing finished product or sterility tests cannot compensate for evidence that the manufacturing environment is out of control.
They also underline that regulators assess the physical condition of facilities and equipment, not merely the adequacy of procedures. Recurring deficiencies across inspection cycles may be seen as evidence of a wider failure to maintain a state of control.
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