USFDA Issues Warning Letter to Zydus: Flags Cross Contamination Risks, Poor Aseptic Techniques

Following the USFDA 483 issued in April 2024 and the OAI classification in July 2024, Zydus’ Jarod facility (FEI 3013712903) was issued a Warning Letter by the USFDA in August 2024. The facility was inspected in April 2024 by FDA investigators Justin A. Boyd and Anastasia M. Shield, who observed significant deviations, including failure to investigate and address cross-contamination risks adequately, inadequate procedures and practices for aseptic processes, and process validations failing to assess variability in the manufacturing process. Following the inspection, Zydus also recalled multiple products due to cross-contamination and glass particle contamination risks.

Cross Contamination risks – Contaminants cannot be uniformly distributed; Testing alone is not sufficient:

The Warning Letter highlights multiple lapses in handling cross-contamination risks, including the failure to assess the impact on all affected batches and equipment, and the failure to assess the adequacy of cleaning methods for all product contact surfaces. Despite a continued trend of cross-contamination, Zydus continued to manufacture and release drug product batches with “not detected” results without any rationale for how contaminants were detected across the entire batch. The firm also failed to investigate and determine the root cause of glass particulate contamination in Cyanocobalamin Injection batches and released batches after successive visual inspections, even though there was a risk of glass particles being present. Moreover, operators were not adequately qualified to detect glass particulates as small as 150 micrometers. In response, Zydus committed to monitor batches produced on shared equipment throughout their shelf life and noted that there had been no customer complaints of glass particulates. They also planned monthly inspections of control samples. However, the FDA found this response inadequate, stating that contaminants are generally not uniformly distributed, and testing alone is insufficient to address cross-contamination risks. The FDA also emphasized that the lack of customer complaints was not enough to conclude that glass particulate contamination was not an issue or that appropriate process controls were in place. As a corrective action, the FDA asked Zydus provide a comprehensive, independent assessment of their systems for investigating deviations, discrepancies, complaints, out-of-specification (OOS) results, and failures, along with an action plan to remediate these systems.

Deficient Aseptic Practices – Risk to sterility of products:

Airflow simulation studies failed to demonstrate unidirectional airflow within the Restricted Access Barrier System (RABS) ISO-5 areas during operator interventions. Operators disrupted first-air in ISO-5 areas during setup, filling, and interventions, touching stoppers and other sterile components. Smoke studies also failed to confirm that HEPA-filtered air was reaching critical areas. Additionally, the design of the stopper conveyor track potentially blocked first-air for stoppers moving along the track. In their response, Zydus attributed the lack of visible smoke to the location and limited number of smoke sticks used during testing, claimed operators followed procedures during new smoke studies, and pointed out that there had been no sterility failures over the past two years. However, the FDA observed that Zydus’ response failed to address the poor aseptic techniques observed during the inspection and did not ensure adequate review and approval of qualification and validation studies where deficiencies may exist. Moreover, Zydus did not commit to a comprehensive review of similar qualification and validation studies.The FDA directed Zydus to conduct a comprehensive risk assessment of all contamination hazards associated with aseptic processes, equipment, facilities, human interventions, material flows, personnel flows, and air quality in ISO-5 areas and surrounding rooms. The firm was also asked to provide a detailed remediation plan, including tangible improvements to the design and control of aseptic operations, ensure proper aseptic practices, and enhance supervisory and Quality Unit (QU) oversight. Additionally, Zydus was instructed to retrospectively assess how poor aseptic techniques might have affected the quality and sterility of their drug products.

Process Performance Qualification – Should characterise intra batch variation:

Process performance qualification (PPQ) was also found to lack sufficient data, and sampling plans were inadequate to evaluate intra- and inter-batch variability, with only singular results reported for critical quality attributes. The firm failed to assess whether stoppering of vials prevented unintended air ingress. Zydus responded that adequate sampling had been performed and that the products were in a state of control, with intra- and inter-batch variability below defined limits. The firm also committed to including acceptance criteria for intra- and inter-batch evaluations, conducting retrospective reviews and additional PPQ studies, and performing 100% leak tests for sterile injectable drug products. However, the FDA deemed Zydus’ response inadequate, as the evaluation of variability was based on previously submitted analytical results with composite samples rather than enhanced sampling. The FDA stressed that each stage of the manufacturing process must be designed to ensure product quality, with process validation studies that include intensive monitoring and testing at each significant process stage to characterize intra-batch variation. The FDA directed Zydus to assess the manufacturing process for each drug product and provide a data-driven, scientifically sound program to identify and control sources of variability, including the suitability of equipment, the sufficiency of testing systems, the quality of input materials, and the reliability of each processing step.

Related readings:

• USFDA Warning letter to Zydus (August 2024)
• Qvents post: Zydus Jarod Facility Classified OAI