Findings citing 21 CFR 211.113

Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes. Your firm also failed to maintain buildings used in the manufacture, processing, packing, or holding of drug products in a good state of repair (21 CFR 211.113(b) and 21 CFR 211.58). Airflow Visualization (AFV) Smoke Study Deficiencies Our inspection noted deficient smoke studies. Our investigators determined you did not perform AFV smoke studies after modifying your (b)(4) Restricted Access Barrier Systems ( (b)(4) RABS) unit by removing the (b)(4) and remounting the nonviable particulate probe in suite (b)(4) of the (b)(4) filling line. Your validation department determined smoke studies were not necessary after the modification, despite your engineers proposing smoke studies be conducted. As another example, two interventions, including product spillage cleaning at the filling station and (b)(4) adjustment lacked adequate smoke to visualize unidirectional airflow. It is not clear whether airflow is adequate to protect the aseptic processing line. In your response, you state you will re-execute AFV studies, develop a standardized AFV protocol template, and revise the change control procedure. Your response is inadequate because you do not explain how you will ensure satisfactory conduct of smoke studies in the future. Thorough smoke studies are essential to evaluate the effects of such interventions on unidirectional airflow and suitability of design modifications. We also note that your Grade A suites (b)(4) are described as (b)(4) RABS. Although your firm characterizes these processing lines as (b)(4) RABS, their design and operation involve an excessive number of interventions and do not meet the minimum standards of a restricted access barrier system. The Grade A area is critical because sterile products are exposed during aseptic production and therefore are vulnerable to contamination if operations are not well designed and diligently controlled. Your aseptic processes should be designed, and operations executed, to prevent contamination hazards to your sterile product. Flaws in the design of cleanrooms and aseptic processing lines, or improper execution of operations, can promote influx of contamination into the critical processing area in which sterile drugs are exposed. Inadequate Environmental Monitoring We observed inadequate EM technique and insufficient EM locations. Our investigators observed the surface swabbing of the (b)(4) did not include the (b)(4) . Additionally, the analyst did not swab the maximum accessible area of the (b)(4) of each (b)(4) . In your response, you state the procedures will be updated and a retrospective EM review will be performed. You also performed a historical review of your EM data since 2024 which you indicate has no adverse trends. Your response is inadequate because the quality of the data was compromised by insufficient technique and locations. Environmental monitoring is only as meaningful as the quality of its sampling technique and locations. The purpose of environmental monitoring in an aseptic processing facility is to apply a risk-based approach to reliably detect routes of contamination. Facility Maintenance Deficiencies Your firm did not properly maintain classified areas used in the manufacture of drug products. Our inspection noted peeling paint on the walls and plastic debris on the floors within your Grade C hallway and product transfer room (b)(4) in Suite (b)(4) . In your response, you commit to implement post-cleaning visual inspection, require cleaning verification in the cleaning logs, and repair the facility. Your response is inadequate because your product impact evaluation states “…types of debris observed (e.g., paint, plastic) are non-viable particulates...” However, you do not explain the basis for the assertion that paint debris could not harbor microorganisms. In addition, your response does not adequately evaluate the cause of the paint bubbling and peeling from the walls and whether this has contributed to mold identified throughout all your classified areas. Deteriorating surfaces such as peeling paint are potential sources of particulate and microbial contamination. It is critical that the building is maintained to prevent exposure of sterile articles to potential contamination hazards in the manufacturing operation. In response to this letter, provide: Your systematic plan to assure adherence to appropriate aseptic practices, cleanroom behavior, and written procedures, including but not limited to an independent assessment of the following with accompanying CAPA: o suitability of actual practices based on extensive retrospective review and prospective observation of aseptic processing operations o deficiencies in production management oversight, and identification of specific improvements to ensure effective and routine supervisory oversight for all batches o frequency and depth of quality unit oversight (e.g., audit, ad hoc, daily interactions) of aseptic processing and its support operations o adequacy of written procedures o evaluate how poor aseptic technique and cleanroom behavior may have affected the quality and sterility of your drugs A thorough, independent evaluation of airflow unidirectionality in your aseptic process. Ensure smoke studies are conducted under dynamic conditions, with thorough and complete evaluations of aseptic processing line airflow unidirectionality, including the impact of dynamic interactions and aseptic interventions. These thorough smoke studies should be performed after you remediate your aseptic operation and be conducted using proper practices (e.g., neutrally buoyant media) to appropriately visualize airflow. Your CAPA plan to implement routine, vigilant operations management oversight of facilities and equipment.…

Failure to establish and follow appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile, including procedures for validation of all aseptic and sterilization processes, as required by 21 CFR 211.113(b). For example, your firm has not validated the aseptic processes used to manufacture your umbilical cord derived products. Your umbilical cord derived products purport to be sterile and are expected to be sterile.

Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)). Media Fills Your firm continued to manufacture and release sterile drug products manufactured by aseptic processing following media fill failures on June 21, 2024, September 4, 2024, and November 4, 2024 as well as inconclusive media fill results and other significant quality events. Your firm lacked timely and adequate media fill investigations. For instance, your root causes were unsupported and lacked effective corrective actions. Following the inspection, you committed to recalling (b)(4) batches of drug products made from (b)(4) which reflects the timeframe between the failing media fills. In addition, you commit to improving your quality unit (QU) escalation procedures to ensure proper awareness and to engaging an outside consultant to provide oversight of your QU for six months. Your response is inadequate. You did not provide a retrospective review of all media fills to ensure additional deviations, atypical events, and unexpected results during commercial manufacturing were adequately represented in your media fill programs. Poor Practices in the Aseptic Processing Areas We observed poor practices and behaviors in ISO 5 areas during commercial operations and media fills. These poor practices, included but are not limited to: Operators inserting their upper torso into the (b)(4) restricted access barrier system ( (b)(4) RABS) during interventions, breaching the ISO 5 barrier. An operator performing a (b)(4) RABS intervention directly with the (b)(4) RABS (b)(4) instead of using forceps. Shorter operators opening the (b)(4) RABS (b)(4) and bypassing the (b)(4) during difficult-to-reach interventions, while taller operators used the (b)(4) RABS (b)(4) . In your response, you commit to retraining the operators on appropriate aseptic behaviors. Also, you commit to revising procedures and engaging outside consultants to review practices. Your response is inadequate. You do not address how you plan to ensure operators follow appropriate procedures in the future, including supervisory and quality assurance oversight. Additionally, these poor aseptic practices were not investigated to determine the impact to sterile drug products manufactured under these conditions and distributed to the U.S. market. Your response also fails to reevaluate your aseptic processing design. Specifically, you do not identify and evaluate hazards posed by various manual activities (e.g., planned interventions, unplanned interventions, (b)(4) ) or address the risks that insufficient design poses. Airflow Visualization Studies (AVS) and Process Design Our inspection identified aseptic processing design deficiencies which pose significant hazards to drug product sterility, as well as multiple inadequacies in your airflow visualization studies (i.e., smoke studies). For example, unidirectional airflow could not be evaluated in certain AVS. There were interventions performed in which the camera is placed behind the operator and the impact of the intervention on the airflow cannot be visualized. Our inspection also noted other AVS deficiencies. For example, the smoke source was not always positioned at the HEPA filter face to confirm unidirectional airflow and uniform velocity. We previously discussed inadequate smoke studies in our August 3, 2023, Warning Letter issued to your firm. In addition, the worst-case locations for environmental monitoring of the ISO 5 filling room and (b)(4) RABS have not been defined through adequate risk assessment. In your response, you commit to suspending filling operations until remediation activities, including improvements to AVS, are completed. You also acknowledge appropriate smoke studies are required to demonstrate unidirectional airflow patterns and proper aseptic techniques and behaviors are critical elements of sterility assurance. You commit to improve your smoke study protocol with the assistance of external consultants and to re-execute smoke studies in ISO 5, 7, and 8 areas prior to resuming operations. Your response is inadequate. You did not address how drug products made with inadequate aseptic processing design and distributed to the U.S. market will be evaluated to ensure their sterility assurance. Your response also fails to consider line design changes that would minimize the need for frequent operator interaction with the aseptic processing line. See FDA’s guidance document Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice to help you meet the CGMP requirements when manufacturing sterile drugs using aseptic processing at https://www.fda.gov/media/71026/download. In response to this letter: Provide your action plan to address any product quality or patient safety risks for your drug products in U.S. distribution, including potential customer notifications and recalls. Review prior “passing” aseptic process simulations (media fills) for previously missed deviations, unusual activities, and unexpected results. Explain actions taken to evaluate and address the acceptability of (b)(4) drugs produced using your aseptic filling process that were distributed to the U.S. market. Perform a critical evaluation of airflow unidirectionality in your aseptic process, with the assistance of a qualified consultant. Ensure smoke studies are conducted under dynamic conditions, with thorough and complete evaluations of aseptic processing line airflow unidirectionality, including the impact of dynamic interactions and aseptic interventions. These thorough smoke studies should be performed after you remediate your aseptic operation and be conducted using proper practices (e.g., (b)(4) ) to appropriately visualize airflow.…

Your firm failed to perform operations within specifically defined areas of adequate size and to have separate or defined areas or such other control systems necessary to prevent contamination or mix-ups in aseptic processing areas. Your firm also failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile and that include validation of all aseptic and sterilization…

Your firm failed to follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)). Smoke studies demonstrated a lack of unidirectional airflow in your ISO 5 aseptic processing operation. Multiple instances of turbulent airflow in critical areas of ampoule filling line (b)(4) were noted, including during the…

Your firm failed to follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)). The airflow visualization studies (i.e., smoke studies) you performed for the (b)(4) aseptic vial filling line you use to fill sterile powder drug products for the U.S. market did not demonstrate unidirectional airflow. This…