Findings citing 21 CFR 211.42

Your firm failed to establish an adequate air supply filtered through high-efficiency particulate air filters under positive pressure in the aseptic processing areas (21 CFR 211.42(c)(10)(iii)).

Your firm failed to have separate or defined areas or such other control systems necessary to prevent contamination or mix-ups (21 CFR 211.42(c)), and your firm failed to establish and follow adequate control procedures to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product (21 CFR 211.110(a)). Inadequate Equipment Cleaning and Sterilization Your aseptic processing operation is inadequately designed to prevent contamination of your sterile (b)(4) drug products. For example, you did not appropriately sterilize critical container-closure contact surfaces, such as the (b)(4) , bowl, track and (b)(4) equipment, as well as the (b)(4) , bowl, track, and (b)(4) equipment. Instead, you wipe these surfaces with sporicidal disinfectants. To ensure sterility, it is imperative that only sterilized equipment comes into direct contact with the sterile formulation, containers, and closures. Inadequate Environmental Monitoring You also failed to ensure adequate environmental monitoring (EM) of classified areas used for aseptic production of sterile (b)(4) drug products. The EM program used to monitor critical areas was deficient. You failed to demonstrate that the locations and frequencies established for viable air sampling, surface monitoring, and non-viable particulate sampling were adequately justified and sufficient to promptly detect contamination risks. For example, sampling was not adequate to evaluate the environment in proximity to containers and closures, nor on the surfaces of barriers facing your ISO 5 (Grade A) spaces. Because you had not established a sufficient EM program, you lacked evidence of daily environmental control that is foundational to assuring sterility of aseptically processed products. A vigilant, ongoing personnel and environmental monitoring program is essential to detect and respond to potential product contamination hazards in your manufacturing environment in a timely manner. Loss of environmental control in an aseptic manufacturing facility can ultimately pose a serious hazard to patients. Inadequate Visual Inspection Program Your visual inspection program for sterile (b)(4) drug products was deficient. Your firm failed to routinely categorize defects as part of your visual inspection program. In addition, you did not establish appropriate acceptance criteria. Notably, your process has experienced significant defect rates. It is important that visible particulate contamination is appropriately evaluated. When categorizing visible particles, extrinsic or foreign matter should receive special attention, as it may indicate possible insanitary or microbial contamination. Sterile manufacturing operations should be designed to prevent foreign contaminants, and such contamination should trigger a thorough investigation and appropriate CAPA. In your response, you state you will assess your (b)(4) filling line and improve its design. You state you will also revise cleaning and disinfection procedures, and conduct an EM risk assessment and subsequent EM performance qualification. Additionally, your response commits to improvements in visual inspection equipment, with better categorization of rejects and established acceptance criteria. Your response is inadequate. It fails to systematically address the need for robust aseptic processing operations and collection of more meaningful data to support aseptic operational control. It also lacks details describing how you will ensure use of sterilizable equipment in the future and conduct EM with sufficient frequency at locations where significant activity or exposure occurs during aseptic production. Additionally, you failed to provide the details of your improved visual inspection program, including how you will ensure thorough investigations, when appropriate. In response to this letter, provide: A comprehensive, independent risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities, including but not limited to: o All human interactions within the ISO 5 area (e.g., risk reduction or elimination of (b)(4) interventions wherever possible) o Equipment suitability (e.g., reliability, capability, ergonomics, placement) and sufficient cleanroom space o Air quality in the ISO 5 area and surrounding room including, but not limited to, air volume and flow o Facility layout o Personnel Flow and Material Flow (movement throughout all rooms used to conduct and support sterile operations, and all material transfers) o Disinfection practices and procedures o Specific CAPA recommendations that will comprehensively address the design and control hazards identified in the risk assessment A detailed remediation plan with timelines to address the findings of the contamination hazards risk assessment. Describe specific tangible improvements to be made to aseptic processing operation design and control at your facility and explain how this CAPA plan will robustly remediate your deficient sterile manufacturing operations. Include comprehensive changes to the design of (b)(4) your aseptic processing lines and cleanrooms. Also, describe your plans for qualification and validation of your extensively remediated operations. A CAPA plan, based on the retrospective assessment of your cleaning and disinfection program, that includes appropriate remediations to your cleaning and disinfection processes and practices, and timelines for completion.…

Your firm failed to establish an adequate system for maintaining equipment used to control the aseptic conditions (21 CFR 211.42(c)(10)(vi)).

Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).

Aseptic processing areas are deficient regarding the system for environmental monitoring to prevent contamination, as required by 21 CFR 211.42(c)(10)(iv). For example, your firm has not established an adequate program for environmental and personnel monitoring in the aseptic processing area where your product is manufactured. At the time of the inspection, environmental and personnel monitoring was not performed in association with each production shift.

Aseptic processing areas are deficient regarding the system for cleaning and disinfecting the room and equipment to produce aseptic conditions, as required by 21 CFR 211.42(c)(10)(v). For example, your firm has not validated the cleaning and disinfection processes for your ISO (b)(4) cleanroom or ISO (b)(4) where your product is manufactured.