Findings citing 21 CFR 211.58

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.…

You failed to maintain buildings used in the manufacture, processing, packing or holding of drug products in a good state of repair (21 CFR 211.58). Outsourcing facilities must comply with CGMP requirements under section 501(a)(2)(B) of the FDCA. FDA’s regulations regarding CGMP requirements for the preparation of drug products have been established in 21 CFR parts 210 and 211. FDA intends to promulgate more specific CGMP regulations for outsourcing facilities. FDA has…

Your firm failed to maintain buildings used in the manufacture, processing, packing, or holding of drug products in a good state of repair (21 CFR 211.58). Your firm did not properly maintain classified areas and cleanrooms used in the manufacture of drug products. Our investigators observed peeling paint on the ceiling as well as bubbled paint and rust at the bottom of the door in ISO 7 room (b)(4) . Room (b)(4) provides access into aseptic filling line (b)(4) . These…

Your firm failed to maintain buildings used in the manufacture, processing, packing, or holding of drug products in a good state of repair (21 CFR 211.58). Bird droppings and feathers were observed during the inspection in the AHU area, specifically on the air purification units, (b)(4) ducts, a (b)(4) tank, a cleaning (b)(4) , and on the floors surrounding multiple (b)(4) inside your drug manufacturing facility. The conditions in your AHU area raise concerns about potential…

Your firm failed to maintain buildings used in the manufacture, processing, packing, or holding of drug products in a good state of repair (21 CFR 211.58). Our investigator observed a black mold-like substance at the base of the hose reel and behind the water storage tank in the (b)(4) clean out of place (b)(4) room. The black substance was within one foot of stainless-steel pails and other product-contact equipment used for OTC drug production. The base of the wall behind…

Your firm failed to maintain buildings used in the manufacture, processing, packing, or holding of drug products in a good state of repair (21 CFR 211.58). You failed to maintain your over-the-counter (OTC) drug manufacturing facility in a good state of repair. Our investigator observed paint peeling from the floor, and windows that were cracked and repaired with tape. In addition, vents and light fixtures above tablet presses were covered in white powder. It is essential…