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 (21 CFR 211.113(b)).

Failure to establish procedures designed to prevent micro-contamination in products purporting to be sterile (21 CFR 211.113(b). Several of your (b)(4) (e.g., (b)(4) ) are labeled as “sterile.” We note that your OTC products including (b)(4) are not sterilized. In your response to our Form FDA 483, you stated, “Our (b)(4) are manufactured under a controlled process designed to meet the microbial limits specified in the Certificate of Analysis (C of A).” Of note, your COA does not indicate your drugs are sterile, even though your labelling purports them to be so. Sterile (b)(4) may be used by (b)(4) , if labeled as sterile, must have controls in place to ensure sterility. The inspection documented that you do not perform sterility testing of the drug products at the time of release. Your Specification and Analysis Method on (b)(4) tests the Finished Product Quality Standards to the Chinese standard (b)(4) , with acceptance criteria of ≤ (b)(4) colony forming units (cfu)/gram of total aerobic bacteria, ≤ (b)(4) cfu/gram of mold and yeast, and no fecal coliforms. Your microbial count laboratory worksheet data for (b)(4) batch number (b)(4) , released (b)(4) , reported the presence of (b)(4) cfu/gram of total aerobic bacteria. This specification is unacceptable for drug products labeled sterile. Drugs purported to be sterile must comply with applicable 21 CFR 211 CGMP requirements including sterility assurance. In response to this letter, provide your action plan to address any product quality or patient safety risks for batches of your OTC drug products that are labeled as “sterile” and are in U.S. distribution, including potential customer notifications and recalls or market withdrawals.

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)). Poor Aseptic Practices and Cleanroom Behavior You manufacture sterile, (b)(4) drug products (including (b)(4) ). We observed poor aseptic practices during set-up and filling operations including, but not limited to: Operators repeatedly broke first air by reaching their arms, torsos, and heads over open sterile tubes, (b)(4) , and open (b)(4) during (b)(4) interventions. Operators used (b)(4) directly over open bottles, (b)(4) , and caps. An operator was observed working in the Grade A area of the (b)(4) line wearing a visibly stained gown. Inadequate Smoke Studies Dynamic airflow visualization (smoke) studies demonstrated that airflow patterns failed to adequately protect the aseptic processing line, including exposed sterile product and product contact equipment, from significant contamination hazards. For example, your dynamic smoke studies did not demonstrate unidirectional airflow protection of the production line when barrier (b)(4) were open. The studies showed air moving at a sharp angle upward toward return vents, leaving critical areas of your aseptic processing lines unprotected throughout the period in which the (b)(4) are opened. This fundamental design flaw enables the entrainment of lower-quality air from the surrounding lower-classified (Class 10,000/ISO 7) cleanroom into the Class 100 (ISO 5) aseptic processing line, posing a severe risk to product sterility. We also observed other design flaws in your production equipment that led to poor ergonomics and deficient aseptic practices that compromised unidirectional airflow. In addition, smoke studies were incomplete, as they failed to sufficiently evaluate airflow directionality during critical aseptic processing activities. In your response, you state you will assess and redesign your (b)(4) filling line (b)(4) to address deficiencies noted by FDA, and you will perform smoke studies on the newly redesigned line. Additionally, you state you will conduct extensive classroom and hands-on training, along with qualification to improve aseptic operator behavior. We acknowledge your commitment to redesigning the (b)(4) solution line, and your decision to decommission your (b)(4) solution lines. Your response is inadequate. It lacks a comprehensive program to effectively monitor personnel practices during commercial production, which is especially concerning given our past inspectional findings of poor aseptic behavior. Further, your response failed to provide sufficient plans to improve your airflow visualization program. Notably, your response lacked adequate provisions to improve quality assurance oversight, and ensure thorough and objective evaluation of future airflow unidirectionality studies by qualified subject matter experts. Your aseptic manufacturing 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 aseptic operations can promote influx of contamination into the critical processing area. 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 corrective action and preventive action (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 (QU) oversight (e.g., audit, ad hoc, daily interactions) of aseptic processing and its support operations. o Adequacy of written procedures and operational ergonomics. o The assessment should also evaluate how poor aseptic technique and cleanroom behavior may have affected the quality and sterility of your drugs. An independent, comprehensive evaluation of airflow unidirectionality in your aseptic processing operations. Ensure smoke studies are conducted under dynamic conditions with thorough and complete evaluations of aseptic processing line airflow unidirectionality, including the impact of aseptic interventions and dynamic interactions with the surrounding cleanroom. Conduct these smoke studies after you remediate your aseptic operation and using proper practices (e.g., neutrally buoyant media) to appropriately visualize airflow.

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)].

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)).

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 process used to manufacture your product. Your product purports to be sterile and is expected to be sterile.