Hanlim Pharm Co., Ltd. — FDA Warning Letter Findings

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’s quality unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22). Your firm failed to establish an adequate QU with the responsibilities and authority to oversee the manufacture of drug products. For example, you failed to ensure: Adherence to a stability program that supports the drug products’ expiration dating (21 CFR 211.166(a)). Contemporaneous documentation of EM and personnel monitoring sampling data in laboratory records (21 CFR 211.194(a)). In response to this letter, provide: A comprehensive assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous (ALCOA) records throughout your operation. A comprehensive assessment and remediation plan to ensure your QU is given the authority, independence, and resources to effectively function that includes, but is not limited to: o A determination of whether procedures used by your firm are robust and appropriate o Provisions for independent QU oversight throughout your operations to ensure satisfactory procedures and adherence to appropriate practices o A complete and final review of each batch and its related information before the QU disposition decision o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products o Also, describe how executive management will support robust quality assurance at your firm, including but not limited to timely provision of resources that enable proactive detection and resolution of emerging manufacturing/quality issues to assure a continuing state of control Ineffective Quality System Significant findings in this letter demonstrate that your firm does not operate an effective quality system in accord with CGMP. In addition to the lack of effective management oversight of your production and laboratory operations, we found your QU is not enabled to exercise proper authority and/or has insufficiently implemented its responsibilities. Executive management should immediately and comprehensively assess your company’s global manufacturing operations to ensure that your systems, processes, and products conform to FDA requirements. Your firm’s quality systems are inadequate. For guidance on establishing and maintaining CGMP-compliant quality systems, see FDA guidances: Q8(R2) Pharmaceutical Development at https://www.fda.gov/media/71535/download, Q9(R1) Quality Risk Management at https://www.fda.gov/media/167721/download and Q10 Pharmaceutical Quality System at https://www.fda.gov/media/71553/download. Drug Production Ceased and Suspended We acknowledge your commitment to suspend production of (b)(4) Drugs at this facility for the U.S. market and to cease production of all other (b)(4) solutions. If you plan to resume any manufacturing operations regulated under the FD&C Act, notify this office before resuming your drug manufacturing operations. If you resume CGMP activities, you are responsible for resolving all deficiencies and systemic flaws to ensure your firm is capable of ongoing CGMP compliance. In addition, based upon the nature of the violations we identified at your firm, you should engage a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. The qualified consultant should also perform a comprehensive six-system audit 1 of your entire operation for CGMP compliance and evaluate the completion and efficacy of all CAPA, before you pursue resolution of your firm’s compliance status with FDA. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance. In your notification to the Agency, provide a summary of your remediations to demonstrate that you have appropriately completed all CAPA. Repeats Violation at Facility In a previous warning letter (WL 320-19-01), FDA cited similar CGMP violations. You proposed specific remediations for these violations in your response. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate. Additional Guidance on Aseptic Processing 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.

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.…