2023.11.21 FDA公布了其关于 cipla其下一家无菌工场的教化信（2023.02.06-2023.02.17检讨）村上里沙qvod。
相比特地念念的是，这家公司的无菌模拟罐装，发现项1（483原文及翻译拖到最底下）时界说为革兰氏阳性菌浑浊，到最终483回应说明为，或者说又发现了？革兰氏阴性菌。
具体大家我方看吧……
图片
图片
2. 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)).2. 您的公司未能引诱并衔命符合的书面门径，以堤防宣称无菌的药品受到微生物浑浊，并包括对通盘无菌和灭菌工艺的考证（21 CFR 211.113（b））。
Media Fill Contamination Incidents培养基罐装浑浊事件
You failed to appropriately evaluate a pattern of media fill failures in your facility and afford sufficient attention to potential correlations among these contamination events. Between February 2021 and March 2022， there were multiple aborted and contaminated media fills on(b)(4) filling lines (b)(4) and (b)(4) (solution and suspension lines). For example，您未能符合评估设施中培养基罐装失败的阵势，也未能充分关心这些浑浊事件之间的潜在计议性。在 2021 年 2 月至 2022 年 3 月时间，（b）（4）灌装线（b）（4）和（b）（4）（溶液和混悬剂管线）上存在多个中止和受浑浊的培养基罐装物。举例
In September 2021， you isolated a gram-negative microbe， Ralstonia picketii， from multiple media fill (b)(4) of Batch # (b)(4) manufactured on the (b)(4) suspension line. You identified multiple deviations such as damaged filter housing， choked (b)(4)， dislocation of the filter， and ineffective (b)(4) processes. 2021 年 9 月，您从（b）（4）吊挂线上出产的批次 # （b）（4）的多个培养基罐装物（b）（4）均分散出一种革兰氏阴性微生物 Ralstonia picketii。您发现了多个偏差，举例过滤器外壳损坏、窒息（b）（4）、过滤器错位和无效（b）（4）工艺。
In November 2021， you isolated Pseudomonas stutzeri from one (b)(4) of media fill Batch # (b)(4) manufactured on the (b)(4) suspension line. This media fill (Batch # (b)(4)) was performed as part of the initial qualification of the suspension line and as a corrective action for a previously failed media fill on the same line (Batch #(b)(4)). You identified Pseudomonas stutzeri to be a gram-negative opportunistic pathogen. Your investigation， reviewed during the inspection and further described in your response， indicated this contamination was due to a puncture in the body of the (b)(4) by a (b)(4) during handling or movement of the filled samples， storage， or visual inspection， prior to incubation. However， you lacked adequate evidence that described mishandling of (b)(4). Further， your investigation also does not include comprehensive steps to prevent future mishandling of incubated units， and indicates use of (b)(4) will still be permitted. Your QU approved the investigation and the media fill run for Batch # (b)(4)， and you used this media fill as one of three successful runs required to qualify filling line (b)(4) for suspension products. 2021 年 11 月，您从（b）（4）吊挂线上出产的（b）（4）培养基罐装批次 # （b）（4）均分散出 Pseudomonas stutzeri。该培养基罐装（批次 # （b）（4））是手脚吊挂线初次考证的一部分实践的，亦然对归拢世产线上先前失败的培养基罐装的改革措施（批次 #（b）（4））。您细目 Pseudomonas stutzeri 是一种革兰氏阴性菌。您的拜谒在检讨时间进行了审查，并在您的回应中进行了进一步描摹，标明这种浑浊是由于（b）（4）在处理或迁移罐装的样品、储存或目视检讨时间被（b）（4）刺穿，在孵育之前。关联词，您短少敷裕的凭据来描摹对（b）（4）的不当处理。此外，您的拜谒也莫得包括堤防异日对孵化单元处理不当的轮廓门径，并标明仍允许使用（b）（4）。您的 QU 批准了批次 # （b）（4）的拜谒和培养基罐装运行，何况您将此培养基罐装用作说明混悬剂居品灌装线（b）（4）所需的三次告捷运行之一。
In March 2022， you isolated Stenotrophomonas maltophilia in multiple media fill (b)(4) of Batch # (b)(4). You identified Stenotrophomonas maltophilia to be a drug-resistant gram-negative emerging global opportunistic pathogen with a known propensity for biofilm formation. You determined the root cause to be a leakage caused by a damaged valve gasket and deformed filter. 2022 年 3 月，您在批次 # （b）（4）的多种培养基罐装（b）（4）均分散出嗜麦芽窄食单胞菌。您细目嗜麦芽窄食单胞菌是一种耐药革兰氏阴性的新兴全球契机性病原体，具有已知的生物膜酿成倾向。您细看法根蒂原因是阀门垫圈损坏和过滤器变形导致的泄漏。
You failed to appropriately investigate root causes and implement effective CAPAs to prevent recurrence of contamination events. For example， you failed to substantively evaluate the personnel and environmental monitoring (EM) data obtained during the production of these media fill batches， and to comprehensively assess additional historical data from the manufacturing area.您未能符合拜谒根蒂原因并实施灵验的CAPA 来堤防浑浊事件再次发生。举例，您未能对这些培养基灌装批次出产工艺中赢得的东谈主员和环境监测（EM）数据进行本色性评估，也未能全面评估来克己造区域的其他历史数据。
Your response is inadequate because there is no overall assessment of these atypical invalidations of media fills， explanation of the adverse pattern of gram-negative microbe findings in your aseptic processing operational environment， or major improvements to ensure more reliable aseptic operational design and equipment maintenance.您的反映不充分，因为莫得对培养基灌装的这些非典型无效进行全面评估，莫得解释无菌出产操作环境中革兰氏阴性微生物发现的不良阵势，也莫得对确保更可靠的无菌操作筹画和设备调治进行要紧改革。
The presence of any highly pathogenic microorganism in your aseptic processing environment presents a heightened risk to patients who are， for example， immunocompromised， have cystic fibrosis， or have chronic obstructive airway disease. Presence of such microbes should receive urgent investigation and effective remediation. Further， it is critical to ensure appropriate equipment design and maintenance， as equipment failures may not be easily observable and contamination events during commercial manufacturing may go undetected for substantial periods of time.无菌出产环境中存在职何高致病性微生物齐会给免疫功能低下、囊性纤维化或慢性结巴性气谈疾病等患者带来更高的风险。此类微生物的存在应得到遑急拜谒和灵验救济。此外，确保符合的设备筹画和调治至关关键，因为设备故障可能碎裂易不雅察到，交易制造工艺中的浑浊事件可能在很长一段时期内未被发现。
It is essential to address potential contamination hazards in your manufacturing environment in a timely manner. Any adverse microbiological trends and potential routes of contamination should be identified promptly， allowing for implementation of appropriate follow-up measures to prevent contamination. It should also be noted that finished product testing alone cannot establish sterility of all units because contamination is typically episodic and not uniformly distributed.实时处分制造环境中的潜在浑浊危害至关关键。应速即查明任何不利的微生物趋势和潜在的浑浊门道，以便取舍符合的后续措施来堤防浑浊。还应该端庄的是，仅靠制品测试并不成细目无菌性，因为浑浊经常是偶发的，而不是均匀分散的。
Environmental Monitoring环境监测
You failed to provide adequate justification for the discontinuation of filling(b)(4) surface monitoring on your (b)(4) lines. For example， prior to January 2020， your EM plan required collection of surface samples from (b)(4) filling (b)(4) at the (b)(4) of filling of (b)(4) batch. However， from January 2020 to August 2022， you did not collect surface samples from the (b)(4) filling (b)(4) at the (b)(4) of filling of (b)(4) batch.您未能提供敷裕的原理来住手在您的（b）（4）出产线上进行罐装（b）（4）名义监测。举例，在 2020 年 1 月之前，您的 EM 权略要求在（b）（4）批次的（b）（4）罐装中网罗（b）（4）罐装的名义样品。关联词，在 2020 年 1 月至 2022 年 8 月时间，您莫得在（b）（4）批次的（b）（4）罐装（b）（4）中集中名义样本。
You revised your EM plan in August 2022 to perform surface monitoring of(b)(4) filling (b)(4)， the (b)(4)， at the (b)(4) of filling of (b)(4) batch. You lack a justification for sufficiency of your sampling plan， including its failure to rotate sampling among each of the (b)(4).您在 2022 年 8 月修改了 EM 权略，以在（b）（4）批次的（b）（4）罐装时对（b）（4）罐装（b）（4）和（b）（4）进行名义监测。您短少取样权略充分的原理，包括未能在（b）（4）中的每一个之间轮疏浚样。
人体艺术网In your response， you state you have adequate controls in place to assure sterility of products manufactured on your(b)(4) lines and there is no impact on the sterility of batches manufactured on these lines.在您的回应中，您声明您有敷裕的戒指措施来确保在您的（b）（4）出产线上出产的居品的无菌性，何况对在这些出产线上出产的批次的无菌性莫得影响。
Your response is inadequate in that it lacks a scientifically sound EM plan.您的回答是不够的，因为它短少科学合理的 EM 权略。
Vigilant and responsive EM programs should be designed to provide meaningful information on the state of control of your aseptic processing environment and ancillary classified areas.应筹画警惕且反映速即的 EM 权略，以提供相关无菌出产环境和援救分类区域戒指景况的有道理的信息。
In response to this letter， provide the following:手脚对这封信的回应，请提供以下内容：
A comprehensive， independent third-party review of your media fill program. 对您的培养基罐装权略进行全面、落寞的第三方审查。
An independent review of the source of recurring gram negatives isolated from your aseptic processing equipment train. 对从无菌出产设备均分散出的反复出现的革兰氏阴性物资的开端进行落寞审查。
Your CAPA plan to implement routine， operations management oversight of facilities and equipment. This plan should include， at a minimum: 您的 CAPA 权略对设施和设备实施例行的运营握住监督。该权略至少应包括：
o Improved production management oversight that ensures prompt detection of equipment， facility， and process performance issueso 改革出产握住监督，确保实时发现设备、设施和工艺性能问题 o Timely upgrades to equipment and facilitieso 实时升级设备设施 o Adherence to appropriate preventive maintenance scheduleso 顺从符合的退缩性调治权略 o Effective execution of repairso 灵验实践维修 o Allocation of appropriate resources， staffing， and competencieso 分拨符合的资源、东谈主员和智商 o Appropriately qualified production supervisors and managerso 具有符合股历的出产操纵和司理o Improved systems for ongoing management reviewo 改革的执续握住审查轨制o A provision(s) that appropriate actions are taken throughout the company networko 在通盘公司层面中取舍符合行动的法规o A thorough evaluation and risk assessment that addresses the suitability of your equipment for its intended use. Include an evaluation whether equipment is of appropriate design and your ongoing control and maintenance program is effective.o 全面的评估和风险评估，以处分您的设备是否允洽其预期用途。包括评估设备是否筹画合适，以及您的执续戒指和调治权略是否灵验。
A retrospective evaluation by a qualified consult of the sufficiency of investigations and the failure modes related to the capability of your aseptic processing operation to robustly produce sterile drugs including， but not limited， to: 由及格的议论东谈主员对拜谒的充分性以及与无菌出产操作得当出产无菌药物的智商计议的故障阵势进行讲究性评估，包括但不限于：
o All media fill contamination events， invalidated media fills， and sterility positive test results for the past four years， regardless of whether the batch was shipped to the U.S.o 以前四年的通盘培养基灌装浑浊事件、无效培养基灌装和无菌阳性检测效果，无论该批次是否运往好意思国。o Identification of all potential failure modes associated with these media fill and sterility positives.o 识别与这些培养基罐装和无菌阳性计议的通盘潜在故障阵势。o A detailed evaluation and description of each aseptic connection and manipulation made starting with， and downstream of， the (b)(4) filter including but not limited to any manipulations at sampling ports in the product flow pathway prior to filling.o 对从（b）（4）过滤器开动和卑劣进行的每个无菌纠合和操作的细心评估和描摹，包括但不限于灌装前在居品流路中取样口进行的任何操作。o A comparison of your aseptic manufacturing process to the process simulation protocol to identify areas in which media fills may be improved to simulate actual operations more accurately.o 将您的无菌出产工艺与工艺模拟决策进行相比，以细目不错改革培养基罐装的限制，以更准确地模拟执行操作。o Detailed media fill criteria used by your firm， and adequacy of provisions to ensure thorough investigation of any contamination.o 贵公司使用的细心培养基罐装圭臬，以及确保对任何浑浊进行透彻拜谒的法规是否充分。o All changes implemented to your aseptic operations in response to any aseptic process simulation incidents and sterility failures for the past four years， including an evaluation of their adequacy and sufficiency， and a risk assessment of any distributed product affected by deficient aseptic processing operations that occurred during this period.o 在以前四年中，为应答任何无菌工艺模拟事件和无菌失败而对您的无菌操作实施的通盘调动，包括对其充分性和充分性的评估，以及对在此时间发生的受无菌出产操作过失影响的任何分销居品的风险评估。o Your plan to ensure appropriate aseptic practices and cleanroom behavior during production. Include steps to ensure routine and effective supervisory oversight for all production batches. Also， describe the frequency of QU oversight (e.g.， audit) during aseptic processing and its support operations.o 您的权略，以确保在出产工艺中取舍符合的无菌实践和洁净室行动。包括确保对通盘出产批次进行例行和灵验监督的门径。此外，描摹无菌出产偏激搭救操作时间QU 监督（举例审核）的频率。
A comprehensive risk assessment of all contamination hazards with respect to your aseptic processes， equipment， and facilities， including an independent assessment that includes， but is not limited to: 对与您的无菌工艺、设备和设施相关的通盘浑浊危害进行全面的风险评估，包括落寞评估，包括但不限于：
o All human interactions within the ISO 5 areao ISO 5 区域内的通盘东谈主际互动o Equipment integrity， placement， and ergonomicso 设备完好性、放弃和东谈主体工程学o Air quality in the ISO 5 area and surrounding roomo ISO 5 区域和周围房间的空气质料o Facility layout o 设施布局o Personnel Flows and Material Flows (throughout all rooms used to conduct and support sterile operations)o 东谈主员流动和物料流动（用于进行和搭救无菌操作的通盘房间）
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.细心的救济权略，包括处分浑浊危害风险评估效果的时期表。描摹对无菌出产操作筹画和戒指进行的具体有形的改革。
A comprehensive assessment and CAPA plan for your EM program to ensure it supports robust environmental control in your aseptic processing facility. Your assessment should include justification of sampling locations， frequency of sampling， alert and action limits， the adequacy of your sampling techniques， and trending program.为您的 EM 权略提供全面的评估和 CAPA 权略，以确保它搭救无菌出产设施中高大的环境戒指。您的评估应包括采样位置的原理、采样频率、警报和行动纵容、取样本领的充分性以及趋势权略。
无论居品批次是否已分销，齐未能透彻审核无法解释的偏差和物料不对格。
以下是发现项及翻译
图片
图片
2021年11月 20日，公司在xxx灌装出产上(用于出产xxx ml规格的混悬剂) 进行无菌工艺模拟议论，考证批号为xxx批号。此次培养基模拟灌装议论是依据考证决策 “混悬剂无菌工艺考证决策”(F/VP/APVSM/01，2021年9月14日批准)进行的。
在 14天的培养时间，公司发当前xxx样品中发现了浑浊。其中微生物被辨认为xxx革兰氏阳性泥土细菌。启动了拜谒DEV-1025-2021-00147，把根原因归结为xxx原因，该原因大齐发生在进行目测检讨之前的灌装样品、居品储存、或目测检讨工序中对样品的处置或迁移中。关联词在灌装出产制造经由和检讨操作中并莫得纪录相通权略外事项，在出产批纪录或是其他实验室分析检讨纪录中也莫得纪录样品误操作的任何凭据。
根据考证决策 F/VP/APVSM/01，培养基灌装可罗致圭臬为xxx圭臬。然后，质料部门批准在莫得找到显明的根原因前提下批准了xxx问题批次的培养基模拟罐装批次。从2022年1月到2022年12月，公司统共从xxx出产线放行了轻便 xxx个交易批次的xxx g/xxx ml规格的混悬剂居品。
图片
图片
无菌工艺区域在环境条款监控系统方面存在过失和不及。
A. 某居品的出产位于某灌装出产线的某区域内 (属于A级区)。尽管烟雾议论莫得评估/讲解该区域的层流不错堤防微生物浑浊，但公司的敷陈 SR/AF/SDC/01“某区域静态和动态条款下的气流流型敷陈”(2022年 10月10日批准)论断是在某灌装线的溶液出产区域进行的烟雾议论是可罗致的。该敷陈也莫得评估某气流流型，该气流流型似乎走漏湍流，该区域的外名义和 C级区域成功斗殴。某无菌灌装区域的环境监测未能确保可能影响要津区域的微生物识别和拜谒。
B.某灌装出产线被用于灌装混悬液/液体制剂居品。某设施位于一个被界说为某级别的房间内。这些行为被界说为属于什么级别区域进行的操作。居品出产用的某设备位于灌装出产线的某位置上，该区域被界说为某级别区域。
在2020年1月16日到 2022年8月30日，公司的环境监控门径莫得要求对某名义进行擦抹取样村上里沙qvod，即便在灌装出产时间也莫得进行过动态取样。在这个时间，统共唐突有xxx个批次的交易化出产居品(举例，混悬剂/液体制剂) 被出产/放行/分销到好意思国阛阓。
本站仅提供存储就业，通盘内容均由用户发布，如发现存害或侵权内容，请点击举报。