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发布日期：2025-03-31 20:46 点击次数：65
2023.11.21 FDA公布了其对于 cipla其下一家无菌工厂的警告信（2023.02.06-2023.02.17检查）。
比较有意思的是，这家公司的无菌模拟罐装，发现项1（483原文及翻译拖到最下面）时定义为革兰氏阳性菌污染，到最终483回复确认为，或者说又发现了？革兰氏阴性菌。
具体大家自己看吧……
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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. 您的公司未能建立并遵循适当的书面程序，以防止声称无菌的药品受到微生物污染，并包括对所有无菌和灭菌工艺的验证（21 CFR 211.113（b））。
Media Fill Contamination Incidents培养基罐装污染事件
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,您未能适当评估设施中培养基罐装失败的模式，也未能充分关注这些污染事件之间的潜在相关性。在 2021 年 2 月至 2022 年 3 月期间，（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污染的培养基罐装物。例如
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）悬挂线上生产的批次 # （b）（4）的多个培养基罐装物（b）（4）中分离出一种革兰氏阴性微生物 Ralstonia picketii。您发现了多个偏差，例如过滤器外壳损坏、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）悬挂线上生产的（b）（4）培养基罐装批次 # （b）（4）中分离出 Pseudomonas stutzeri。该培养基罐装（批次 # （b）（4））是作为悬挂线首次验证的一部分执行的，也是对同一生产线上先前失败的培养基罐装的纠正措施（批次 #（b）（4））。您确定 Pseudomonas stutzeri 是一种革兰氏阴性菌。您的调查在检查期间进行了审查，并在您的回复中进行了进一步描述，表明这种污染是由于（b）（4）在处理或移动罐装的样品、储存或目视检查期间被（b）（4）刺穿，在孵育之前。但是，您缺乏足够的证据来描述对（b）（4）的不当处理。此外，您的调查也没有包括防止未来对孵化单位处理不当的综合步骤，并表明仍允许使用（b）（4）。您的 QU 批准了批次 # （b）（4）的调查和培养基罐装运行，并且您将此培养基罐装用作确认混悬剂产品灌装线（b）（4）所需的三次成功运行之一。
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）中分离出嗜麦芽窄食单胞菌。您确定嗜麦芽窄食单胞菌是一种耐药革兰氏阴性的新兴全球机会性病原体，具有已知的生物膜形成倾向。您确定的根本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.您未能适当调查根本原因并实施有效的CAPA 来防止污染事件再次发生。例如，您未能对这些培养基灌装批次生产工艺中获得的人员和环境监测（EM）数据进行实质性评估，也未能全面评估来自制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.您的响应不充分，因为没有对培养基灌装的这些非典型无效进行全面评估，没有解释无菌生产操作环境中革兰氏阴性微生物发现的不良模式，也没有对确保更可靠的无菌操作设计和设备维护进行重大改进。
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.无菌生产环境中存在任何高致病性微生物都会给免疫功能低下、囊性纤维化或慢性阻塞性气道疾病等患者带来更高的风险。此类微生物的存在应得到紧急调查和有效补救。此外，确保适当的设备设计和维护至关重要，因为设备故障可能不容易观察到，商业制造工艺中的污染事件可能在很长一段时间内未被发现。
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.及时解决制造环境中的潜在污染危害至关重要。应迅速查明任何不利的微生物趋势和潜在的污染途径，以便采取适当的后续措施来防止污染。还应该注意的是，仅靠成品测试并不能确定无菌性，因为污染通常是偶发的，而不是均匀分布的。
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.您未能提供足够的理由来停止在您的（b）（4）生产线上进行罐装（b）（4）表面监测。例如，在 2020 年 1 月之前，您的 EM 计划要求在（b）（4）批次的（b）（4）罐装中收集（b）（4）罐装的表面样品。但是，在 2020 年 1 月至 2022 年 8 月期间，您没有在（b）（4）批次的（b）（4）罐装（b）（4）中采集表面样本。
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 计划，以在（b）（4）批次的（b）（4）罐装时对（b）（4）罐装（b）（4）和（b）（4）进行表面监测。您缺乏取样计划充分的理由，包括未能在（b）（4）中的每一个之间轮换取样。
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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.在您的回复中，您声明您有足够的控制措施来确保在您的（b）（4）生产线上生产的产品的无菌性，并且对在这些生产线上生产的批次的无菌性没有影响。
Your response is inadequate in that it lacks a scientifically sound EM plan.您的回答是不够的，因为它缺乏科学合理的 EM 计划。
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.应设计警惕且响应迅速的 EM 计划，以提供有关无菌生产环境和辅助分类区域控制状态的有意义的信息。
In response to this letter, provide the following:作为对这封信的回复，请提供以下内容：
A comprehensive, independent third-party review of your media fill program. 对您的培养基罐装计划进行全面、独立的第三方审查。
An independent review of the source of recurring gram negatives isolated from your aseptic processing equipment train. 对从无菌生产设备中分离出的反复出现的革兰氏阴性物质的来源进行独立审查。
Your CAPA plan to implement routine, operations management oversight of facilities and equipment. This plan should include, at a minimum: 您的 CAPA 计划对设施和设备实施例行的运营管理监督。该计划至少应包括：
o Improved production management oversight that ensures prompt detection of equipment, facility, and process performance issueso 改进生产管理监督，确保及时发现设备、设施和工艺性能问题 o Timely upgrades to equipment and facilitieso 及时升级设备设施 o Adherence to appropriate preventive maintenance scheduleso 遵守适当的预防性维护计划 o Effective execution of repairso 有效执行维修 o Allocation of appropriate resources, staffing, and competencieso 分配适当的资源、人员和能力 o Appropriately qualified production supervisors and managerso 具有适当资格的生产主管和经理o Improved systems for ongoing management reviewo 改进的持续管理审查制度o A provision(s) that appropriate actions are taken throughout the company networko 在整个公司层面中采取适当行动的规定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，以解决您的设备是否适合其预期用途。包括评估设备是否设计合适，以及您的持续控制和维护计划是否有效。
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: 由合格的咨询人员对调查的充分性以及与无菌生产操作稳健生产无菌药物的能力相关的故障模式进行回顾性评估，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 过去四年的所有培养基灌装污染事件、无效培养基灌装和无菌阳性检测结果，无论该批次是否运往美国。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相关的所有潜在故障模式。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）过滤器开始和下游进行的每个无菌连接和操作的详细评估和描述，包括但不限于灌装前在产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 将您的无菌生产工艺与工艺模拟方案进行比较，以确定可以改进培养基罐装的领域，以更准确地模拟实际操作。o Detailed media fill criteria used by your firm, and adequacy of provisions to ensure thorough investigation of any contamination.o 贵公司使用的详细培养基罐装标准，以及确保对任何污染进行彻底调查的规定是否充分。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 在过去四年中，为应对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所有更改，包括对其充分性和充分性的评估，以及对在此期间发生的受无菌生产操作缺陷影响的任何分销产品的风险评估。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 您的计划，以确保在生产工艺中采取适当的无菌实践和洁净室行为。包括确保对所有生产批次进行例行和有效监督的步骤。此外，描述无菌生产及其支持操作期间QU 监督（例如审核）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、设备和设施有关的所有污染危害进行全面的风险评估，包括独立评估，包括但不限于：
o All human interactions within the ISO 5 areao ISO 5 区域内的所有人际互动o Equipment integrity, placement, and ergonomicso 设备完整性、放置和人体工程学o Air quality in the ISO 5 area and surrounding roomo ISO 5 区域和周围房间的空气质量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 人员流动和物料流动（用于进行和支持无菌操作的所有房间）
365建站客服QQ：800083652A 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.详细的补救计划，包括解决污染危害风险评估结果的时间表。描述对无菌生产操作设计和控制进行的具体有形的改进。
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 计划提供全面的评估和 CAPA 计划，以确保它支持无菌生产设施中强大的环境控制。您的评估应包括采样位置的理由、采样频率、警报和行动限制、取样技术的充分性以及趋势计划。
无论产品批次是否已分销，都未能彻底审核无法解释的偏差和物料不合格。
以下是发现项及翻译
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2021年11月 20日，公司在xxx灌装生产上(用于生产xxx ml规格的混悬剂) 进行无菌工艺模拟研究，验证批号为xxx批号。这次培养基模拟灌装研究是依据验证方案 “混悬剂无菌工艺验证方案”(F/VP/APVSM/01，2021年9月14日批准)进行的。
在 14天的培养期间，公司发现在xxx样品中发现了浑浊。其中微生物被鉴别为xxx革兰氏阳性土壤细菌。启动了调查DEV-1025-2021-00147,把根原因归结为xxx原因，该原因普遍发生在进行目测检查之前的灌装样品、产品储存、或目测检查工序中对样品的处置或移动中。但是在灌装生产制造过程和检查操作中并没有记录类似计划外事项，在生产批记录或是其他实验室分析检查记录中也没有记录样品误操作的任何证据。
根据验证方案 F/VP/APVSM/01，培养基灌装可接受标准为xxx标准。然后，质量部门批准在没有找到明显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，公司总共从xxx生产线放行了大约 xxx个商业批次的xxx g/xxx ml规格的混悬剂产品。
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无菌工艺区域在环境条件监控系统方面存在缺陷和不足。
A. 某产品的生产位于某灌装生产线的某区域内 (属于A级区)。尽管烟雾研究没有评估/证明该区域的层流可以防止微生物污染，但公司的报告 SR/AF/SDC/01“某区域静态和动态条件下的气流流型报告”(2022年 10月10日批准)结论是在某灌装线的溶液生产区域进行的烟雾研究是可接受的。该报告也没有评估某气流流型，该气流流型似乎显示湍流，该区域的外表面和 C级区域直接接触。某无菌灌装区域的环境监测未能确保可能影响关键区域的微生物识别和调查。
B.某灌装生产线被用于灌装混悬液/液体制剂产品。某设施位于一个被定义为某级别的房间内。这些活动被定义为属于什么级别区域进行的操作。产品生产用的某设备位于灌装生产线的某位置上，该区域被定义为某级别区域。
在2020年1月16日到 2022年8月30日，公司的环境监控程序没有要求对某表面进行擦拭取样，即便在灌装生产期间也没有进行过动态取样。在这个期间，总共大概有xxx个批次的商业化生产产品(例如，混悬剂/液体制剂) 被生产/放行/分销到美国市场。
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