2023.11.21 FDA公布了其关于 cipla其下一家无菌工场的警告信（2023.02.06-2023.02.17检查）骚女qq。

比拟非凡念念的是，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混浊，到最终483讲述阐述为，或者说又发现了？革兰氏阴性菌。

具体环球我方看吧……

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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. 您的公司未能建筑并解任顺应的书面要领，以驻防宣称无菌的药品受到微生物混浊，并包括对扫数无菌和灭菌工艺的考证（21 CFR 211.113（b））。

Media Fill Contamination Incidents培养基罐装混浊事件

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，您未能顺应评估设施中培养基罐装失败的口头，也未能充分暄和这些混浊事件之间的潜在关系性。在 2021 年 2 月至 2022 年 3 月时代，（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混浊的培养基罐装物。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）均分裂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）均分裂出 Pseudomonas stutzeri。该培养基罐装（批次 # （b）（4））是算作吊挂线初次考证的一部分实施的，亦然对团结世产线上先前失败的培养基罐装的校正措施（批次 #（b）（4））。您细目 Pseudomonas stutzeri 是一种革兰氏阴性菌。您的探问在检查时代进行了审查，并在您的讲述中进行了进一步描绘，标明这种混浊是由于（b）（4）在处理或转移罐装的样品、储存或目视检查时代被（b）（4）刺穿，在孵育之前。可是，您缺少充足的把柄来描绘对（b）（4）的不当处理。此外，您的探问也莫得包括驻防翌日对孵化单元处理不当的详尽设施，并标明仍允许使用（b）（4）。您的 QU 批准了批次 # （b）（4）的探问和培养基罐装运行，况兼您将此培养基罐装用作阐述混悬剂产物灌装线（b）（4）所需的三次凯旋运行之一。

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）均分裂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，具有已知的生物膜变成倾向。您细主义压根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.您未能顺应探问压根原因并实施灵验的CAPA 来驻防混浊事件再次发生。举例，您未能对这些培养基灌装批次出产工艺中取得的东谈主员和环境监测（EM）数据进行本色性评估，也未能全面评估来好处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口头，也莫得对确保更可靠的无菌操作野心和开采珍重进行首要改造。

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王人会给免疫功能低下、囊性纤维化或慢性阻挠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要紧探问和灵验赈济。此外，确保顺应的开采野心和珍重至关要害，因为开采故障可能拆开易不雅察到，生意制造工艺中的混浊事件可能在很长一段时候内未被发现。

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.实时措置制造环境中的潜在混浊危害至关要害。应速即查明任何不利的微生物趋势和潜在的混浊阶梯，以便领受顺应的后续措施来驻防混浊。还应该注主义是，仅靠制品测试并不可细目无菌性，因为混浊常常是偶发的，而不是均匀漫衍的。

Environmental Monitoring环境监测骚女qq

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.您未能提供充足的情理来罢手在您的（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 筹划要求在（b）（4）批次的（b）（4）罐装中网罗（b）（4）罐装的名义样品。可是，在 2020 年 1 月至 2022 年 8 月时代，您莫得在（b）（4）批次的（b）（4）罐装（b）（4）中相聚名义样本。

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 筹划，以在（b）（4）批次的（b）（4）罐装时对（b）（4）罐装（b）（4）和（b）（4）进行名义监测。您缺少取样筹划充分的情理，包括未能在（b）（4）中的每一个之间轮疏浚样。

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.在您的讲述中，您声明您有充足的戒指措施来确保在您的（b）（4）出产线上出产的产物的无菌性，况兼对在这些出产线上出产的批次的无菌性莫得影响。

香蕉视频无限次数在线观看视频

Your response is inadequate in that it lacks a scientifically sound EM plan.您的回答是不够的，因为它缺少科学合理的 EM 筹划。

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.应野心警惕且反映速即的 EM 筹划，以提供斟酌无菌出产环境和补助分类区域戒指现象的非凡旨的信息。

In response to this letter， provide the following:算作对这封信的讲述，请提供以下内容：

A comprehensive， independent third-party review of     your media fill program.     对您的培养基罐装筹划进行全面、幽静的第三方审查。

An     independent review of the source of recurring gram negatives isolated from     your aseptic processing equipment train.     对从无菌出产开采均分裂出的反复出现的革兰氏阴性物资的起原进行幽静审查。

Your     CAPA plan to implement routine， operations management oversight of     facilities and equipment. This plan should include， at a minimum:     您的 CAPA 筹划对设施和开采实施例行的运营束缚监督。该筹划至少应包括：

o Improved production management oversight that ensures prompt detection of equipment， facility， and process performance issueso 改造出产束缚监督，确保实时发现开采、设施和工艺性能问题    o Timely upgrades to equipment and facilitieso 实时升级开采设施    o Adherence to appropriate preventive maintenance scheduleso 遵照顺应的驻防性珍重筹划    o Effective execution of repairso 灵验实施维修    o Allocation of appropriate resources， staffing， and competencieso 分拨顺应的资源、东谈主员和能力    o Appropriately qualified production supervisors and managerso 具有顺应经验的出产附近和司理o Improved systems for ongoing management reviewo 改造的握续束缚审查轨制o A provision(s) that appropriate actions are taken throughout the company networko 在通盘公司层面中领受顺应行动的规则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，以措置您的开采是否顺应其预期用途。包括评估开采是否野心合适，以及您的握续戒指和珍重筹划是否灵验。

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:     由及格的商议东谈主员对探问的充分性以及与无菌出产操作庄重出产无菌药物的能力关系的故障口头进行追思性评估，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 夙昔四年的扫数培养基灌装混浊事件、无效培养基灌装和无菌阳性检测后果，非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关系的扫数潜在故障口头。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）过滤器运行和下贱进行的每个无菌相连和操作的详备评估和描绘，包括但不限于灌装前在产物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比拟，以细目不错改造培养基罐装的边界，以更准确地模拟本质操作。o Detailed media fill criteria used by your firm， and adequacy of provisions to ensure thorough investigation of any contamination.o 贵公司使用的详备培养基罐装要领，以及确保对任何混浊进行澈底探问的规则是否充分。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 在夙昔四年中，为应付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扫数改造，包括对其充分性和充分性的评估，以及对在此时代发生的受无菌出产操作残障影响的任何分销产物的风险评估。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 您的筹划，以确保在出产工艺中领受顺应的无菌实践和洁净室步履。包括确保对扫数出产批次进行例行和灵验监督的设施。此外，描绘无菌出产偏执复古操作时代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、开采和设施斟酌的扫数混浊危害进行全面的风险评估，包括幽静评估，包括但不限于：

o All human interactions within the ISO 5 areao ISO 5 区域内的扫数东谈主际互动o Equipment integrity， placement， and ergonomicso 开采完好性、舍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（用于进行和复古无菌操作的扫数房间）

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.详备的赈济筹划，包括措置混浊危害风险评估后果的时候表。描绘对无菌出产操作野心和戒指进行的具体有形的改造。

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 筹划提供全面的评估和 CAPA 筹划，以确保它复古无菌出产设施中雄壮的环境戒指。您的评估应包括采样位置的情理、采样频率、警报和行动截至、取样时刻的充分性以及趋势筹划。

非论产物批次是否已分销，王人未能澈底审核无法解释的偏差和物料不对格。

以下是发现项及翻译

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2021年11月 20日，公司在xxx灌装出产上(用于出产xxx ml规格的混悬剂) 进行无菌工艺模拟研究，考证批号为xxx批号。此次培养基模拟灌装研究是依据考证决策 “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天的培养时代，公司发当今xxx样品中发现了浑浊。其中微生物被阔别为xxx革兰氏阳性泥土细菌。启动了探问DEV-1025-2021-00147，把根原因归结为xxx原因，该原因多数发生在进行目测检查之前的灌装样品、产物储存、或目测检查工序中对样品的处置或转移中。可是在灌装出产制造历程和检查操作中并莫得记载相似筹划外事项，在出产批记载或是其他实验室分析检查记载中也莫得记载样品误操作的任何把柄。

根据考证决策 F/VP/APVSM/01，培养基灌装可接受要领为xxx要领。然后，质料部门批准在莫得找到彰着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，公司所有从xxx出产线放行了梗概 xxx个生意批次的xxx g/xxx ml规格的混悬剂产物。

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无菌工艺区域在环境条款监控系统方面存在残障和不及。

A. 某产物的出产位于某灌装出产线的某区域内 (属于A级区)。尽管烟雾研究莫得评估/解释该区域的层流不错驻防微生物混浊，但公司的讲明 SR/AF/SDC/01“某区域静态和动态条款下的气流流型讲明”(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研究是可接受的。该讲明也莫得评估某气流流型，该气流流型似乎清晰湍流，该区域的外名义和 C级区域径直斗争。某无菌灌装区域的环境监测未能确保可能影响关节区域的微生物识别和探问。

B.某灌装出产线被用于灌装混悬液/液体制剂产物。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。产物出产用的某开采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，公司的环境监控要领莫得要求对某名义进行擦抹取样，即便在灌装出产时代也莫得进行过动态取样。在这个时代，所有粗略有xxx个批次的生意化出产产物(举例骚女qq，混悬剂/液体制剂) 被出产/放行/分销到好意思国阛阓。

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