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本帖最后由 roadman 于 2019-7-12 19:59 编辑
原创：翻译组GMP办公室
近日，FDA发布了对AllerQuest LLC的警告信，包含各类典型的无菌产品检查缺陷：
- ISO 5（A级）关键区域有缝隙
- 缝隙在检查过程中用胶带密封
- ISO 5（A级）和洁净室环境监测反复超出行动限，未能彻底处理
- 未使用杀孢子剂
- 依赖现场人员手动记录环境温湿度和压差，缺乏持续监测系统。
- 记录了大量温湿度偏差，但是未报告偏差，也没有实施有效的CAPA。
- 周期性停产，停产期间未对厂房进行充分的监测和控制。
- 未对灯检缺陷制定适当的警戒限和行动限，灯检发现大量可见异物缺陷产品（甚至超过10%）,仍然放行了剩余的产品。
- FDA表示，需要调查可见异物的根本原因并采取有效的CAPA，产品质量不是检验出来的。
缺陷翻译如下：
1. Your firm failed to perform operations within specifically defined areas of adequate size and to have separate or defined areas or such other control systems necessary to prevent contamination or mix-ups (21 CFR 211.42(c)).
未能在足够标准的既定区域中操作，也没有单独或定义的区域或防止污染或混淆所需的其他控制系统(21 CFR 211.42(c))。
You manufacture sterile injectable drug products in a facility that is not adequately designed or controlled for sterile drug operations.
你们在一个设计或控制不充分的设施生产无菌注射剂产品。
For example, your ISO 5 critical area where you aseptically fill ampules directly interfaces with double doors. These double doors have substantial gaps in multiple locations and are immediately adjacent to an unclassified area. This poses a hazard for the influx of unclassified air directly into a critical zone. During the inspection, you applied tape to try to seal the voids.
例如，你们无菌填充安培直接暴露的双扉门 ISO 5 （A级）关键区域。该双扉多处有巨大的缝隙，并紧邻非洁净级别区域。这容易导致非洁净级别空气直接流入关键区域。在检查过程中，你们用胶带试图密封缝隙。
Aseptic processes should be designed to minimize exposure of sterile articles to potential contamination hazards, including but not limited to variation in environmental conditions. Any area that adjoins and can impact an ISO 5 area should be appropriately designed, maintained, and classified.
无菌工艺的设计应尽量减少无菌物品暴露于潜在污染的危害，包括但不限于环境条件的变 化。任何毗邻并可能影响 ISO 5 区域的区域都应进行适当的设计、维护并分级。
Your aseptic processing line design is inadequate. The production line has limited protection and a high degree of exposure to contamination hazards from manual intervention and the surrounding air.
你们的无菌加工生产线的设计是不足的。生产线保护有限，高度暴露于手动干预和周围空气的污染风险。
For 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.
有关无菌处理的其他指导,请参阅 FDA指导文件：无菌加工无菌药品生产GMP指南，以帮助在使用无菌加工生产无菌药品时满足 CGMP 要求。
In your response you committed to engaging third-party consultants to assist with the remediation of your facility. However, you failed to provide adequate supportive documentation to evaluate the effectiveness of your corrective actions and preventive actions (CAPA). You also mention that all batches of your drug product have passed sterility testing for release. However, finished product testing alone is limited in its ability to establish sterility of all units because contamination is not normally uniformly distributed.
在你们的回复中，你们承诺聘请第三方顾问协助修复你们的设施。但是，你们未能提供足够的支持性文档来评估纠正措施和预防措施 (CAPA) 的有效性。你们还提到,你们所有批次的药品都是通过无菌检查放行的。然而，仅仅成品检验对所有产品无菌性的检测能力有限，因为污染分布是不均匀的。
Many significant elements in aseptic processing can influence the quality and safety of sterile drugs. If each element is not strictly controlled, there is potential for a non-sterile drug product.
无菌加工中的许多重要元素会影响无菌药品的质量和安全性。如果未能严格控制每个元素，则有可能破坏无菌性。
2. Your firm failed to perform operations within specifically defined areas of adequate size and to have separate or defined areas or such other control systems necessary to prevent contamination or mix-ups in aseptic processing areas (21 CFR 211.42(c)(10)).
未能在足够标准的既定区域中操作，也没有单独或定义的区域或防止污染或混淆所需的其他控制系统(21 CFR 211.42(c)（10）)。
Your firm had various departures from your established actions limits throughout your ISO 5 critical area and clean rooms but failed to adequately address them. Loss of environmental control can significantly increase contamination risk of drugs intended to be sterile.
贵公司在整个 ISO 5 关键区域和洁净室中都有各种超出既定行动限的情况，且未能充分解决这些问题。环境控制的不足会大大增加无菌药品污染风险。
Cleaning and Disinfection 清洁和消毒
You failed to ensure sufficient use of a sporicidal agent in your disinfection program. For example, your firm identified Bacillus, sp., a spore-forming organism, within the ISO 5 critical area by the ampule feed track on the filling machine. After you found Bacillus, sp. in the aseptic core, you cleaned the area with (b)(4) and (b)(4), neither of which are sporicidal.
你们未能确保在消毒程序中充分使用杀孢子剂。例如，贵公司在灌装机安培进瓶轨道的ISO5关机区域内发现了芽孢杆菌，一种可以形成芽孢的微生物。在发现芽孢杆菌后，贵公司使用 (b)(4) 和 (b)(4) 对该区域进行清洁，这两者都不是杀孢子剂。
Environmental and Personnel Monitoring 环境和人员监测
You did not adequately investigate the cause of multiple excursions above your action limit, including a potential adverse pattern of fungal contamination.
你们未能充分调查多个行动限超标的原因，包括真菌污染的潜在不良形式。
Essential to an adequate environmental monitoring (EM) program is a timely and thorough evaluation of action limit excursions, identifying potential routes of contamination, as well as identifying appropriate follow-up measures to prevent contamination risks to the product.
环境监测 (EM) 计划的关键，是及时和彻底地评估行动限偏离事件，确定潜在的污染途径，并制定适当的后续措施，以防止产品污染的风险。
In addition, your personnel monitoring program is inadequate. For example, fingertip monitoring should have an action limit of one colony forming unit (CFU). However, you established operator annual requalification limits as “NMT (b)(4)CFU” for fingertip sampling. An ongoing goal for manufacturing personnel in the aseptic processing room is to maintain contamination-free gloves throughout operations. Results that do not meet established limits should trigger appropriate attention.
此外，你们的人员监测计划是不充分的。例如，手指（手套）监测应有一个1 CFU)的行动限。但是，你们在人员再确认的时候将手指（手套）采样限度定为"≤(b)(4)CFU"。无菌室生产人员的持续目标是在整个操作过程中保持手套零污染。不符合既定限度的结果应引起适当的关注。
Temperature, Humidity, and Pressure 温度、湿度和压力
Your firm lacks a continuous monitoring system to ensure that the quality of your aseptic processing environment is adequately maintained. You relied on personnel being present at the time of a temperature, humidity, or pressure excursion for it to be manually detected and recorded. Over a period of years, you documented numerous temperature and humidity excursions across your aseptic processing areas. However, you failed to consistently report these excursions appropriately as required by your procedure, and to implement effective CAPAs.
贵公司缺乏一个持续的监测系统，以确保无菌加工环境的质量得到充分维护。你们依靠现场人员在温度、湿度或压力偏离时进行手动检测和记录。在一段时间内，你们记录了无菌加工区域的大量的温度和湿度偏差。但是，你们未能按照程序的要求一致地报告这些偏差，并且无法实施有效的 CAPA。
A suitable facility monitoring system is crucial for detecting changes that can compromise the environmental control of cleanrooms and ultimately the drug product. Notably, your aseptic operations are particularly vulnerable to loss of control, especially because you periodically cease and restart operations at your facility throughout the year with limited monitoring of the facility during these periods.
合适的设施监测系统对于检测可能危及洁净室和最终药品的环境控制的变化至关重要。值得注意的是，你们的无菌操作特别容易受到失控的影响，特别是因为你们整年都有定期停产和重新启动工厂的操作，但是对这期间设施的监测很有限。
In your response, you committed to enhancing your EM program, remediating your HVAC system, and using automated systems to continuously monitor environmental conditions. You also discussed historical EM sampling results and sterility testing. However, you failed to provide adequate supportive documentation to evaluate the adequacy of your CAPA.
在你们的回复中，你们承诺加强你们的环境监测计划，改造空调系统，并使用自动化系统持续监测环境条件。你们也讨论了历史环境监测取样结果和无菌检验。但是，你们没能提供充分的支持性文件来评估你们CAPA的充分性。
3. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).
贵公司未能彻底调查批次或其任何成分的任何无法解释的偏差或偏离其质量标准，无论该批次是否已放行(21 CFR 211.192)。
You found recurrent contamination of your sterile injectable drug products with foreign particulate matter, but you failed to adequately investigate and identify the root causes of the recurrent contamination.
你们发现你们的无菌注射药品反复受到异物污染，但你们未能充分调查和确定反复污染的根本原因。
Thousands of drug-filled glass ampules repeatedly failed to meet your release acceptance criteria of “clear, colorless solution, free from particulate matter.” You refer to such contamination as a “critical defect” and hypothesized during the inspection that the cause may be glass or aluminum from the manufacturing process. However, you have not identified a root cause of the particulate contamination or implemented effective CAPA.
数千只充填了药品的玻璃安培屡次未能达到"无颗粒物质的无色溶液"的放行标准。你们将此类污染称为"严重缺陷"，并在检查过程中猜测原因可能是生产过程中的玻璃或铝。但是，你们还是没有确定颗粒污染的根本原因，也没有实施有效的 CAPA。
There is a lack of assurance of the quality of your drug products. For example, during one of your quality assurance audits following 100% visual inspection, additional particulate contamination was found that was not identified during a previous 100% visual inspection conducted for lot release. In addition, you repeatedly discarded contaminated ampules identified from visual inspection, sometimes exceeding 10% of a batch, and then distributed the remainder of the batch. The high percentage of rejected ampules and particulates found in cleared ampules after 100% visual inspection indicate that you may have released drug product that contains particulates.
你们的药品质量缺乏保证。例如，在 100% 目视检查后的质量保证审核中，发现了前面批放行 100% 目视检查未发现的其他颗粒污染。此外，你们反复丢弃在目视检查中发现的受污染的安培，有时超过批次的 10%，但是还是放行了该批的剩余部分。在 100% 目视检查后，仍然发现较高比例的不合格的安培和颗粒异物，这表明你们可能已经放行了含有颗粒异物的药品。
In your response, you committed to revising your visual inspection SOP, establishing action and alert limits, and performing a risk assessment of drug products on the market. However, you failed to determine the root cause of the particulate contamination. Product quality cannot be inspected into your drug product: it must be assured by an adequate production process. You also failed to provide adequate supportive documentation to evaluate the adequacy of your CAPA.
在你们的回复中，你们承诺修改你们的目视检查 SOP，建立行动和警戒限，并对在售产品进行风险评估。但是，你们未能确定颗粒污染的根本原因。产品质量不是检验出来的：必须通过适当的生产工艺来保证。你们也未能提供足够的支持性文档来评估你们的 CAPA 是否充分。
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发表于 2019-7-12 20:48:06
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