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近期，FDA发布了关于印度Claris Injectables Ltd.的警告信（Warning Letter 320-18-62 ），FDA于2017年7月27日至8月4日对其进行了检查，发现其制剂生产存在严重违反CGMP的行为。
检查缺陷
1. 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). 你公司未能彻底调查已销售和未销售产品批次或其组份所有未能解释的与质量标准的差异或不符合质量标准的情况(21 CFR 211.192)。
Your firm invalidated out-of-specification (OOS) results without adequate investigation and scientific justification. Examples include: 你公司未经充分调查和科学论证即宣布OOS结果无效。例如：
a. In January, 2017, you obtained OOS results for the (b)(4) impurity during stability testing of (b)(4) injection batches (b)(4). Your OOS investigation reports stated that the postulated cause was “poor column efficiency,” although no chromatographic abnormalities were noted and system suitability criteria were met. During the inspection, your lab management indicated that retention times, the oreticalplates, and tailing factor appeared appropriate and no specific root cause had been demonstrated. You repeated the analyses, obtained passing results, and invalidated the OOS results. 2017年1月，你们在XX注射液批号XX的稳定性测试期间得到XX杂质OOS结果。你们的OOS调查报告说假定原因是“柱效太差”，但并未注意到有色谱异常，系统适用标准也是符合的。在检查期间，你们化验室管理人员说保留时间、理论塔板数和拖尾因子显示正常，并未证明有具体的根本原因。你们重新进行了检验，得到了合格结果，并且宣布OOS结果无效。
In March, 2017, you obtained OOS results for the (b)(4) impurity during stability testing of (b)(4) injection batches (b)(4).You suspected the analyst may have incorrectly rinsed the HPLC vials. New samples prepared and tested by a second analyst using both the original column and a new column, as well as old and new vials, also yielded OOS results.Although you lacked sufficient evidence, your investigation concluded that the OOS results were due to sample vial contamination. You invalidated the OOS results after obtaining passing results from testing retain samples. 2017年3月，你们在XX注射液批号XX的稳定性测试期间得到XX杂质OOS结果。你们怀疑是化验员淋洗HPLC进样瓶错误。第二个化验员制备了新样品，使用原始柱和一支新柱，还有原始瓶与一支新进样瓶，分别进行了检测，也得到了OOS结果。尽管你们缺乏足够的证据，你们的调查仍给出结论说OOS结果是因为进样瓶污染。你们在对留样进行检验得到合格结果之后宣布了OOS结果无效。
After the conclusion of the inspection you initiated a voluntary recall of five batches of (b)(4) drug product due to failing (b)(4) levels, superpotent assays, and (b)(4), all obtained during stability testing and including batches (b)(4). 在检查出结论之后，你们启动了5批XX药品主动召回，原因是XX水平不合格、含量过高以及XX，这些都是在稳定性研究期间得到的结果，涵盖有批次XX。
Notably, you informed FDA that the apparent root cause ofthe (b)(4) assay failures was excessive (b)(4) from your (b)(4).However, the investigation lacked an adequate assessment of all other batches distributed to the U.S. and within expiry that may be potentially affected by (b)(4). 值得注意的是，你们通知FDA说XX含量不合格的明显根本原因是XX高出你们的XX。但是，该调查缺乏对所有其它可能受XX影响、已销往美国且仍在效期内的批次进行的足够评估。
b. Your OOS investigation of the failureof (b)(4) batches (b)(4) to meet the (b)(4) specifications under accelerated stability conditions was also inadequate. You obtained OOS results of (b)(4)% and (b)(4)%, respectively (specification Not More Than (b)(4)%). While the investigation lacked a demonstrated assignable root cause in the laboratory, you obtained passing results during repeat analysis and invalidated the OOS without a Phase II production investigation. 你们对XX批次XX在加速稳定性条件下不符合XX质量标准的OOS调查是不充分的。你们得到的OOS结果分别是XX%和XX%（标准为不得过XX%）。调查并未证明化验室内可归结根本原因，你们在复测中得到了合格结果，然后未进行第二阶段生产调查即宣布了OOS结果无效。
After the inspection, you recalled eight batches of (b)(4) due to superpotent assay and (b)(4) results obtained during stabilitytesting. While use of substandard (b)(4) that allow excessive (b)(4) again appears to have caused the specification failures, your response lacked sufficient relevant information on the root cause and scope of this major problem. 在检查之后，由于稳定性研究期间含量超高和XX结果，你们召回了8个XX批次。你们使用了不合标准的XX使得重复出现XX超出，导致了不符合质量标准的情况出现。你们的回复缺乏足够的根本原因方面关联信息，没有此重大问题的范围界定。
In both of the above instances, you failed to expand your OOS investigations in a timely fashion to address potential manufacturing causes. When an investigation lacks conclusive evidence of laboratory error, athorough investigation of potential manufacturing causes must be performed. Your acceptance of the passing results from testing a new set of samples basedon an unproven hypothesis was insufficient to conclude the investigations. 在上述两起事件中，你们均未能及时扩大你们的OOS调查，说明潜在的生产原因。当一个调查缺乏结论性证据证明化验室错误时，必须对潜在的生产原因进行彻底调查。你们根据一个未经证实的假设，重新检测了一套新的样品，接受了其合格结果，这样做出调查结论是不充分的。
Your response stated that you will revise your OOS Management procedure and perform a retrospective review of your OOS investigations.Your response was inadequate because it lacked identification of root causesand implementation of effective corrective actions and preventive actions (CAPA). It also failed to address inadequacies in the (b)(4) you received from your supplier(s), and whether they are still considered qualifiedfor use by your firm. 你们的回复说你们会修订你们的OOS管理程序，对你们的OOS调查实施回顾性审核。你们的回复是不充分的，因为它缺乏对根据原因的识别，以及实施有效的CAPA。它也没有解决你们从供应商处收到的XX中的不充分的情况，以及你们公司是否仍将其作为合格供应商可以使用。
Notably, your firm has had a worrisome history of recalls dueto substandard (b)(4). In 2017, you recalled (b)(4) parenteral drug products due to recurring(b)(4) complaints. In 2010, your firm conducted a Class I recall of all lots of four parenteral products due to loss of (b)(4) integrity and non-sterility. 值得注意的是，你们公司已经有过因低标准XX而召回的不良历史。在2017年，你们召回了XX注射药品，原因是重复发生的XX投诉。在2010年，你们公司对4个注射药品所有批次执行了I级召回，原因是XX完整性失败和无菌问题。
Also, while your firm has discussed adding a (b)(4) as a corrective action for (b)(4), it would not resolve ongoing issues relating to quality of container-closure raw materials or (b)(4) fabrication. Durability and quality of your large volume parenteral container-closure systems is critical to ensure their robustness until administration at a clinical facility, who will remove (b)(4), and cantemporarily store and then transfer the (b)(4) within the facility before use. Your response lacks a commitment to thoroughly review your (b)(4) dependability with respect to both container-closure raw material quality and (b)(4) fabrication process weaknesses. 还有，虽然你们公司已经讨论了增加一个XX作为XX的纠正措施，但这并不能解决持续发生的与容器密闭器原料或XX制造的质量有关问题。你们大容器注射剂容器密闭器系统的耐用性和质量对于确保其稳固性直到在临床设施里被使用是至关重要的。在临床场合，XX会被移除，可以临时存贮，然后转移至设施内的XX里直至使用。你们的回复缺乏进行对你们容器密闭器原料和XX制造工艺弱点的独立性进行彻底审核的承诺。
2. Your firm failed to prepare batch production and control records with complete information relating to the production and control of each batch of drug product produced (21 CFR 211.188).你公司未能制订批生产和批检验记录，在其中放入与所生产的每批药品生产和检验有关的完整信息（21 CFR 211.188）。
Our investigator observed an operator recording unreliable data. Specifically, on July 27, 2017, our investigator observed your operator entering datain your Visual Inspection Test(VIT) For (b)(4) Line document for (b)(4) injection,USP, batch (b)(4) a day after the operation was completed. The document stated that the visual inspections were performed on July 26, 2017. In responseto our question regarding how portions of the documentation had been completed without corresponding data, a senior manager at your site could not provide an explanation. 我们的调查人员发现一名操作工正在记录不可靠的数据。具体情况是，2017年7月27日，我们的调查人员发现你们的操作工在操作结束之后一天进入你们XX注射剂USP批号XX的XX文件中灯检（VIT）数据。在回答我们关于文件端口在没有相应数据情况下是如何结束的问题时，你们工厂的一位高级经理无法做出解释。
We acknowledge your efforts to update SOPs and retrain personnel. However, your response is inadequate because you did not perform a retrospective assessment into other possible events in which data were not reported accurately or contemporaneously. 我们了解你们努力更新SOP并重新培训了员工。但是，你们的回复是不充分的，因为你们并未对其它可能存在的未准确或未同步报告数据事件进行回顾性评估。
3. Your firm failed to maintain buildings used in the manufacture, processing, packing or holding of drug products in a good state of repair (21 CFR 211.58).你公司未能维护用于药品生产、加工、包装或存贮的建筑物使其处于良好的修理状态(21 CFR 211.58)。
Our investigators observed significant evidence of waterdamage in your facility, including warped ceiling panels, puddles of water, and water stains. For example, water damage was evident over the (b)(4), and in sky lights, vents, and ceilings above the finished drug product packaging area and in the personnel corridor outside the Quality Control laboratory. 我们的调查人员在你们的工厂发现了严重的水损证据，包括有天花板变形、水洼和水渍。例如，水损痕迹到处都是：XX上面、天窗、排气和制剂包装区域的天花板以及QC化验室外面的人员通道。
In addition, our investigators observed ceiling panels overthe personnel corridor and (b)(4) that were not sealed, allowing ingress of air from the building’s plenum into post-sterilization areas. 此外，我们调查人员还发现人员通道上的天花板以及XX并未密封，使得空气可以从建筑气窗进入至已灭菌的区域。
It is essential that your plant management maintains the facility in a good state of repair to ensure ongoing suitability for drug manufacturing. 你们工厂的管理人员有必要维护设施使其处于良好的维护状态，以确保其持续适合用于药品生产。
In your response, you attribute the water damage to monsoon rains that fell in the days prior to the inspection. However, the observed staining, rusting pipes, and warping of walls and ceiling panels appeared to indicate the presence of longer-term water and humidity problems in somecases.Your response focuses on water leak repairs and some enhanced preventive measures. However, it does not adequately address production management’s daily responsibilities to promptly address facility damage and the potential for fungal contamination to persist in the facility due to moisture problems. 在你们的回复中，人们将水损归咎于检查之前多日雨季降雨。但是，所发现的脏污生锈的管道，以及墙面和天花板变形说明在多处均长期存在有水，还有湿度问题。你们的回复关注于漏水维修，以及一些加强维护的措施。但是，这并不能充分解决生产管理的日常职责问题，未能积极解决工厂毁坏问题以及由于湿气问题导致的工厂内可能顽固存在的霉菌污染问题。
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