• 依据一个假定的实验室错误判定OOS结果无效

• 滥用离群值检验判定另一个OOS结果无效

• 利用另一份样品而不是相同样品的检验结果来判定初始OOS结果无效

• OOS根本原因没有确凿证据予以论证

• 回复缺陷时表示玻璃器皿中存在清洗剂残留会导致API降解，但是没有提供数据支持。

• 发现严重的色谱系统数据完整性问题（数据删除、试验性进样、未激活审计追踪、积分不规范、系统适应性非连续进样和重复进样）

• 2015年对色谱系统数据完整性进行自查，发现数据删除、试验性进样、未激活审计追踪等问题，但是没有将审查范围进一步扩大。数据完整性纠正预防措施也无法避免类似问题再次发生，检查发现几个月后仍有数据删除问题出现。

• 后来扩大数据完整性自查范围发现积分不规范、系统适应性非连续进样和重复进样等问题，没能评估检验结果的有效性。

• 没能评估数据完整性违规的根本原因

• 车间清洁消毒记录存在电子数据，这些电子数据被覆盖，只保留了粗略的书面记录。

• 在线粒子系统审计追踪功能没有被激活（只关闭了两天都能被发现！）

• 擅自修改在线粒子数据，没有写明是谁修改和修改了什么

• 无菌操作不规范（FDA要求给出QA监督的频率）

该警告信缺陷摘译如下：

1.      Failure to adequately investigate and document out-of-specification results according to a procedure.

未能根据规程充分调查和记录OOS结果。 

Our review of your out-of-specification (OOS) investigations found that you lacked adequate procedures for investigating, and scientific justification to invalidate, OOS results.

我们审核了你们的OOS调查发现你们缺乏充分的调查程序和无效OOS的科学论证。

OOS Results for Assay

含量OOS结果

You initiated an investigation of an initial OOS assay result for (b)(4) batch (b)(4), which was found to be significantly below specification ((b)(4)–(b)(4)%). You also initiated an investigation of an initial OOS assay result for (b)(4) batch (b)(4), which also yielded a test result below specification ((b)(4)–(b)(4)%).

你们对XX批次XX产品发起了一份含量严重低于标准的OOS结果调查。 你们还发起对（b）（4）批次（b）（4）产品的初始OOS结果的调查，其也产生低于标准（（b）（4） - （b）（4）％）的测试结果。

In both cases, your brief investigations found no anomalies and only stated that it was possible that the sample glassware was not thoroughly cleaned. Although you did not identify a laboratory error and lacked scientific justification, you invalidated the OOS results. Your firm released both batches based on passing retests.

在这两种情况下，你们简短的调查都没有发现任何异常现象，只是说样品玻璃器皿可能没有彻底清洗。尽管你们没有发现实验室错误，也没有科学论证，你们还是判定OOS结果无效。贵公司依据复测的合格结果放行了这两批产品。 

Your acceptance of the passing results based on an assumed laboratory error was insufficient to invalidate the original failing result and conclude the investigation.

你们基于假定的实验室错误判定初始OOS结果无效，结束调查并接受复测结果是不充分的。

Re-analysis of the actual solutions, test units, and glassware is an integral part of an investigation to determine whether a laboratory error may have occurred. This assessment, in tandem with hypothesis testing if initial re-examinations do not reveal a root cause, is instrumental in determining whether there was a causative laboratory error. Whenever a laboratory investigation lacks conclusive evidence of laboratory error, it is essential that the investigation extends to a thorough investigation of potential manufacturing causes.

重新分析实际溶液，测试单元和玻璃器皿以确定是否可能发生实验室错误，是调查中不可或缺的一部分。如果初步重新检查没有揭示根本原因，这种评估与假设检验相结合，有助于确定是否存在成为原因的实验室错误。任何实验室调查缺乏与实验室错误的确凿证据，都必须将调查扩展到对潜在生产原因的彻底调查。

Your response acknowledged that there was “no scientific justification or studies performed to evaluate or prove this hypothetical root cause.”

你们的回复承认“没有执行科学论证或研究来评估或证明这个假设的根本原因。”

Since our inspection, your indicated that you have shown that the API may degrade in the presence of residual detergent in glassware. However, your response did not include your study data.

自我们检查以来，你们表示你们已证明API可能会在玻璃器皿中残留清洗剂的情况下降解。但是，你们的回复不包括你们的研究数据。

OOS Results for Residual Solvent

残留溶剂OOS结果

You initiated investigation P201611001 for an initial OOS result of (b)(4) parts per million (ppm) in your (b)(4)residual solvent test (specification: not more than (b)(4) ppm) for (b)(4) API batch (b)(4). The investigation did not reveal laboratory testing anomalies. You tested another sample preparation three times and obtained results very close to the specification upper limit ((b)(4), and (b)(4) ppm). You invalidated the initial failing result, stating that your statistical analysis showed a significant difference between the original value and the retest results. Your investigation lacked further assessment of the root cause of the failing result.

你们对XX批次XX原料残留溶剂检验XXppm的初始OOS结果发起调查。调查未查出实验室异常。你们检验了另一份样品三次并得到非常接近标准上限的结果。你们判定初始OOS结果无效，并声明你们的统计学分析显示初始值与复测值有显著差异。你们的调查未能进一步评估不合格结果的根本原因。

You released the batch to use as an intermediate in your in-house production of (b)(4) batches of (b)(4) API (batches (b)(4)).

你们放行了这个批次作为中间体用于XX批XX原料药的生产。

It is not appropriate to use an “outlier test” to invalidate your API test results. Such statistical treatments do not identify the cause of an extreme observation and are only of informational use. In this case, your investigation included multiple retests that were near the upper limit of (b)(4) ppm, similar to the original OOS result.

使用离群值检验来判定API检验结果无效是不恰当的。这种统计学处理未能确定极端原因，仅供信息使用。在此事例中，你们的调查包括多个接近标准上限的复测结果，其实与初始OOS结果相似。

Furthermore, your OOS investigation procedure, Q0100012.001, was inadequate because it did not adequately address the need to retest the original sample and specify when a new sample should be tested.

此外，你们的OOS调查规程也不充分，因为它没能充分满足复测原始样品的要求并规定何时应该检验新的样品。 

We acknowledge receipt of your revised OOS investigation procedure. However, your response is inadequate because it does not meet CGMP. Your response stated that you can use an outlier test in determining whether to “waive the requirement for conducting appropriate laboratory investigation to determine definitive or potential root cause(s) for the atypical result(s).” It is inappropriate for your procedure to permit waiver of this requirement. Your OOS procedure should specify that outlier tests cannot be used for anything other than auxiliary, informational purposes.

我们收到了你们修订后的OOS调查规程。但是，你们的回复是不充分的，因为它不符合CGMP。你们的回复说你们还是允许使用离群值检验来决定是否“免去适当的实验室调查以确定异常结果的确切或潜在根本原因的要求。”你们的规程允许免去这些要求是不恰当的。你们的OOS规程应规定离群值检验不能用于辅助，信息目的之外的任何其他方面。

Your response also indicated that your firm was retrospectively assessing effects of previously-reported OOS results on your products. However, your response did not provide related records to document your review or summarize findings. It is unclear whether the retrospective review included an evaluation of your use of the statistical outlier test to invalidate OOS results.

你们的回复还表明贵公司正在回顾性地评估先前报告的OOS结果对产品的影响。但是，你们的回复未提供相关记录以证实你们的回顾或总结结果。目前尚不清楚该回顾性审查是否包括对使用统计学离群值检验判定OOS结果无效的评估。

2.      Failure of your quality unit to ensure that critical deviations are investigated and resolved.

质量部门未能确保关键偏差得到调查和解决。

You did not adequately investigate findings from your February 2015 retrospective review of analytical chromatography data irregularities (e.g., data deletion, sample trial injections, and missing audit trails). You did not sufficiently expand the scope of your limited review to a larger data set when you found significant data integrity lapses. Your investigation was also insufficient because your corrective actions failed to prevent recurrence of major data integrity deviations. For example, our investigators found that your firm deleted the initial chromatographic injection of (b)(4) API, batch (b)(4), during batch release testing performed several months after the retrospective investigation.

你们没有充分调查2015年2月对分析色谱数据不合规（例如，数据删除，样品试验性进样和缺少审核跟踪）的回顾性审查结果。当你们发现严重的数据完整性问题时，你们没有将审查范围充分扩大到更大的数据集。你们的调查也不充分，因为你们的纠正措施无法防止严重数据完整性偏差再次发生。例如，我们的调查人员发现，在该回顾性审查几个月后进行的批放行检验期间，贵公司删除了（b）（4）批（b）（4）API的初始色谱进样。

Your response stated that you performed a further retrospective review (protocol SD-Q0100011.000) of analytical chromatographic data and found further residual solvents results with inappropriate integration, system suitability testing data showing non-consecutive injections of the reference solution, and repeat injections. Your response was inadequate because you did not include sufficient details to demonstrate that you confirmed the validity of initial test results. Such detail would include retest sample testing dates and results, comparison of retest data to original data, and your “comprehensive review records” for the batches included in the assessment. Your response also lacked an assessment of the root cause of data integrity breaches and corrective actions for any products that failed to meet specifications.

你们的回复表明你们进行了进一步的分析色谱数据回顾性审查（方案：SD-Q0100011.000），发现了多个残留溶剂结果包含不恰当积分，系统适用性测试数据显示标准溶液的非连续进样和重复进样。你们的回复不充分，因为你们没有提供足够的详细信息来证明你们确认了初始测试结果的有效性。这些细节包括复测样品样检验日期和结果，重测数据与原始数据的比较，以及评估中包含的批次的“综合审查记录”。你们的回复还缺乏对数据完整性违规的根本原因评估和对任何未能符合标准的产品的纠正措施。

Additional Concerns Related to Aseptic Processing

其他关于无菌工艺的问题

Our investigators found additional examples of incomplete data relating to the sterile manufacturing operations evaluated as part of our pre-approval inspection. For instance, your firm failed to maintain electronic data documenting decontamination cycles for the grade A area of workshop (b)(4) where you aseptically manufacture sterile powders. Your firm overwrote the electronic data and kept only a cursory written record.

我们的调查人员还发现了的与无菌生产操作相关的数据不完整的其他事例，这也作为我们的预批准检查评估的一部分。例如，贵公司未能保存记录无菌粉末生产车间A级区域的清洁消毒周期的电子数据。贵公司覆盖了电子数据，只保留了粗略的书面记录。

You also did not assure reliability of electronic data for monitoring non-viable particles in your manufacturing areas. Our investigators observed that you disabled the electronic audit trail function for your non-viable particle monitoring system for grade A and B areas of workshops (b)(4) and (b)(4) on at least two days in August 2017 when sterile API was manufactured. Also, data files containing particle counts had been modified with no indication of who made the changes or what was modified.

你们还未能确保用于监测生产区域在线粒子的电子数据的可靠性。我们的调查人员发现， 2017年8月至少有两天你们的（b）（4）和（b）（4）区域在线粒子监测系统的电子审计跟踪功能是关闭的，此时仍有无菌API在生产。此外，修改了包含粒子计数的数据文件，但没有写明谁进行了修改和修改了什么。

In your response, you provided a review of these findings. Your firm committed to assess the effects on your products of any additional insufficient non-viable particulate monitoring records since the last FDA inspection in March 2015. Your response was inadequate because you did not provide sufficient data to support your conclusions, or commit to a more comprehensive CAPA to assess data systems integrity.

在你们的回复中，你们提供了对这些缺陷的审查。，贵公司承诺评估自2015年3月上次FDA检查以来其他任何非活性粒子监测记录不充分对产品的影响。你们的回复是不充分，因为没有提供足够的数据来支持你们的结论，或承诺更多全面的CAPA评估数据系统的完整性。

Our inspection also revealed poor aseptic processing operation behaviors. In response to this letter, provide:

我们的检查还发现了无菌生产操作不规范行为。回复此函请提供：

Your plan to assure appropriate aseptic practices and cleanroom behavior during production. Include specific steps to ensure routine supervisory oversight for all production batches. Also describe the frequency of quality assurance oversight during aseptic processing and other operations.

你们确保在生产过程中适当的无菌操作和洁净室行为的计划。包括确保所有生产批次的日常监督监管的具体步骤。同时，描述无菌生产和其他操作过程中QA监督的频率。

Comprehensive identification of all contamination hazards with respect to your aseptic processes, equipment, and facilities. Provide a risk assessment that covers all human interactions with the ISO 5 area, equipment placement and ergonomics, air quality in the ISO 5 area and surrounding room, facility layout, personnel flow, and material flow. Also include a detailed CAPA plan, with timelines, to address the findings of the contamination hazards risk assessment. 

全面识别与无菌工艺，设备和设施相关的所有污染危害。提供风险评估，涵盖所有人员对ISO 5区域（A级）的干扰，设备装配和人体工程学，ISO 5区域和周围房间的空气质量，设施布局，人流和物流。同时，给出详细的CAPA计划，包括时间表，以解决污染危害风险评估的结果。