近日，FDA发布了Amneal Pharmaceuticals 的警告信，其中提及内毒素检查相关的缺陷，该公司存在内毒素检查过程中：
移液枪使用不规范
未按要求停顿以检查凝胶硬度
第一个内毒素检测人员判读速度过快，无法充分观察或确认整个过程，第二个检测人员仍在确认记录上签字确认
未实时记录阴性结果
在实际观察并确认结果前，已将阳性对照结果判定为合格
FDA在警告信中表示：该公司必须彻底、系统审查其实验室流程、检验方法、设备能力及文件记录操作，以确保符合CGMP要求，并防止未来再次发生类似问题，并要求提供详细的整改计划。
缺陷翻译如下：
During our inspection, we observed the preparation and reading of bacterial endotoxin tests and identified numerous deficiencies:
在检查过程中，我们观察了细菌内毒素试验的准备与结果判读过程，并发现多项缺陷：
Failure to completely discharge the micropipette solution during preparation of water for injection samples, which may compromise the accuracy and reproducibility of the test results.
制备注射用水样品时，未将移液枪中的溶液完全排出，这可能影响测试结果的准确性和可重复性。
Transfer of gel-clot sample tubes from the incubator to the waste container in a single rapid motion during microbiological analysis, without the crucial pause required to inspect the firmness of the gel for endotoxin detection.
微生物测试过程中，将凝胶法（gel-clot）样品管从培养箱转移至废弃物容器过程中，未按要求停顿以检查凝胶硬度，而该步骤对细菌内毒素检测至关重要。
The analyst responsible for the (b)(4) verification of the gel-clot assessment was unable to adequately observe or verify the process due to the primary microbiologist’s rapid assessment. Despite this basic deficiency, the secondary analyst signed off on the verification.
负责凝胶法（b）（4）结果确认的检测人员，因第一个微生物检测人员判读速度过快，无法充分观察或确认整个过程。尽管存在这一基础性缺陷，第二个检测人员仍在确认记录上签字确认。
Inadequate documentation practices when recording sample results of bacterial endotoxin tests for water for injection, including non-contemporaneous documenting of negative sample results and assigning a passing result to a positive control sample prior to the actual observation and confirmation of the result.
记录注射用水内毒素试验样品结果时，记录操作存在不足，包括：未实时记录阴性结果；在实际观察并确认结果前，已将阳性对照结果判定为合格。
In your response, you state that you revised various procedures, provided associated training, retested reserve samples of potentially impacted drug products, and purchased new equipment to increase laboratory automation.
贵公司在回复中表示，已修订多项程序、开展相关培训、对可能受影响药品的留样进行重新检验，并采购新设备以提高实验室自动化水平。
Your response is inadequate due to its limited scope, which primarily addressed the specific deficiencies identified during the FDA inspection. You did not conduct a comprehensive evaluation to determine if similar deficiencies exist in other laboratory operations or address additional opportunities for laboratory equipment automation.
贵公司的回复范围有限，仅针对 FDA 检查中发现的特定缺陷进行了回应，因此回复是不充分的。贵公司未开展全面评估，以确认其他实验室操作中是否存在类似缺陷，也未探讨实验室设备自动化可进一步提升的空间。
It is imperative that your organization conducts a more thorough and systemic review of all laboratory processes, testing methodologies, equipment capabilities, and documentation practices to ensure compliance with CGMP and prevent recurrence of similar issues in the future.
贵公司必须对所有实验室流程、检验方法、设备能力及文件记录操作进行更彻底、系统性的审查，以确保符合CGMP要求，并防止未来再次发生类似问题。
In response to this letter, provide:
回复此函，请提供以下：
A comprehensive assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.
对贵公司的实验室操作、程序、方法、设备、文档记录及分析人员能力进行全面评估。基于该评估，提供详细的整改计划，并说明将如何评估实验室体系整改后的有效性。
A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.
对贵公司生产和实验室操作全流程所使用的文件记录体系进行全面评估，明确文件记录操作存在不足的环节。同时提供详细的CAPA计划，全面整改贵公司文件记录操作，确保在整个操作过程中，所有记录均具备可追溯性、清晰性、完整性、原始性、准确性和实时性。
此前，FDA对百特制药印度工厂的检查中还提及内毒素检查OOS处理不当的缺陷：
You failed to conduct adequate investigations into endotoxin testing and your 100% automated visual inspection system. You conducted investigations that were not thorough, expanded to an appropriate scope, or based on scientifically supported root cause(s). You did not identify and implement appropriate corrective actions and preventive actions (CAPA). Specifically,
你们未能对内毒素检测和100%自动灯检系统进行充分调查。你们进行了不彻底、未能扩展到适当范围或基于科学支持的根本原因的调查。你们没有确定并实施适当的纠正措施和预防措施（CAPA）。具体说来：
Your firm invalidated multiple endotoxin tests for finished products upon discovery of particulate matter in one or more wells used to perform the kinetic-turbidimetric assay (KTA) method. You failed to characterize the particulate matter and attributed the particulates to environmental and laboratory conditions, such as air ducts and activities being performed by personnel in the immediate vicinity of the analysis. You did not definitively identify the source or sources of the particulate matter, define the scope of potentially impacted operations (including potential manufacturing causes), and implement scientifically justified CAPA in a timely manner.
贵公司在用于执行动力学比浊测定（KTA）方法的一个或多个孔中发现颗粒物后，判定多个成品的内毒素测试无效。你们未能确认这些颗粒物，并将颗粒归因于环境和实验室条件，例如空气管道和检测（区域）附近人员正在进行的活动。你们没有明确确定颗粒物的来源，定义可能受影响的范围（包括潜在的生产原因），并及时实施科学合理的 CAPA。
In a previous inspection (May 2022), FDA cited your firm for inadequate investigations into these and other similar out-of-specification (OOS) endotoxin testing that you invalidated due to uncharacterized particulate contamination in one or more wells during KTA analyses. Prior to and during an October 5, 2022 regulatory meeting with your firm, we requested you perform a retrospective assessment of investigations associated with OOS endotoxin results or endotoxin testing deviations. During the current inspection, your personnel explained that these investigations were not reopened or otherwise reassessed. Although you retained a third-party consultant to perform a retrospective assessment of endotoxin investigations associated with OOS endotoxin result investigations, you did not provide the third-party consultant with an investigation cited during the May 2022 inspection. You also did not ensure the assessment included approximately 20 invalidated laboratory tests generated in 2021 and 2022 (including multiple investigations since the May 2022 inspection).
在之前的检查（2022 年 5 月）中，FDA 引用了贵公司对这些和其他类似的不合格 （OOS） 内毒素测试的调查不充分，这些测试在 KTA 分析期间一个或多个孔中存在未表征的颗粒污染被判定无效。在 2022 年 10 月 5 日与贵公司举行监管会议之前和期间，我们要求你们对与 OOS 内毒素结果或内毒素检测偏差相关的调查进行回顾性评估。在本次检查期间，你们的人员解释说，这些调查没有重新开始或以其他方式重新评估。尽管你们聘请了第三方顾问对与 OOS 内毒素结果调查相关的内毒素调查进行回顾性评估，但你们没有向第三方顾问提供 2022 年 5 月检查期间引用的调查。你们也没有确保评估包括 2021 年和 2022 年产生的大约 20 项无效实验室测试（包括自 2022 年 5 月检查以来的多项调查）。
