近日，FDA发布了Yangzhou Sion Commodity Co., Ltd的警告信，其中提及大量实验室数据完整性问题，该公司在缺陷回复中表示：QA经理对GMP要求没有很好的理解：

 

实验室记录数据缺失

 

实验室记录使用涂改液进行修改

检验记录的原始版本和誊抄版本与COA之间不一致

检验过程没有保存原始数据，包括天平打印单、时间、样品准备和设备日志

 

该公司在回复中甩锅QA经理，然而FDA对此回复并不接受。

 

缺陷翻译如下： 

 

CGMP Violations

 

违规行为 

 

During our inspection, our investigators observed specific violations including, but not limited to, the following. CGMP

 

在检查过程中，我们的检查人员发现了以下具体违规行为，包括但不限于：

 

1.Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. Your firm also failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(1) and 211.84(d)(2)). 

 

贵公司未能对原辅料进行鉴定，也未确认其是否符合所有关于纯度、强度和质量的书面标准。贵公司还未能在适当的时间间隔验证并确定原辅料供应商COA的可靠性。 

 

You manufacture over-the-counter (OTC) drug products including(b)(4). Your firm failed to test incoming components used in manufacturing your finished OTC drug products to determine identity, purity, strength, and quality, and your firm did not establish a vendor qualification program for your raw material suppliers. 

 

贵公司生产药品，其中包括（b)(4)。贵公司未对用于生产成品药品的进厂原辅料进行鉴定、纯度、强度和质量检验，并且也未针对原辅料供应商建立供应商确认程序。 

 

Your firm used results from your suppliers’ certificates of analysis (COAs) without establishing the reliability of your suppliers’ analyses through appropriate validation and without conducting at least one specific identity test on each incoming lot of components. You may not rely on your suppliers’ COA to verify the identity of your components. 

 

贵公司在未通过适当验证确定供应商分析结果可靠性，且未对每批进货的成分进行至少一项特定身份测试的情况下，就使用了供应商的分析证书（COA）。

 

贵公司不能依靠供应商的 COA 来验证成分的身份。 

 

In previous correspondence on September 28, 2023, associated with an FDA records request under section 704(a)(4) of the act, your firm committed to performing independent testing, to include identity testing for each shipment of high-risk component, as required by 21 CFR 211.84 (d)(1) & (2), using equivalent or better methods to those in the United States Pharmacopeia (USP). 

 

在 2023 年 9 月 28 日与 FDA 根据该法案第 704 (a)(4) 条提出的记录请求相关的通信中，贵公司承诺按照《联邦法规汇编》第 21 章第 211.84 (d)(1) 和 (2) 条的要求，使用与美国药典（USP）相当或更优的方法，对每批高风险成分进行独立检测，包括进行身份测试。 

 

However during the inspection, and contrary to previous commitments, your firm failed to demonstrate that you adequately tested each shipment of each lot of the incoming components at high-risk of(b)(4) contamination. These include, but are not limited to, testing of (b)(4) solution you used in manufacturing drug products to determine their appropriate identity. Identity testing for these and certain other high-risk drug components1 include a limit test in the USP to ensure that the component meets the relevant safety limits for levels of (b)(4). Because you did not perform identity testing on each shipment of each lot using the USP identification test that detects these hazardous impurities, you failed to assure the acceptability of these components for use in manufacture of your drug products. 

 

然而，在此次检查中，与之前的承诺相悖，贵公司未能证明已对每批存在（b)(4) 污染高风险的进货成分进行了充分检测。这些成分包括但不限于用于生产药品的（b)(4) 溶液，贵公司未对其进行适当的身份检测。对于这些及其他某些高风险药品成分 1 ，身份检测包括美国药典中的一项限度测试，以确保成分的（b)(4) 含量符合相关安全限值。由于贵公司未使用美国药典中能检测这些有害杂质的身份测试方法对每批进货成分进行检测，因此无法保证这些成分可用于药品生产。

 

The use of ingredients contaminated with(b)(4) has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document (b)(4) to help you meet the CGMP requirements when manufacturing drugs containing ingredients at high-risk for (b)(4) contamination at (b)(4). 

 

使用受（b)(4) 污染的成分已在全球范围内导致多起人类致命中毒事件。有关在生产含有高风险（b)(4) 污染成分的药品时如何满足 CGMP 要求，请参阅 FDA 的指导文件（b)(4) ，文件链接为（b)(4)。

 

Additionally, you failed to perform identity testing on the component(b)(4) and lacked adequate impurities testing on (b)(4) before being used in manufacturing. Furthermore, (b)(4) was not adequately monitored for (b)(4). 

 

此外，你们没有对（b)(4) 成分进行身份检测，在将其用于生产前也缺乏足够的杂质检测。而且，对于（b)(4) 中的（b)(4) 也没有进行充分监测。

 

In your response on October 18, 2024, you indicate that you have updated your procedures to mandate the testing of identity and purity of active ingredients and the testing of identity of nonactive ingredients. Your response is inadequate because you did not address your plans for qualification of your component suppliers, did not address your previous commitments to perform identity testing on high-risk components, and failed to clarify whether your firm tested all lots of drug products that you distributed to the United States for risk of(b)(4). You also failed to adequately address quality attributes of your components. 

 

在 2024 年 10 月 18 日的回复中，你们表示已更新程序，要求对活性成分的身份和纯度以及非活性成分的身份进行检测。但你们的回复并不充分，因为你们没有提及对组件供应商进行资质审核的计划，没有回应之前对高风险成分进行身份检测的承诺，也没有说明贵公司是否对运往美国的所有批次药品进行了（b)(4) 风险检测。此外，你们也没有充分说明组件的质量属性。 

 

2.Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22). 

 

贵公司的质量控制部门未能履行其职责，以确保所生产的药品符合药品生产质量管理规范（CGMP），并达到既定的关于药品身份、含量、质量和纯度的标准。

 

Your QU did not provide adequate oversight for the manufacture of your drug products. For example, your QU failed to:

 

你们的质量部门未能为你们的药品的制造提供足够的监督。例如，你们的质量部门未能：

 

Perform assay testing for the strength of the active ingredient in(b)(4) drug products (21 CFR 211.165(b)).

 

对(b)(4)药品中活性成分的含量进行检测。

 

Ensure an adequate stability program (including assessment of product potency over the shelf life) to support your claimed(b)(4) expiry for (b)(4) drug products (21 CFR 211.166). 

 

确保有足够的稳定性计划（包括产品有效期内的效力评估），以支持你们声称的药品有效期（21 CFR 211.166）。 

 

Ensure that personnel had adequate training and experience for the production and analysis of(b)(4) drug products (21 CFR 211.25(a)). 

 

确保工作人员在(b)(4)药品的生产和检验方面有足够的培训和经验（21 CFR 211.25(a)）。

 

Testing is essential to ensure that the drug products you manufacture conform to all pre-determined quality attributes appropriate for their intended use. Because you lacked adequate testing of each batch of your drug products, you do not know whether they conform to all appropriate finished product specifications and are suitable for release to consumers. 

 

检验是必要的，以确保你们生产的药品符合所有既定的质量属性，适合他们的预期用途。由于你们未对每一批药品进行充分的测试，因此你们不知道它们是否符合所有适当的成品标准，是否适合放行。

 

You did not ensure that your QU implemented its basic functions. Your management should immediately and comprehensively assess your company’s manufacturing operations to ensure that your systems, processes, and products meet CGMP. 

 

你们没有确保质量部门实现了其基本职能。你们的管理层应该立即和全面地评估贵公司的生产业务，以确保你们的系统、工艺和产品符合CGMP的要求。 

 

See FDA’s guidance documentQuality Systems Approach to Pharmaceutical CGMP Regulations for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/media/71023/download. 

 

请参阅FDA指南：关于药品CGMP法规的质量体系方法，以帮助实施质量体系和风险管理方：https://www.fda.gov/media/71023/download。 

 

3. Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards (21 CFR 211.194(a)). Your laboratory records lacked complete and original data to support the analyses performed. For example: 

 

贵公司未能确保实验室记录包含来自所有必要测试的完整数据，以确保符合既定的规范和标准（21 CFR 211.194(a)）。 你们的实验室记录缺乏完整的和原始的数据来支持所执行的分析。例如：

 

Your laboratory records included missing data. Furthermore, there were discrepancies between the original and re-written versions of testing records and COAs pertaining to active and non-active ingredients used in the manufacture of OTC drug products. 

 

你们的实验室记录数据缺失。此外，关于药品生产中使用的活性成分和非活性成分的检验记录的原始版本和誊抄版本与COAs之间存在差异。

 

Your firm did not retain original data to support testing of components used to manufacture OTC drug products for the U.S. market. During our inspection, you confirmed that original data, including balance printout slips,(b)(4) times, (b)(4), sample preparations, and equipment logs were not maintained. 

 

贵公司没有保留原始数据来支持所生产药品的部件的检验。在我们的检查过程中，你们确认没有保存原始数据，包括天平打印单、(b)(4)时间、(b)(4)、样品准备和设备日志。

 

The use of correction fluid (white-out) was also observed to make corrections on paper records documenting microbial analyses of finished products and raw materials. These documentation practices raise concerns about the integrity, authenticity, and reliability of all your data, and quality of your drug products. Document control is essential to maintaining an adequate quality system. 

 

还观察到使用涂改液来对成品和原辅料的微生物检验记录进行涂改。这些做法引起了对所有数据的完整性、真实性和可靠性以及药品质量的关切。文件控制对于保持一个适当的质量体系是至关重要的。

 

In your response, you acknowledge that “QA management did not have a sound understanding of CGMP requirements.” You also commit to performing retrospective testing of “materials,” and state that you have updated procedures and re-trained personnel. Your response is inadequate, as you fail to fully consider comprehensive data integrity (DI) remediation to address the gaps and uncertainties caused by a significant adverse pattern of data that was discarded, lost, or not recorded contemporaneously. Additionally, your response did not consider plans to assess your manufacturing operation’s documentation system to determine where they are insufficient. 

 

在你们的回复中，你们承认“QA经理对CGMP要求没有很好的理解”，你们还承诺对“物料”进行回顾性测试，并声明已经更新了SOP并重新培训了人员。你们的回复是不充分的，因为没有充分考虑全面的数据完整性（DI）补救措施，以解决由被丢弃、丢失或未同时记录的重大不利数据模式所造成的差距和不确定性。此外，你们的回复没有考虑评估的你们的生产操作文件体系以确定其不足的计划。

 

Reliability of data is fundamentally compromised when there is a failure to record or maintain complete and accurate records of test results, or conditions associated with all tests. Furthermore, the lack of reliable data compromises the quality unit’s (QU) ability to exercise its function of ensuring compliance to applicable standards. 

 

当未能记录或维护与所有测试相关的测试结果或条件的完整和准确的记录时，数据的可靠性将从根本上受到损害。此外，由于缺乏可靠的数据，也损害了质量部门（QU）行使其确保遵守适用标准的功能的能力。

 

Data Integrity Remediation 

 

数据完整性修正

 

Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant DI practices at https://www.fda.gov/media/119267/download. 

 

你们的质量体系不能充分确保数据的准确性和完整性，以支持所生产药物的安全性、有效性和质量。关于建立和遵循符合CGMP的DI实践的指导，请参阅FDA指南：药物CGMP数据完整性和符合：https://www.fda.gov/media/119267/download

 

We acknowledge that you are using an independent third-party consultant to perform DI training. However, we strongly recommend that you retain an independent third-party qualified consultant to audit your operation and assist in your DI remediation to meet FDA requirements.  

 

我们知道，你们正在使用一个独立的第三方顾问来进行DI培训。然而，我们强烈建议你们聘请一名独立的第三方合格顾问来审计你们的操作，并协助你们的DI补救，以满足FDA的要求。

来源：Internet

关键词： 数据完整性