FDA为何警告中国药科大学

2月4日，美国食品药品监督管理局（FDA）网站发布对中国药科大学分析测试中心主任沈文斌出具的警告信，指出经现场检查发现，该中心在检测药品活性成分（APIs）时，与现行药品生产质量管理规范 （CGMP）存在重大偏差（significant deviations）。这使得其检测的APIs依据联邦法规被划定为掺假产品。

该警告信在1月23日签发，FDA做现场检查的日期则是2024年9月18日至20日。工作人员发现的分析测试中心的具体偏差包括：实验室记录未能保存完整的测试数据、未能及时提供实验室记录、没有足够措施防止计算机系统未经授权的访问或数据篡改。

警告信还提及，分析测试中心没有建立质量部门（QU）以确保对药品做适当检测并报告检测结果。“当被问及贵公司是否跟踪任何偏差和实验室错误时，你们回答说只提供检测结果。实验室主任表示，公司不参与CGMP活动。但你们的客户将检测数据用于CGMP目的。”

FDA在警告信中要求，分析测试中心针对上述事项提供风险评估及整改计划，在15个工作日内回函。

Dear Mr. Shen:

The U.S. Food and Drug Administration (FDA) inspected your contract testing laboratory, Center for Instrumental Analysis of China Pharmaceutical University, FEI 3005037448, at Zhongyang Road, No. 24 Tongjiaxing Road, Nanjing, Jiangsu, from September 18 to 20, 2024.

This warning letter summarizes significant deviations from Current Good Manufacturing Practice (CGMP) for active pharmaceutical ingredients (APIs).

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, the APIs you tested are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

We reviewed your September 23, 2024 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

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

FDA 于2024 年 9 月 18 日至20 日检查了位于江苏省南京市通嘉兴路 24 号中阳路的中国药科大学仪器分析中心（FEI 3005037448）。本警告信总结了活性药物成分 （API） 与CGMP的重大违规。由于你们的制造、加工、包装或保存方法、设施或控制不符合CGMP，你们所测试的 API 按照FD&C 法案501（a）（2）（B）、21 U.S.C. 351（a）（2）（B）被认定为掺假。我们详细审阅了你们于 2024 年 9 月 23 日对FDA 483的回复，并确认收到你们的后续信件。在我们的检查过程中，我们的检查人员观察到了具体的缺陷，包括但不限于以下：

1. Failure to have laboratory control records that include complete data derived from all laboratory tests conducted to ensure your API and intermediates complies with established specifications and standards.

Your firm is a contract testing laboratory that analyzes APIs and intermediates, including samples of crude(b)(4), (b)(4), and (b)(4) USP, for the presence of (b)(4) using 1H Nuclear Magnetic Resonance spectroscopy (NMR).

Your firm failed to ensure that laboratory testing records were complete. For example, your test record of samples, “(b)(4)(USP) Experiment Records” for Lot (b)(4) contained only two lines of numbers with no explanation headers or titles. During the inspection, you explained that these numbers represented the testing date, lot number, and processing data for (b)(4) samples you analyzed for your customers. Further, the testing records did not document sample preparation, the test procedure(s), and system suitability. Additionally, not all the testing records were reviewed by a second person prior to the results being shared with your customers.

Your firm also failed to ensure that laboratory records were readily available during the inspection. You informed our investigators that your(b)(4) 1H NMR testing data before November 2023 were stored on external hard drives. However, when our investigators requested to review this data, you stated that it might be difficult to locate the data because there were many archived hard drives and only the archiving personnel could retrieve the data. As a result, you did not provide any CGMP data stored on the external hard drives for review during the inspection. We acknowledge that you provided limited data after the inspection.

Additionally, your firm failed to ensure that your computerized systems, such as the computers used to control to the NMR equipment, and to store raw data files or process data, have adequate controls in place to prevent unauthorized access or changes to data. The NMR equipment was also used for academic teaching and research, and it appears that various users shared one login ID with full administrative access.

In your response, you acknowledge your failure to keep adequate records and have now established procedures outlining requirements for laboratory documentation and sample tracking. You also state that you implemented user management settings on your computerized system and completed the system validation.

Your response is inadequate because the procedures appear to lack sufficient detail to be effective. Moreover, you did not consider a retrospective review and risk assessment to evaluate the potential impact of the inadequate documentation and lack of access controls, along with their associated risks, on the validity of your test results.

未能建立实验室控制记录，其中包括从所有实验室测试中获得的完整数据，以确保API 和中间体符合既定规范和标准。贵单位是一家合同检测实验室，使用 1H 核磁共振波谱 （NMR） 分析 API和中间体，包括粗品 （b）（4）、（b）（4） 和 （b）（4） USP 样品中是否存在（b）（4）。贵单位未能确保实验室检测记录完整。例如，你们的样品测试记录，XX批次的“XX（USP）实验记录”仅包含两行数字，没有说明标题或抬头。在检查期间，你们解释说，这些数字代表你们为客户分析的 （b）（4） 样品的检测日期、批号和处理数据。此外，检测记录未记录样品制备、检测程序和系统适用性。此外，在与客户共享结果之前，并非所有测试记录都由第二人审核。贵单位也未能确保在检查期间随时提供实验室记录。你们告知我们的检查人员，你们在2023 年 11 月之前的 （b）（4） 1H NMR 测试数据都存储在外部硬盘驱动器上。但是，当我们的检查人员要求查看此数据时，你们表示可能很难找到数据，因为有许多归档的硬盘驱动器，并且只有归档人员才能检索数据。因此，在检查期间，你们没有提供存储在外部硬盘驱动器上的任何CGMP 数据以供审计。我们也知道你们在检查之后提供了有限的数据。此外，贵单位未能确保你们的计算机化系统（例如用于控制NMR 设备以及存储原始数据文件或过程数据的计算机）具有足够的控制措施来防止未经授权的访问或更改数据。NMR 设备还用于学术教学和研究，似乎不同的用户共享同一个具有完全管理访问权限的登录 ID。在你们的回复中，你们承认未能保存足够的记录，并且现在已经建立了概述实验室文件和样品追溯要求的程序。你们还声明在计算机化系统上实施了用户管理设置并完成了系统验证。你们是回复是不充分的，因为这些程序似乎缺乏足够的细节来确保有效。此外，你们没有考虑进行回顾性审查和风险评估，以评估文件不充分和缺乏访问控制及其相关风险对测试结果有效性的潜在影响。

In response to this letter, provide:

作为对这封信的回复，请提供:

A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:

一份全面的评估和整改计划，以确保质量部门（QU）被授予足够的权力和资源，以有效履行其职能。该评估还应包括但不限于以下内容：

o A determination of whether procedures used by your firm are robust and appropriate.

确定公司所使用的程序是否健全且适用。

o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.

QU在公司运营的各个环节进行监督，以评估是否遵守了适当的规范。

o A complete and final review of the laboratory record for each sample and its related information before the QU disposition decision.

在QU做出处置决定之前，对每个样品的实验室记录及其相关信息进行全面且最终的审查。

o Oversight and approval of investigations and discharging of all other QU duties to ensure validity of the laboratory test results without having negative impact on identity, strength, quality, and purity of your customers’ drug products.

对调查进行监督和批准，并履行所有其他QU职责，以确保实验室检测结果的有效性，不会对客户药品的鉴别、规格、质量或纯度产生负面影响。

A comprehensive, independent assessment of your change management system. This assessment should include, but not be limited to, your procedures to ensure changes, such as changes to or deviations from a validated test method, are justified, reviewed, investigated, and approved by your QU. Your change management program should also include provisions for determining change effectiveness.

对您的变更管理系统进行全面、独立的评估。该评估应包括但不限于，您的程序，以确保变更，如变更或偏离已验证的检测方法，经过论证、审核、调查，并由您的QU批准。您的变更管理计划还应该包括确定变更有效性的条款。

An adequate QU overseeing all elements of CGMP is necessary to consistently ensure drug product quality. Your firm’s quality systems are inadequate. See FDA’s current thinking on quality systems in the FDA guidance documentQuality Systems Approach to Pharmaceutical CGMP Regulations at https://www.fda.gov/media/71023/download for help in implementing quality systems and risk management approaches.

为了始终如一地确保药品质量，有必要建立一个充分的质量管理体系来监督CGMP的所有要素。你们公司的质量体系不完善。参见网址：https://www.fda.gov/media/71023/download中FDA指南《制药CGMP法规的质量系统方法》中FDA对质量体系的最新想法，以帮助实施质量体系和风险管理方法。

Drug Testing Ceased

药品检测的停止

We acknowledge your commitment to cease all drug testing services for the U.S. market. In response to this letter, clarify whether and when you intend to resume drug testing for the U.S. market at this facility in the future.

我们确认您承诺停止美国市场的所有药品检测服务。作为对这封信的回复，请澄清您是否以及何时打算在该机构恢复美国市场的药品检测。

If you plan to resume any CGMP operations regulated under the FD&C Act, notify this office before resuming your operations. You are responsible for resolving all deficiencies and systemic flaws to ensure your firm is capable of ongoing CGMP compliance.

如果您计划恢复FD&C法案规定的任何CGMP操作，请在恢复操作前通知本办公室。您有责任解决所有的不足和系统缺陷，以确保您的公司能够持续符合CGMP。

Responsibilities of a Contract Testing Lab

合同检测实验室的职责

FDA considers contractors as extensions of the manufacturer’s own facility. Your failure to comply with CGMP may affect the quality, safety, and efficacy of the drugs you test for your customers. It is essential that you understand your responsibility to operate in full compliance with CGMP, and that you inform all your customers of any out-of-specification results or significant problems encountered during the testing of these drugs.

FDA认为合同商是生产商自有设施的延伸。您未能遵守CGMP可能会影响您为客户检测的药品的质量、安全性和有效性。您必须理解您完全按照CGMP进行操作的责任，并告知您的所有客户在这些药品的检测过程中遇到的任何不合格结果或重大问题。

CGMP Consultant Recommended

CGMP顾问建议

Based upon the nature of the deviations we identified at your firm, you should engage a consultant qualified to evaluate your operations to assist your firm in meeting CGMP requirements.

根据我们在贵公司发现的偏差的性质，贵公司应该聘请有资质的顾问来评估贵公司的运营，以帮助贵公司达到CGMP的要求。

Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

您使用顾问并不能解除贵公司遵守CGMP的义务。贵公司的执行管理层仍然负责解决所有的不足和系统缺陷，以确保持续的CGMP合规性。

Conclusion

结论

Correct any deviations promptly. FDA may withhold approval of new applications or supplements listing your firm as a manufacturer until any deviations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to any deviations.

及时纠正任何偏差。FDA可能会拒绝批准将贵公司列为生产商的新申请或补充申请，直到任何偏差得到完全解决，并且我们确认贵公司符合CGMP。我们可能会重新检查，以确认您已经完成了对任何偏差的纠正措施。

Failure to address any deviations may also result in the FDA refusing admission of articles manufactured by your customers and tested at the Center for Instrumental Analysis of China Pharmaceutical University, at Zhongyang Road, No. 24 Tongjiaxing Road, Nanjing, Jiangsu, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority that appear to be adulterated may be detained or refused admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).

根据《FD&C法案》第801(a)(3)节，21 U.S.C. 381(a)(3 ),未能解决任何偏差还可能导致美国食品和药物管理局拒绝允许您的客户生产并在中国药科大学仪器分析中心(位于江苏省南京市童家巷路24号中央路)检测的物品进入美国。根据《FD&C法案》第501(a)(2)(B)节,《美国法典》第21卷第351(a)(2)(B)节的含义，在此授权下的似乎掺假的物品可能会被扣留或拒绝入境，因为其生产中使用的方法和控制措施似乎不符合CGMP。

This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done to address any deviations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

这封信通知您我们的发现，并为您提供解决上述不足的机会。收到此信后，请在15个工作日内以书面形式回复本办公室。请具体说明您为解决任何偏差并防止其再次发生所做的工作。作为对这封信的回复，您可以提供更多信息供我们考虑，因为我们将继续评估您的活动和规范。如果您不能在15个工作日内完成纠正措施，请说明您延迟的原因和您的完成时间表。

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3005057567 and ATTN: Emily Wu.

将您的电子回复发送到CDER-OC-OMQ-Communications@fda.hhs.gov。回复中明确标明FEI 3005057567，收件人:Emily Wu。

以下是对中药科大学仪器分析中心缺陷的总结：