引言

        2024年6月初，恒瑞医药的一处生产场地收到了483表格，历经一个月左右的时间，FDA还是公布了对江苏恒瑞医药有限公司的警告信，本次警告信仍然是对恒瑞医药位于连云港的一处制剂生产场地，恒瑞医药其它公司未受到影响。

正文

July 11, 2024
7月 11， 2024

Dear Mr. Dai:
尊敬的戴先生：

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Jiangsu Hengrui Pharmaceuticals Co., Ltd., FEI 3007373503, at 38 Huanghe Road, Economic and Technological Development Zone, Lianyungang, from January 8 to 16, 2024.
美国食品药品监督管理局（FDA）于2024年1月8日至16日检查了位于连云港经济技术开发区黄河路38号的药品生产设施江苏恒瑞药业有限公司（FEI 3007373503）。

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).
本警告信总结了成品药严重违反现行药品生产质量管理规范 （CGMP） 法规的行为。请参考联邦法规 （CFR） 第 21 篇第 210 和 211 部分（21 CFR 第 210 和 211 部分）。

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug product 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).
由于贵司的生产、加工、包装或保存的方法、设施或控制不符合CGMP要求，贵司的药品根据《联邦食品、药品和化妆品法》(FD&C Act)第501(a)(2)(B)条和21 U.S.C. 351(a)(2)(B)条的规定被认定为掺假。

We reviewed your March 7, 2024 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
我们详细审查了贵司 2024 年 3 月 7 日对 FDA 483 表格的回复，并确认收到随后的信件。

During our inspection, our investigators observed specific violations including, but not limited to, the following.
在我们的检查过程中，我们的调查人员观察到了具体的违规行为，包括但不限于以下内容。

1. 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).
1. 贵公司的质量控制部门未能履行其职责，确保生产的药品符合CGMP标准，并符合既定的特性、 规格 、质量和纯度规范（21 CFR 211.22）。

Your firm failed to provide adequate oversight and ensure the reliability of data related to the quality of finished drug products manufactured at your facility. For example, our inspection documented serious quality assurance (QA) deficiencies, such as discarded original CGMP records found stacked in a bag underneath a vehicle and in a nearby trash can, as well as your production manager’s unrestricted access to blank production batch records and other CGMP documents without QA issuance. Your QA department was not exercising its basic responsibilities for the oversight and control over the adequacy and reliability of all CGMP data at your facility. In addition, your QA department is responsible for ensuring your employees understand and adhere to batch issuance procedures and data integrity principles.
贵公司未能提供足够的监督并确保与贵工厂生产的成品药品质量相关的数据的可靠性。例如，我们的检查记录了严重的质量保证缺陷，例如发现废弃的原始CGMP记录堆放在车辆下方的袋子里和附近的垃圾桶里，以及贵工厂的生产经理在没有QA授权的情况下无限制地访问空白的生产批记录和其他CGMP文件。贵司的QA部门没有履行监督和控制贵工厂所有CGMP数据充分性和可靠性的基本职责。另外，贵司的QA部门负责确保员工理解并遵守批签发程序和数据完整性原则。

Your production manager repeatedly accessed and printed uncontrolled blank copies of production records, media fill records, visual inspection records, process validation batch records, and cleaning validation records saved on his computer or through your document management system. When production employees reported an “error” in a record, your production manager printed a blank copy and had the employee transcribe the information on the new record and discarded the old record. There is no assurance that archived data is original or accurate.
贵司的生产经理反复访问和打印保存在其计算机上或贵司的文件管理系统中不受控制的空白生产记录、介质填充记录、目视检查记录、工艺验证批记录和清洗验证记录，当生产员工报告记录中的“错误”时，贵司的生产经理打印一份空白记录副本，让员工誊写在新记录上，并丢弃旧记录。不能保证存档的数据是原始的或准确的。

In your response, you indicate you will perform a risk re-assessment on your document management software for better controls. You created new procedures for document destruction, revised existing procedures, and trained your employees on the new and revised procedures.
在回复中，贵司表示将对文档管理软件进行风险重新评估，以便更好地进行控制。贵司创建了新的文档销毁程序，修订了其它现有程序，并对员工进行了新的和修订的程序进行培训。

Your response is inadequate. Your response does not include a comprehensive assessment into employees creating new records to correct errors, and you do not identify the root cause or scope of the “errors” made with potential impact to CGMP documents and data.
贵司的回答是不充分的。回复不包括对员工创建新记录以纠正错误的全面评估，并且贵司没有确定对CGMP文档和数据产生潜在影响的“错误”的根本原因或范围。

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 QA department is given the authority and resources to effectively function. The assessment should also include, but not be limited to:
    o A determination of whether procedures used by your firm are robust and appropriate
    o Provisions for QA oversight throughout your operations to evaluate adherence to appropriate practices
    o A complete and final review of each batch and its related information before the QA disposition decision
    o Oversight and approval of investigations and discharging of all other QA duties to ensure identity, strength, quality, and purity of all products
• Describe how senior and executive management supports QA and reliable operations, including but not limited to, timely provision of resources to proactively address emerging manufacturing/quality issues and to assure a continuing state of control.
• A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed corrective and preventive action (CAPA) plan that comprehensively remediates your firm’s documentation practices to ensure you retain contemporaneous, attributable, legible, complete, original, and accurate records throughout your operation.
• Describe your plans to prevent manipulation and enhance control of all CGMP records. Specifically, describe your reconciliation and integrity improvements for all CGMP records that may be in loose form or otherwise vulnerable to manipulation. Based on an independent review by a qualified consultant, provide a gap analysis and specific CAPA measures you will take to safeguard integrity of records (e.g., recording data in logbooks, pre-paginated documents, and validated electronic systems).
• 全面的评估和整改计划，以确保 QA 部门获得有效运作的权力和资源。评估还应包括但不限于：
    o 确定贵公司使用的程序是否健全和适当
    o 在整个运营过程中提供 QA 监督，以评估对适当做法的遵守情况
    o 在QA处置决定之前，对每批次及其相关信息进行全面和最终的审查
    o 监督和批准调查并履行所有其他 QA 职责，以确保所有产品的特性、规格、质量和纯度
• 描述高级管理层和执行管理层如何支持质量保证和可靠运营，包括但不限于及时提供资源以主动解决新出现的生产/质量问题并确保持续的控制状态。
• 对整个生产和实验室操作中使用的文档系统进行全面评估，以确定文档操作不足的地方。包括详细的纠正和预防措施 （CAPA） 计划，全面修复贵公司的文档操作，以确保在整个运营过程中保留同期的、可归因的、清晰的、完整的、原始的和准确的记录。
• 描述贵司为防止操纵和加强对所有CGMP记录控制的计划。具体来说，描述贵司对所有可能形式松散或容易被操纵的CGMP记录的核对和完整性改进计划。根据合格顾问的独立审核，提供差距分析和贵司将采取的具体CAPA措施，以保障记录的完整性(例如，在日志、预分页文件和验证的电子系统中记录数据)。

2. Your firm failed to perform operations within specifically defined areas of adequate size and to have separate or defined areas or such other control systems necessary to prevent contamination or mix-ups in aseptic processing areas (21 CFR 211.42(c)(10)).
2. 贵公司未能在特定的足够大小的区域内开展业务，也没有单独或定义的区域或防止无菌加工区域污染或混淆所需的其他控制系统（21 CFR 211.42（c）（10））。

Inadequate Design of Facility
设施设计不足

There is inadequate physical separation between Grade A and Grade B classified areas to ensure appropriate conditions for the aseptic manufacture of sterile drugs at your facility. For example, the “transitional” Grade A areas on either side of the(b)(4) conventional filling machine are where production employees transfer (b)(4) sterile equipment for assembly and (b)(4) vials of drug products for (b)(4). The transitional Grade A areas and surrounding Grade B areas are separated only by an (b)(4). This design does not provide adequate protection and can compromise the sterility of the (b)(4) drug products and the sterile equipment.
A 级和 B 级分类区域之间的物理分隔不足，无法确保在贵司的设施中进行无菌生产的适当条件。例如，（b）（4）传统灌装机两侧的“过渡”A级区域是生产员工转移（b）（4）无菌设备进行组装的地方，以及（b）（4）小瓶药品用于（b）（4）的地方。过渡性A级区域和周围的B级区域仅由（b）（4）分隔。这种设计不能提供足够的保护，并且可能会损害（b）（4）药品和无菌设备的无菌性。

Additionally, your drug product contact equipment and utensils are sterilized and transferred(b)(4) through this Grade A and Grade B open air transition area which may compromise sterility.
此外，贵司的药品接触设备和器具经过灭菌并通过 A 级和 B 级敞开过渡区转移 （b）（4），这可能会影响无菌性。

Furthermore, you lacked smoke studies to demonstrate the airflow in the transition between the Grade A and Grade B areas outside of the filling machine. Thorough smoke studies are essential to evaluate and qualify your aseptic processing operations and ensure appropriate implementation of needed design remediations.
此外，贵司缺乏烟雾研究来证明灌装机外部 A 级和 B 级区域之间过渡的气流。彻底的烟雾研究对于评估和鉴定贵司的无菌处理操作以及确保适当实施所需的设计整改措施至关重要。

Lastly, the cart used to transfer(b)(4) drug product vials to the (b)(4), is open on both the front and rear sides. Air turbulence was visible in the smoke study video when the transfer cart moved through the Grade B area. Furthermore, during the transfer of (b)(4) vials, non-viable particles are not being monitored in the transfer cart, only a settling plate is used for environmental monitoring.
最后，用于将 （b）（4） 药品小瓶转移到 （b）（4） 的推车的正面和背面都是打开的。当转运车穿过 B 级区域时，烟雾研究视频中可以看到空气湍流。此外，在（b）（4）小瓶的转移过程中，转移车中没有监测非活颗粒，仅使用沉降板进行环境监测。

In your response, you commit to(b)(4) between the Grade A transitional area and the adjacent Grade B area on the (b)(4) of the filling machine to provide better protection. You acknowledge in your response that airflow in the areas between the Grade A transitional area and Grade B area are not characterized and you commit to evaluate these airflows through execution of smoke studies. You commit to (b)(4) sterilized equipment and validate the new loading patterns of the (b)(4) equipment.
在贵司的回复中，贵司承诺在灌装机 （b）（4） 的 A 级过渡区域和相邻的 B 级区域之间设置 （b）（4），以提供更好的保护。贵司在回复中承认，A 级过渡区域和 B 级区域之间的气流没有特征，并且贵司承诺通过执行烟雾研究来评估这些气流。贵司承诺对 （b）（4） 灭菌设备进行消毒，并验证 （b）（4） 设备的新装载模式。

Your response is inadequate. Although you commit to(b)(4) of the barrier of the Grade A laminar flow transition area you do not provide a risk assessment on the contamination hazards and lack of sterility assurance of having inadequate protection between the room Grade A area and Grade B area. In addition, the smoke study provided demonstrating the air visualization between the Grade A and Grade B areas is not dynamic and does not provide an operational view of the airflow during production. Furthermore, in your response and change control document you do not propose placing sterilization (b)(4) protection on all sterilized equipment transferred into the Grade A and Grade B transition areas.
贵司的回答是不充分的。尽管贵司承诺 A 级层流过渡区域的屏障 （b）（4），但贵司没有提供关于污染危害和缺乏无菌性的风险评估，以确保房间 A 级区域和 B 级区域之间的保护不足。此外，提供的烟雾研究演示了 A 级和 B 级区域之间的空气可视化不是动态的，并且不提供生产过程中气流的操作视图。此外，在贵司的回复和变更控制文件中，贵司不建议对转移到 A 级和 B 级过渡区域的所有灭菌设备进行灭菌 （b）（4） 保护。

In response to this letter, provide:
作为对这封信的回复，请提供：

• Comprehensive risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities, including an independent assessment that includes, but is not limited to:
    o All human interactions within the ISO 5 area
    o Equipment placement and ergonomics
    o Air quality in the ISO 5 area and surrounding room
    o Facility layout
    o Personnel Flows and Material Flows (throughout all rooms used to conduct and support sterile operations)
• A detailed remediation plan with timelines to address the findings of the contamination hazards risk assessment. Describe specific tangible improvements to be made to aseptic processing operation design and control.
• 对无菌工艺、设备和设施的所有污染危害进行全面风险评估，包括独立评估，包括但不限于：
    o ISO 5 区域内的所有人机互动
    o 设备放置和人体工程学
    o ISO 5 区域和周围房间的空气质量
    o 设施布局
    o 人流和物流（用于进行和支持无菌操作的所有房间）
• 详细的整改计划，并附有解决污染危害风险评估结果的时间表。描述对无菌处理操作设计和控制要进行的具体切实改进。

Data Integrity Remediation
数据完整性修复

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 documentData Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/119267/download.
贵司的质量体系无法充分确保数据的准确性和完整性，以支持贵司生产的药物的安全性、有效性和质量。请参阅FDA的指导文件数据完整性和药物CGMP合规性，以获取有关在 https://www.fda.gov/media/119267/download 建立和遵循符合CGMP标准的数据完整性实践的指导。

We acknowledge that you are using a consultant to audit your operation and assist in meeting FDA requirements. In response to this letter, provide:
我们承认贵司正在使用顾问来审核贵司的操作并协助满足FDA的要求。作为对这封信的回复，请提供：

A. A comprehensive investigation into the extent of the inaccuracies in data records and reporting. Your investigation should include:
• A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and a justification for any part of your operation that you propose to exclude.
• Interviews of current and former employees to identify the nature, scope, and root cause of data inaccuracies. We recommend that these interviews be conducted by a qualified third party.
• An assessment of the extent of data integrity deficiencies at your facility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility’s operations in which you discovered data integrity lapses.
• A comprehensive retrospective evaluation of the nature of the testing and manufacturing data integrity deficiencies. We recommend that a qualified third party with specific expertise in the area where potential breaches were identified should evaluate all data integrity lapses.
对数据记录和报告的不准确程度进行全面调查。贵司的调查应包括：
• 详细的调查协议和方法;评估涵盖的所有实验室、生产操作和系统的摘要;以及贵司打算清除任何部分的理由。
• 对现任和前任员工进行访谈，以确定数据不准确的性质、范围和根本原因。我们建议由合格的第三方进行这些访谈。
• 评估贵司设施的数据完整性缺陷程度。识别遗漏、更改、删除、记录销毁、非同时期记录完成和其他缺陷。描述贵司发现数据完整性漏洞的设施运营的所有部分。
• 对检验和生产数据完整性的缺陷进行全面的回顾性评估。我们建议寻找具有特定专业知识的合格第三方对发现潜在违规行为的所有数据完整性漏洞进行评估。

B. A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity and analyses of the risks posed by ongoing operations.
B.所观察到的缺陷对药品质量的潜在影响进行风险评估。贵司的评估应包括对因数据完整性失效而影响放行的药品对患者造成风险的分析，以及对正在进行的操作带来的风险的分析。

C. A management strategy for your firm that includes the details of your global corrective action and preventive action plan. Your strategy should include these elements:
• A detailed corrective action plan that describes how you intend to ensure the reliability and completeness of all the data you generate including analytical data, manufacturing records, and all data submitted to FDA.
• A comprehensive description of the root causes of your data integrity lapses including evidence that the scope and depth of the current action plan is commensurate with the findings of the investigation and risk assessment. Indicate whether individuals responsible for data integrity lapses remain able to influence CGMP-related or drug application data at your firm.
• Interim measures describing the actions you have taken or will take to protect patients and to ensure the quality of your drugs, such as notifying your customers, recalling product, conducting additional testing, adding lots to your stability programs to assure stability, drug application actions, and enhanced complaint monitoring.
• Long-term measures describing any remediation efforts and enhancements to procedures, processes, methods, controls, systems, management oversight, and human resources (e.g., training, staffing improvements) designed to ensure the integrity of your company’s data.
• A commitment to have a qualified consultant conduct extensive annual audits, for at least two years, to assist in evaluating CAPA effectiveness after you have executed your data integrity remediation protocol.
• Inform FDA if you will be hiring a Chief Integrity Officer who is fully empowered to maintain anonymity of employees who report data integrity concerns and with authority to investigate potential breaches.
• A status report for any of the above activities already underway or completed.
C. 贵公司的管理策略，包括贵司的全球纠正措施和预防措施计划的详细信息。贵司的策略应包括以下要素：
• 详细的纠正措施计划，描述贵司打算如何确保贵司生成的所有数据的可靠性和完整性，包括分析数据、生产记录以及提交给 FDA 的所有数据。
• 全面描述数据完整性失误的根本原因，包括证明当前行动计划的范围和深度与调查结果和风险评估结果相称的证据。说明对数据完整性失败负责的个人是否仍然能够影响贵公司的CGMP相关数据或药品应用数据。
• 描述贵司为保护患者和确保药物质量而采取或将要采取的行动的临时措施，例如通知贵司的客户、召回产品、进行额外检验、增加稳定性计划以确保稳定性、药物应用行动和加强投诉监控。
• 描述任何整改措施和对程序、流程、方法、控制、系统、管理监督和人力资源（例如，培训、人员配备）的改进，旨在确保公司数据的完整性。
•承诺在贵司执行数据完整性整改方案后，聘请合格的顾问进行至少两年的广泛年度审计，以协助评估CAPA的有效性。。
• 如果贵司要聘请首席诚信官，请告知FDA，该首席诚信官完全有权对报告数据完整性问题的员工保持匿名，并有权调查潜在的违规行为。
• 已经进行或完成的上述任何活动的状况报告。

Conclusion
结论

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.
本信中引用的违规行为并不是贵司设施中存在的所有违规行为的清单。贵司有责任调查和确定任何违规行为的原因，并防止其再次发生或其他违规行为的发生。

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b). This also allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.
如果贵司正在考虑采取可能导致贵工厂生产的药品供应中断的行动，FDA要求贵司立即联系CDER的药品短缺工作人员(drugshortages@fda.hhs.gov)，以便FDA可以与贵司合作，以最有效的方式使贵司的运营符合法律规定。根据21 U.S.C. 356C(b)的规定，联系药品短缺工作人员还可以让贵司履行报告药品停产或中断的任何义务。这也使FDA能够尽快考虑可能需要采取何种行动(如果有的话)来避免短缺并保护依赖贵司产品的患者的健康。。

Correct any violations promptly. FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any violations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to any violations.
及时纠正任何违规行为。FDA可能会拒绝批准将贵公司列为药品生产商的新申请或补充申请，直到任何违规行为得到完全解决，并且我们确认贵司遵守CGMP的规定。我们可能会重新检查，以验证贵司是否已完成对任何违规行为的纠正措施。

Failure to address any violations may also result in the FDA refusing admission of articles manufactured at Jiangsu Hengrui Pharmaceuticals Co., Ltd., 38 Huanghe Road, Economic and Technological Dev Zone, Lianyungang, Jiangsu, China 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).
如果不解决任何违规行为，还可能导致FDA根据FD&C法案第801（a）（3）条（21 U.S.C. 381（a）（3））拒绝允许中国江苏恒瑞制药有限公司（位于中国江苏连云港经济技术开发区黄河路38号）生产的产品进入美国。根据该授权，看似掺假的药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似乎不符合《FD&C法案》第501（a）（2）（B）条所指的CGMP，21 U.S.C. 351（a）（2）（B）。

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 days1. Specify what you have done to address any violations 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.
本函通知贵司我们的调查结果，并为贵司提供解决上述缺陷的机会。收到此信函后，请在 15 个工作日内以书面形式回复本办公室。具体说明贵司为解决任何违规行为并防止其再次发生而采取的措施。作为对本函的回复，贵司可以在我们继续评估贵司的活动和做法时提供其他信息供我们考虑。如果贵司无法在 15 个工作日内完成纠正措施，请说明贵司的延迟原因和完成时间表。

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3007373503 and ATTN: Erika V. Butler.
将贵司的电子回复发送给 CDER-OC-OMQ-Communications@fda.hhs.gov。通过 FEI 3007373503 和 ATTN：Erika V. Butler 确定贵司的回复。

Sincerely,

Francis Godwin

Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research