Warning Letter:日本协和Kyowa Hakko Bio Co., Ltd. 20180810

恨我不成钢

Mr. Yasuo Morita, Regulatory Office Manager

Kyowa Hakko Bio Co., Ltd.

1-1   Kyowa-cho, Hofu-shi, Yamaguchi, Japan 747-8522

Dear Mr. Morita:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Kyowa Hakko Bio Co., Ltd. at 1-1 Kyowa-cho,Hofu-shi, Yamaguchi, from September 4 to 8, 2017.

美国FDA于2017年9月4-8日检查了你们位于日本山口的Kyowa Hakko Bio Co., Ltd.生产场所。

This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutica lingredients (API).

本警告信总结了原料药生产严重违反CGMP的行为。

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your API 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).

由于你们的原料药生产、加工、包装或保存的方法、场所或控制不符合CGMP要求，你们的原料药根据FDCA的501(a)(2)(B)以及21U.S.C. 351(a)(2)(B)被认为是掺假药品。

We reviewed your September 26, 2017, response in detail and acknowledge receipt of your subsequent correspondence.

我们已详细审核了你公司2017年9月26日的回复，并此告知已收到后续通信。

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

检查期间，我们的调查人员发现的具体问题包括但不仅限于以下：

1.      Failure of your quality unit to exercise its responsibility to ensure the API manufactured at your facility are in compliance with CGMP. 你们质量部门未能履行其职责确保在你们工厂生产的API符合CGMP。

Your firm performed retesting or manipulated data after obtaining out-of-specification (OOS) or other unacceptable results. For example, investigation 2016-C-023 stated that the system suitability test (SST) was nonconforming and that “some data were manipulated to meet SST specification” for the high-performance liquid chromatography (HPLC) an alysisof your raw material (b)(4). You attributed the root cause to your firm’s “lack of awareness of the seriousness” of CGMP deviations, and to an “environment where test data could be easily manipulated.” Your investigation stated that you reanalyzed the crude sample and concluded that it met the specification. You provided no further details on the root causes and on the effect of using a system that failed SST to test your raw material.

你公司在得到OOS或其它不可接受的结果之后进行了复测或捏造数据。例如，调查2016-C-023说你们原料XX的HPLC分析的系统适用性测试（SST）不合格，“一些数据是捏造出来以符合SST标准”。你们将根本原因归因于你们公司“缺乏明白CGMP偏差严重性的意识”，以及“易于捏造数据的环境”。你们的调查说你们重复分析了精品样品并得出结论说其符合质量标准。你们未提供更多根本原因以及使用不合格SST系统检测原料的影响的详细内容。

Your response stated that no product in distribution was found to be OOS, but you included no data to support this conclusion. Your response is inadequate. You identified additional data integrity issues, but failed to provide details regarding the corrective measures your firm has implemented.

你们的回复说未发现销售中的产品为OOS，但你们没有放入数据来支持此结论。你们的回复是不充分的。你们发现了更多的数据完整性问题，但未提交关于你们公司已实施的纠正措施的详细信息。

In response to this letter, provide a thorough assessment of your overall system for investigating deviations, discrepancies, OOS results, complaints, and other failures. In addition, provide a retrospective review of all distributed lots within expiry to determine whether your firm released lots not conforming to established specifications or appropriate manufacturing standards.

在回复此函时，请提交一份对你们偏差、差异、OOS结果、投诉和其它失败调查的整体系统的彻底评估。另外，请提供一份对所有已销售且仍在效期内的批准的回顾性审核，确定你们公司是否有放行不符合既定标准或适当生产标准的批次。

For more information about handling failing, OOS,out-of-trend, or other unexpected results and documentation of your investigations, see FDA’s guidance document, Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production, athttps://www.fda.gov/downloads/drugs/guidances/ucm070287.pdf.

更多OOS处理信息请参见官网指南。

2.      Failure to exercise sufficient controls over computerized systems to prevent unauthorized access or changes to data, and failure to have adequate controls to prevent omission of data. 未能对计算机化系统进行充分控制以防止未经授权的访问或对数据的修改，且没有足够的控制防止数据遗漏。

Your firm’s controls over your HPLC systems are inadequate. Some HPLC systems did not have audit trail capability or audit trails enabled. In addition, unique user names and passwords were not required to perform HPLC activities. You stated that you did not create unique user names and passwords sothat operators in different (b)(4) could continue what previous operators had initiated.

你公司对你们HPLC系统的控制是不充分的。一些HPLC系统并无审计追踪能力或审计追踪未激活。另外，未要求有唯一用户名和密码来执行HPLC活动。你们声称你们并未创建唯一用户名和密码，因此不同XX的操作员可以继续之前的操作员已开始的工作。

In your annual product reviews, you used unprotected Excel worksheets to perform calculations and statistical evaluations of production data, such as standard deviation and process capability. These electronic files were not secured to prevent unauthorized changes, and have no change history.

在你们的年度产品回顾中，你们使得了未经保护的EXCEL表格对生产数据进行计算和统计评估，如标准偏差和工艺能力。这些电子文件并未受到保护以防止未经授权的修改，亦无修改历史。

Your firm’s lack of data control calls the reliability of your data into question.

你们公司对数据缺乏控制，导致你们公司数据的可靠性存在问题。

Your response stated that you stopped operating these HPLC systems without audit trail capability. Your response also stated that you will create a procedure for control of your electronic worksheets. Your response is inadequate because you have not assessed the effects of using data from uncontrolled HPLC systems or unsecured worksheets on your products.

你们的回复声称你们已停止使用这些没有审计追踪能力的HPLC系统。你们的回复亦声称你们将建立程序对电子工作表进行控制。你们的回复是不充分的，因为你们并未评估使用不受控制HPLC系统的数据或没有安全保护的工作表对你们产品的影响性。

In response to this letter, provide a comprehensive,independent review of controls and procedures for electronic data generated from all of your laboratory equipment. Based on this review, provide a detailed corrective action and preventive action (CAPA) plan to remediate laboratory systems, including but not limited to data creation, modification, maintenance, retention, and system security. Your plan should also include the process you will use to evaluate CAPA effectiveness.

在回复此函时，请提交一份对你们化验室仪器获得的电子数据的控制和程序的独立全面审核。基于此审核，请提交一份详细的CAPA计划用以补救化验室系统，包括但不仅限于数据创建、修改、维护、保存和系统安全。你们的计划亦应包括你们将用于评估CAPA有效性的流程。

Also see additional requests under the Data Integrity Remediation section below.

亦请参见以下数据完整性补救措施部分里的其它要求。

Repeat observations at multiple sites多个工厂重复缺陷

In a previous warning letter (WL 320-10-009), FDA cited similar CGMP deviations related to your quality unit’s failure to thoroughly investigate and document OOS events. FDA also cited similar CGMP observations at your Ube site during our September 2017 inspection. These repeated failures at multiple sites demonstrate that executive management oversight and controlover the manufacture of drugs is inadequate.

在之前的警告信（WL 320-10-009）中，FDA引用了类似的质量部门未能彻底调查和记录OOS事件的CGMP偏差。FDA在2017年9月检查期间对你们的Ube工厂亦引用了类似缺陷。这些在多个工厂的重复失败说明执行管理人员对药品生产的监管和控制是不充分的。

Your executive management remains responsible for fully resolving all deficiencies, and ensuring ongoing CGMP compliance. You shouldimmediately and comprehensively assess your company’s global manufacturingoperations to ensure that systems and processes, and ultimately, the products manufactured, conform to FDA requirements.

你们的执行管理人员负有解决所有缺陷以及确保持续CGMP合规的义务。你们应立即对你公司的全球生产运作进行全面评估，以确保系统和工艺，以及最终，所生产的产品符合FDA要求。

Data Integrity Remediation 数据完整性补救措施

Your quality system does not adequately ensure the accuracyand integrity of data to support the safety, effectiveness, and quality of thedrugs you manufacture. We acknowledge that you are using a consultant to audit your operation and assist in meeting FDA requirements. Each third party consultant used by your firm must be qualified for their specific assigned function, including data integrity remediation.

你们的质量体系不能充分确保数据的准确性和完整性，无法支持你们生产的药品的安全性、有效性和质量。我们被告知你们正在使用一个顾问审计你们的运作情况，协助符合FDA要求。你们公司所用的每个第三方顾问均必须具备其指定领域的资质，包括数据完整性补救。

In response to this letter, provide the following.

在回复此函时请提交以下资料：

A.    A comprehensive investigation into theextent of the inaccuracies in data records and reporting. Your investigationshould include:一份对数据记录和报告不准确性程度的全面调查。你们的调查应包括

• 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.
• 详细的调查方案和方法学；对评估所覆盖的所有化验室、生产操作和系统的总结，以及对你们意在排除的操作中所有部分的论证。
• 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.
• 与现有的和已离职的员工进行面谈，找出数据不准确的表现、范围、根本原因。我们建议这些面谈由一个有资质的第三方来实施。
• 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.
• 你们工厂数据完整性缺陷的程度的评估。识别出省略、修改、删除、记录销毁、不同步记录填写和其它缺陷。描述你们工厂操作中发现数据完整性问题的所有部分。
• A comprehensive retrospective evaluation of the nature of the testing, manufacturing, and other 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.
• 一份对数据完整性缺陷状况的全面回顾性评估。我们建议由一个有资质的第三方里具有该领域专业水平的专家评估所有数据完整性问题。
  
  

B.   A current risk assessment of the potential effects of the observed failures onthe quality of your drugs. Your assessment should include analysesof the risksto patients caused by the release of drugs affected by a lapse of dataintegrity, and risks posed by ongoing operations.

对你们药品质量中所发现的不合格情况的潜在影响的当前风险评估。你们的评估应包括由于受到数据完整性问题影响的药品放行导致的患者风险的分析，以及持续运营所具有的风险。

C.    A management strategy for your firmthat includes the details of your global corrective action and preventiveaction plan. Your strategy should include:

你们公司的管理策略，包括你们全球CAPA计划详细情况。你们的策略应包括：

• 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.
• 详细的CA计划，描述你们如何确保你们生成的所有数据的可靠性和完整性，包括分析数据、生产记录和所有提交给FDA的数据。
• 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.
• 一份完整的描述你们数据完整性问题的根本原因的描述，包括认定当前行动计划的范围和深度与调查和风险评估发现相称的证据。说明是否对数据完整性问题承担责任的个人仍有能力对你公司对CGMP相关或药物应用数据产生影响。
• 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.
• 临时措施，描述你们已采取的行动，或即将采取用以保护患者确保你们药品质量的努力，例如通知你们的客户、召回产品、实施额外测试、向稳定性试验计划中增加批次以确保稳定性、药品申报行动以及加强投诉监测。
• 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.
• 长期措施，其中描述所有对用以确保你们公司数据完整性的程序、流程、方法、控制、系统、管理监管和人力资源（例如培训、员工提高）的弥补和提升。
• A status report for any of the above activities already underway or completed.
• 对上述活动已开展或已经完成的状态报告。
  
  

Conclusion结论

Deviations cited in this letter are not intended as anall-inclusive list. You are responsible for investigating these deviations, for determining the causes, for preventing their recurrence, and for preventing other deviations in all your facilities.

此函中所引用的违规并不是全部。你们有责任对这些偏差进行调查，确定原因，防止其再次发生，防止其它偏差的发生。

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 thatyou contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effectiveway 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) and 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.

如果你们在考虑要采取的措施可能会导致你们工厂所生产的药品供应中断，FDA要求你立即联系CDER药品短缺负责人员，这样FDA可以与你们一起采用最为高效的方式引导你们的操作符合法规要求。联系药品短缺负责人员还能让你满足依据21 U.S.C. 356C(b)你可能必须报告你们药品中止或中断的义务，让FDA尽快考虑是否需要采取何种措施来避免短缺，保护依赖于你们药品的患者健康。

Until you correct all deviations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug manufacturer.

在贵公司未能完成所有偏差纠正并且由我们确认你们符合CGMP之前，FDA可能会搁置所有将你公司列为药品生产的新申报和增补申报的批准。

Failure to correct these deviations may also result in FDA refusing admission of articles manufactured at Kyowa Hakko Bio Co., Ltd. at 1-1Kyowa-cho, Hofu-shi, Yamaguchi, into the United States under section 801(a)(3)of the FD&C Act, 21 U.S.C. 381(a)(3). Under the same authority, articlesmay be subject to refusal of admission, in that the methods and controls usedin their manufacture do not appear to conform to CGMP within the meaning ofsection 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).

未能纠正这些偏差可能还会导致FDA依据FDCA第801(a)(3)条和21 U.S.C. 381(a)(3)拒绝接受在上述地址生产的产品进入美国。

After you receive this letter, respond to this office inwriting within 15 working days. Specify what you have done since our inspectionto correct your deviations and to prevent their recurrence. If you cannotcomplete corrective actions within 15 working days, state your reasons fordelay and your schedule for completion.

在收到此函后，请在15个工作日内回复至本办公室。在回复中说明自从检查后，你们做了哪些工作来纠正你们的偏差，防止其再次发生。如果不能在15个工作日内完成纠正措施，说明延迟的原因以及完成计划。

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov or mail your reply to:

Towanda Terrell

Compliance Officer

U.S. Food and Drug Administration

White Oak Building 51, Room 4359

10903 New Hampshire Avenue

Silver Spring, MD 20993

USA

Please identify your response with FEI 3002807424.

Sincerely,

/S/

Francis Godwin

Acting Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research

syhorchid

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