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ViaUPS Warning Letter 320-17-04 Return Receipt Requested November 8, 2016 Mr. Hideo Tagashira President Sekisui Medical Co., Ltd. 3-13-5, Nihombashi, Chuo-ku Tokyo 103-0027 Japan Dear Mr. Tagashira: The U.S. Food and Drug Administration (FDA) inspected your drugmanufacturing facility, Sekisui Medical Co., Ltd., at 4-115 Matsuo,Hachimantai, Iwate, from June 13 to 17, 2016. FDA在2016年6月13-17日检查了你们在岩手的生产场所。 This warning letter summarizes significant deviations from current goodmanufacturing practice (C GMP) for active pharmaceutical ingredients (API). 本警告信总结了你们原料药生产CGMP严重违规情况。 Because your methods, facilities, or controls for manufacturing,processing, packing, or holding do not conform to CGMP, your API areadulterated 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). 由于你们生产、加工、包装和保存的方法、设施和控制不符合CGMP要求，你们的药品根据FDCA的定义被认为是掺假药品。 We reviewed your July 8, 2016, response in detail and acknowledge receiptof your subsequent correspondence. 我们详细审核了你们于2016年7月8日及随后发来的回复。 During our inspection, our investigator observed specific deviationsincluding, but not limited to, the following. 在我们检查期间，我们的调查人员发现的违规情况包括但不仅限于以下： 1. Failure to maintain complete data derived from alllaboratory tests conducted to ensure compliance with established APIspecifications and standards. 未能维护化验室实施用以确保产品符合既定的原料药质量标准的测试中所产生的完整数据。 Our investigator found that you failed to maintain complete data from alllaboratory analyses, and that you relied on the incomplete information todetermine whether your drugs met established specifications. For example: 我们的调查人员发现你们未能维护所有化验室分析中产生的完整性数据，你们依赖这些不完整的信息决策你们的药品是否符合既定的质量标准。例如： a. Numerous data files were found in the recycle binfolder on the computer connected to gas chromatography instruments GC-4 andGC-6. Specifically, our investigator found deleted data for residual solventtesting for (b)(4) lot (b)(4) in the recycle bin. Your recordsshow that you retested the lot without documented justification or aninvestigation. You retained only the final test result. 在与气相色谱仪器GC-4和GC-6连接的计算机的回收站文件夹里发现大量数据文件。具体情况是这样的，我们的调查人员在回收站里发现了被删除的某某批号的残留溶剂检测数据。你们的记录显示你们重新检测了这个批号，但没有文件记录的论证，也没有调查。你们只保存了最后的检测结果。 b. During the inspection our investigator requestedresidual solvent release test data for two of your API, (b)(4) and (b)(4).You were unable to retrieve this data. 在检查期间，我们的调查人员要求查看2批原料药的残留溶剂放行检测数据。你们无法恢复这些数据。 Any data created as part of a CGMP record must be retained so that it canbe evaluated by the quality unit as part of release criteria and maintained forCGMP purposes. 所有作为CGMP记录创建的数据都必须保存，这样才能由质量部门作为放行标准的一部分进行评估，并且为符合CGMP要求而进行保存。 We acknowledge that you commit to revising your SOP for archiving data.Your response is inadequate because it does not explain your failure tomaintain complete records prior to the inspection. You also did not addressvalidation of the systems you use to archive your data. 我们知晓你们承诺要修订你们归档数据的SOP。你们的回复是不充分的，因为这并没能解释你们未能在检查之前维护完整记录的原因。你们也没有说明你们用来归档数据的系统的验证问题。 2. Failure to prevent unauthorized access or changes todata, and failure to provide adequate controls to prevent omission of data. 未能防止未经授权的进入或更改数据，未能提供足够的控制来防止数据删除。 Our investigator observed that your laboratory systems lacked controls toprevent deletion of and alterations to electronic raw data. You do not haveadequate controls for seven of (b)(4) high performance liquidchromatography (HPLC) systems and one of (b)(4) gas chromatographysystems. For example, the audit trail on HPLC 15 did not record the (b)(4)batch (b)(4) assay. Your records indicate that the assay was performedon March 3, 2014, but your audit trail shows no assays performed betweenFebruary 28 and March 4, 2014. Moreover, your analyst demonstrated to ourinvestigator that he could change the data, including injection time and date,without the changes being captured in the audit trail, prior to printing theresults. 我们的调查人员发现你们化验室系统缺乏控制，不能防止对电子原始数据的删除和修改。你们的9台HPLC系统和1台GC系统都没有充分的控制。例如，HPLC15的审计追踪没有记录某批次的含量。你们的记录显示含量是在2014年3月3日检测的，但你们的审计追踪显示在2014年2月28日至3月4日之间都没有检测过含量。还有，你们的化验员向我们的调查人员证实他可以在结果打印之前更改数据，包括进样时间和日期，并且其操作是审计追踪无法捕获的。 We acknowledge that you have committed to upgrading your analyticalsystems to be compliant with CGMP requirements. However, procuring newinstruments, installing new and upgraded data acquisition software, andenabling various features on software are not sufficient alone. These stepswill be effective only if you implement appropriate procedures and systems toensure that your quality unit reviews all production and control data andassociated audit trails as part of the batch release process. 我们知晓你们已承诺要更新你们的分析系统，以符合CGMP要求。但是，采购新的仪器、安装新的和升级过的数据采集软件、激活不同的软件属性本身并不充分。只有当你们实施适当的程序和系统来确保你们的质量部门会审核所有生产和分析数据以及相关的审计追踪，作为批放行过程的一部分时才是有效的。 3. Failure to ensure that your analytical methods usedto test API are appropriately validated and verified. 未能确保你们用于检测原料药的分析方法经过适当的验证和确认。 Our investigator found that your microbiological test methods were notadequately verified and that stability test methods were inadequatelyvalidated. For example: 我们的调查人员发现你们的微生物检验方法没有经过适当的确认，稳定性测试方法的验证不充分。例如： a. (b)(4) of your nonsterile API are intended foruse in the manufacture of sterile finished dosage forms for U.S. distribution.You did not appropriately verify your test methods for total aerobic microbialcount and total combined yeasts and molds. Specifically, you did not show thatthese methods are capable of recovering microorganisms in the presence of theAPI. 你们的非无菌原料药某个批次要用于美国市场的无菌制剂生产，但你们没有恰当地确认你们的TAMC和TCYM检验方法。具体情况是这样的，你们没有展示出这些方法有能力在有原料药存在的情况下具有回收微生物的能力。 b. You did not demonstrate that your stability testmethods are capable of detecting and resolving degradants from the maincomponent as well as other (b)(4) components. Specifically, you did notperform forced degradation studies for the related-substance test methods for (b)(4),(b)(4), and (b)(4). 你们没有证明你们的稳定性检测方法有能力从主成分及其它成分中检出和分离降解产物。具体情况是，你们没有实施某相关物质检验方法的强降解试验。 We acknowledge that you have committed to verifying and validating yourtest methods, but you did not include a plan to evaluate API within expiry thatwere distributed to the United States. 我们知晓你们已承诺要确认和验证你们的检验方法，但你们没有包括一份评估已销往美国且仍在有效期内的原料药的计划。 Data Integrity Remediation 数据完整性弥补措施 Your quality system does not adequately ensure the accuracy and integrityof data to support the safety, effectiveness, and quality of the drugs youmanufacture. We acknowledge that you are using a consultant to audit youroperation and assist in meeting FDA requirements. In response to this letter,provide the following. 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。我们知道你们聘请了顾问来审计你们的操作，协助符合FDA要求。在回复此函时，提供以下资料： A. A comprehensive investigation into the extent of the inaccuraciesin data records and reporting. Your investigation should 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 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 theobserved failures on the quality of your drugs. Your assessment should includeanalysesof the risks to patients caused by the release of drugs affected by alapse of data integrity, 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 firm that includes the details ofyour global corrective action and preventive action plan. Your strategy shouldinclude: 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 of 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.
- 临时描述，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 Deviations cited in this letter are not intended as anall-inclusive list. You are responsible for investigating these deviations, fordetermining the causes, for preventing their recurrence, and for preventingother deviations. If you are considering an action that is likely to leadto a disruption in the supply of drugs produced at your facility, FDA requeststhat you contact CDER’s Drug Shortages Staff immediately, atdrugshortages@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 DrugShortages Staff also allows you to meet any obligations you may have to reportdiscontinuances 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 dependon your products. Until you correct all deviations completely and weconfirm your compliance with CGMP, FDA may withhold approval of any newapplications or supplements listing your firm as a drug manufacturer. Failure to correct these deviations may also result inFDA refusing admission of articles manufactured at Sekisui Medical Co., Ltd.4-115 Matsuo, Hachimantai, Iwate, into the United States under section801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Under the same authority,articles may be subject to refusal of admission, in that the methods andcontrols used in their manufacture do not appear to conform to CGMP within themeaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B). 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. Runa Musib, Interdisciplinary Scientist 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 3002806840. Sincerely, /S/ Francis Godwin Acting Director Office of Manufacturing Quality Office of Compliance Center for Drug Evaluation and Research
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