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原文官网链接：http://www.fda.gov/ICECI/Enforce ... /2016/ucm508554.htm
Warning Letter: 320-16-18 ViaUPS Return Receipt Requested June 16, 2016 Ms. Ying Kan
President Shanghai Desano Chemical Pharmaceutical Co., Ltd. 1479 Zhangheng Road Zhangjiang High-Tech Park Shanghai 201203 China Dear Ms. Kan: The U.S. Food and Drug Administration (FDA)inspected your drug manufacturing facility, Shanghai Desano Chemical PharmaceuticalsCo., Ltd. at No.417 Binhai Road, Laogang Town, Pudong District, Shanghai, fromMay 4–7, 2015. 美国FDA于2015年5月4-7日检查了你们位于上海浦东的迪赛诺化学制药公司生产场所。 This warning letter reviews significantdeviations from current good manufacturing practice (C GMP) for activepharmaceutical ingredients (API). 本警告信回顾了原料药生产中严重违反CMP的行为。 Because your methods, facilities, or controlsfor manufacturing, processing, packing, or holding do not conform to CGMP, yourAPI are adulterated within the meaning of section 501(a)(2)(B) of the FederalFood, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B). 由于你们生产、加工、包装和存贮原料药所用的方法、设施或控制不符合CGMP要求，你们的原料药根据FDCA被认为是掺假药物。 We reviewed your firm’s May 22, 2015, responsein detail and acknowledge receipt of your subsequent responses. 我们详细审核了你们公司于2015年5月22日及之后提交的回复。 Our investigator observed specific deviationsduring the inspection, including, but not limited to the following. 我们的调查人员在检查期间发现的包括但不仅限于以下具体问题： 1. Failure to have laboratorycontrol records that include complete data derived from all tests conducted toensure compliance with established specifications and standards. 未能保证化验室控制记录，包括从所有确保既定标准的测试中生成的完整数据。 Your laboratory personnel conducted “unofficial”testing without appropriate documentation, justification, and investigation. 你们化验室人员在没有适当文件记录、论述和调查的情况下实施了“非正式”的测试。 The original, unofficial analyses were stored in aseparate “Test” folder and were not part of the official quality controlrecords. Our inspection found that your firm performed circa 8,400 of theseunofficial chromatographic analyses between 2012 and 2014. According to yourSOP-B-QC-022-01, Instrument Use Standard Operating Procedure, analysisof samples must be documented. The volume of data in these auxiliary “TestFolders” suggests that performing unofficial analyses is a common practice atyour facility. 原始的非正式分析数据被存贮在一个单独的“测试”文件夹，没有作为正式质量控制记录的一部分。我们检查发现你们公司在2012年-2014年间进行了约8400次非正式色谱分析。根据你们的SOP-B-QC-022-01“仪器使用标准操作规程”，样品分析必须记录。在这些备用的“测试文件夹”里数据量显示在你们工厂经常进行这样的非正式分析。 Your quality unit must review all pertinent analyticaldata when making batch release decisions in order to determine batch quality.During the inspection, a member of your staff told our investigator that youwere now in the process of reviewing these unofficial analyses. 你们质量部门在确定批准质量做出批放行决策之前必须审核所有相关的分析数据。在检查期间，你们有一位员工告诉我们调查人员说你们现在正在审核这些非正式的分析。 In your post-inspection response, you indicated thatsome of the analyses were related to out-of-specification (OOS) investigations,and you would review all of the approximately 8,400 injections by December,2015. You also committed to continue reviewing all analytical data generated byyour laboratory and to retrain employees. 在你们对检查的回复中，你们说有些分析是与OOS调查相关的，你们会在2015年12月之前审核所有约8400次进样。你们还承诺要持续审核所有在你们化验室产生的分析数据，并对员工进行再次培训。 Your response is inadequate because it lacks acomprehensive assessment of your laboratory practices and management oversight.Your response did not provide the extent of the unofficial analyses throughoutyour laboratory and the products affected. 你们的回复是不充分的，因为它缺乏对你们化验室做法和管理层监管的全面评估。你们的回复没有提供你们整个化验室里非正式分析的涉及程度，以及受影响的产品情况。 2. Failure to ensure all productiondeviations are reported and evaluated, and that critical deviations areinvestigated and the conclusions are recorded. 未能保证对所有生产偏差都进行报告和评估，以及调查关键偏差和记录结论。 Your firm failed to investigate and document a numberof production deviations. During the inspection, our investigator found manyelectronic logs of production deviations in a folder titled “GMP Anomalies.”Our investigator randomly selected folder 01/2014 from your electronic log,compared it to your firm’s official deviation logbook for 2014, and found thatthe deviations in the “GMP Anomalies” folder were not investigated or reportedin the official deviation logbook. 你们公司未能调查和记录大量生产偏差。在检查期间，我们的调查人员发现许多生产偏差电子清单，在一个题目为“GMP异常”的文件夹里。我们的调查人员从你们的电子清单里随机选择了2014年1月的文件夹，与你们公司2014年的正式偏差登记本进行了比较，发现在“GMP异常”文件夹里的偏差并没有在正式偏差登记本里进行调查或报告。 Production deviations included, but were not limitedto: 生产偏差包括但不仅限于： - out-of-limit temperature readings for critical process parameters
- 关键工艺参数温度读数超限
- incomplete batch records
- 不完整的批记录
- batch records pre-filled before manufacturing
- 批记录在生产之前就预先填写了
- failure to record temperature, humidity, and pressure
- 未能记录温度、湿度和压力
- failure to add portions of raw materials during manufacturing
- 在生产中未加入一部分原料
In your response, you attribute the root cause ofthese failures to deficient procedures and operators’ errors. You stated thatyou will conduct a retrospective review for all deviations made in the (b)(4)products “Production Coordination Log” from January 2014 through April 2015, todetermine whether any CGMP deviations may have compromised product quality. 在你们的回复中，你们将这些失败的根本原因归因于程序有缺陷，以及操作人员错误。你们声称你们会对2014年1月至2015年4月期间某产品的“生产协调登记本”中所有偏差进行回顾审核，以确定是否有CGMP偏差可能对产品质量产生影响。 Your response is inadequate as your protocol did notinclude a thorough review of complaints to determine if undocumented deviationscould be linked to product quality defects. 你们的回复是不充分的，因为你们的方案并没有包括对投诉的全面审核，以确定是否未记录的偏差可能与产品质量缺陷有关联。 Conclusion 结论 Deviations cited in this letter are not intended as anall-inclusive list. You are responsible for investigating these deviations, fordetermining causes, for preventing their recurrence, and for preventing otherdeviations. 在本函中所引用的偏差并无意包括所有问题。你们有义务调查这些偏差，以确定原因，防止其再次发生，并防止其它偏差发生。 If, as a result of receiving this warning letter orfor other reasons, you are considering a decision that could reduce the numberof drugs produced by your manufacturing facility, FDA requests that you contactCDER’s Drug Shortages Staff immediately at drugshortages@fda.hhs.gov so that wecan work with you on the most effective way to bring your operations intocompliance with the law. Contacting the Drug Shortages Staff also allows you tomeet any obligations you may have to report discontinuances in the manufactureof your drug under 21 U.S.C. 356C(a)(1), and allows FDA to consider, as soon aspossible, what actions, if any, may be needed to avoid shortages and protectthe health of patients who depend on your products. In appropriate cases, youmay be able to take corrective action without interrupting supply, or toshorten any interruption, thereby avoiding or limiting drug shortages. 如果，作为收到此警告信的结果或者由于其它原因，你们考虑决定减少你们工厂生产的药品数量，FDA要求你们立即通过 drugshortages@fad.hhs.gov联系CDER药品短缺员工，这样我们可以与你们一起以最有效的方式将你们的运行状态改进至符合法律的模式。联系药品短缺人员也让你们能够履行你们必须报告药品生产中断的义务，让FDA可以考虑尽快采取必要的措施来避免短缺，保护依赖于你们药品的患者。在适当的情形下，你们可以采取纠正措施，不中断供应，或者缩短中断时间，这样避免或减少药品短缺。 After you receive this letter, you have 15 businessdays to respond to this office in writing. Specify what you have done since ourinspection to correct deviations and to prevent their recurrence. 在你们收到此函后，你们有15个工作日的时间来书面回复此办公室。说明你们在我们检查之后所采取的纠正和防止再次发生的措施。 Your quality system does not adequately ensure theaccuracy and integrity of data to support the safety, effectiveness, andquality of the drugs you manufacture. In response to this letter, provide thefollowing. 你们的质量体系并不能充分保证数据准确和完整性，用以支持你们生产的药品的安全、有效性和质量。在回复此函时，请提供以下： 1. A comprehensive investigation into the extentof the inaccuracies in data records and reporting. Your investigation shouldinclude: 一份对数据记录和报告不准确的程度的全面调查。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；所有化验室、生产操作和评估所包括的系统汇总，你们建议不包括在方案里的系统被排除的论述。
- 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.
- 对现在的和之前的员工进行面谈，找出数据不准确的性质、范围和根本原因。我们建议这些审核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.
- 对你们工厂的数据完整性缺陷的程度进行的评估。找出忽略、篡改、删除、记录毁坏、不及时完成记录和其它缺陷。说明你们发现工厂运行中所有数据完整性有问题的部分。
- A comprehensive retrospective evaluation of the nature of all data integrity deficiencies. We recommend that a qualified third party with specific expertise in the area where potential batches were identified should evaluate all data integrity lapses.
- 一份对所有数据完整性缺陷性质的全面回顾性评估。我们建议由一个在潜在受影响批次领域具备专家背景的有资质的第三方，来评估所有数据完整性问题。
2. A current risk assessment of the potentialeffects of the observed failures on the quality of your drugs. Your assessmentshould include analyses of the risks to patients caused by the release of drugsaffected by a lapse of data integrity, and risks posed by ongoing operations. 当前所发现的问题对你们药品质量潜在影响的风险评估。你们的评估应该包括受数据完整性影响的产品放行对患者造成风险的分析，以及持续运行的风险。 3. A management strategy for your firm that includesthe details of your global corrective action and preventive action plan. Yourstrategy should include: 你们公司的管理策略，包括你们全球纠正预防措施的详细情况。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.
- 详细的纠正措施计划，描述你们如何保证你们产生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.
- 一份你们数据完整性问题根本原因的全面描述，包括当前行动计划的范围和深度与调查结果和风险评估相当的证据。说明对数据完整性问题负有责任的个人是否仍有能力对你们公司的CGMP相关或药品申报数据产生影响。
- 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. 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.
- 临时措施，措施你们已采取或者将要采取的保护患者保证你们药品质量的措施，例如通知你们客户、召回产品、实施附加测试、增加稳定性计划批次来保证稳定性，药品申报行动，加强投诉监测。长期措施，描述所有改正努力和对程序、工艺、控制、系统、管理监管和人力资源方面的加强（例如，培训、员工提升），用以保证你们公司数据的完整性。
- A status report for any of the above activities that are already underway or completed.
- 上述所有活动中正在执行或已完成的状态报告。
If you cannot complete corrective actions within 15working days, state your completion date and reasons for delay. 如果你们不能在15个工作日内完成纠正措施，请说明你们的完成日期和延期原因。 Until you completely correct all deviations and weconfirm your compliance with CGMP, FDA may withhold approval of any new applicationsor supplements listing your firm as an API manufacturer. Failure to correctthese deviations may also result in FDA refusing admission of articlesmanufactured at Shanghai Desano Chemical Pharmaceutical Co., Ltd., Shanghai,China, into the United States under section 801(a)(3) of the FD&C Act, 21U.S.C. 381(a)(3). Under the same authority, articles may be subject to refusalof admission, in that the methods and controls used in their manufacture do notappear to conform to CGMP within the meaning of section 501(a)(2)(B) of theFD&C Act, 21 U.S.C. 351(a)(2)(B). 在你们完成对所有偏差的纠正，我们确认你们是否符合CGMP之前，FDA可能会暂停所有将你们作为原料药生产商的新申报和增补申报的批准。不能纠正这些偏差可能还会导致FDA拒绝接受上海迪赛诺化学制药公司所生产的物品进入美国。 Send your reply to: Cesar E. Matto Compliance Officer U.S. Food and Drug Administration White Oak, Building 51, Room 4359 10903 New Hampshire Ave Silver Spring, MD 20993 USA Please identify your response with FEI 3006895951. Sincerely, /S/ Francis Godwin Acting Director Office of Manufacturing Quality Office of Compliance Center for Drug Evaluation and Research
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发表于 2016-6-30 11:24:20
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