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ViaUPS Warning Letter: 320-17-05 Return Receipt Requested November 8, 2016 Mr. Srinivasan Subramaniam Managing Director Srikem Laboratories Pvt. Ltd. Plot No. 17/24, MIDC Taloja Navi Mumbai, MH 410208 India Dear Mr. Subramaniam: The U.S. Food and Drug Administration (FDA) inspected your drugmanufacturing facility, Srikem Laboratories Pvt. Ltd., Plot No. 17/24, MIDC Taloja,Navi Mumbai, from December 14 to 18, 2015. FDA在2015年12月14-18日检查了你们在孟买的生产场所。 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 January 12, 2016, response in detail and acknowledgereceipt of your subsequent correspondence. 我们详细审核了你们于2016年1月12日及随后发来的回复。 During our inspection, our investigators observed specific deviations,including, 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 have laboratory control records thatinclude complete data derived from all laboratory tests conducted to ensurecompliance with established specifications and standards. 化验室检验记录没有来自所有化验室检验中产生的完整数据，这些检测是为了确保药品符合既定质量标准而实施的。 The audit trail for High Performance Liquid Chromatography (HPLC)instrument QCIEQPI40 showed multiple integrations conducted on the 18-monthstability tests for unknown impurity content for (b)(4), USP lots (b)(4),without appropriate documentation, justification, and investigation. HPLC仪器QCIEQP140仪器的审计追踪显示某USP批号某产品18个月稳定性检测有未知杂质含量多个积分，但没有适当的文件记录、论证和调查。 Your quality assurance manager agreed that these integrations were inappropriate.When our investigator asked you to reprocess the chromatograms usingappropriate integration parameters, the results were out-of-specification forunknown impurity content. Your quality unit must review all pertinentanalytical data when making batch release decisions in order to determine batchquality. 你们质量保证部经理认可这些积分是不恰当的。当我们的调查人员要求你们使用适当的积分参数对这些色谱数据进行重新处理时，处理结果显示未知杂质含量超标。你们的质量部门在做出批放行决策时必须审核所有相关的分析数据，以确定批产品质量。 In your response, you provided passing 24-month stability results for (b)(4)lots (b)(4), and committed to use the auto integration function. Yourresponse is inadequate because it does not address the failing 18-monthstability results for these lots and does not demonstrate how you will ensurethat you retain complete and accurate records of all tests. 在你们的回复中，你们提供了该批号24个月的稳定性结果，承诺要使用自动积分功能。你们的回复是不充分的，因为回复并没有对失败的18个月稳定性结果进行说明，也没有证明你们要如何确保你们能够保存所有检测的准确完整记录。 2. Failure to follow and document laboratory controls atthe time of performance. 未能在实施检验时遵守和记录化验室检验情况。 Our investigator observed inconsistently-dated laboratory records. Forexample, your executed protocol records show that a 24-month time-pointstability testing sample of (b)(4), USP batch (b)(4), entered thelaboratory on February 14, 2015. Our investigator requested the HPLC data. Youprovided our investigator HPLC chromatogram printouts showing that the samplewas tested on February 12 and 13, 2015: one or two days before your protocolshows that the samples even entered the lab. You were unable to find any rawdata corresponding to these tests. The use-log of the HPLC does not containentries for these runs. 我们的调查人员发现化验室记录日期不一致的情况。例如，你们实施的方案记录显示24个月稳定性测试样品是在2015年2月14日进入化验室的。我们的调查人员要求查看HPLC数据。你们给我们调查人员提供的HPLC图谱打印件显示样品是在2015年2月12日和13日检测的，在你们的方案显示样品甚至还没进到化验室的1-2天之前。你们没有发现对应这些测试的原始数据。HPLC的使用日志也没有这些样品检验运行的记录。 In another example, a printed chromatogram from related substance analysisperformed by gas chromatography for (b)(4), batch (b)(4), wasdated August 26, 2014. The data saved to your computer system from thisanalysis was dated December 28, 2013: nearly eight months before the date onthe printed chromatogram. 在另一个例子中，GC对某批号所做的有关物质分析打印图谱里，日期是2014年8月26日。在你们的电脑系统中存贮的此分析的日期为2013年12月28日：比打印图谱早了接近8个月。 In your response, you attributed data discrepancies to softwaremalfunctions, power outages, and personnel shift changes. Your response isinadequate because you have not sufficiently explained how you are improvingcontrols, notwithstanding these claimed sources of discrepancies, to ensure thereliability and accuracy of the data you rely on to evaluate the quality ofyour drugs. 在你们的回复中，你们将数据不一致归结于软件故障，断电和人员换班。你们的回复是不充分的，因为你们没有充分地解释你们要如何改善你们的控制，不管这些所声明的不一致的原因是什么，都应确保你们赖以评估你们药品质量的数据的准确性。 DataIntegrity Remediation 数据完整性弥补措施
Your quality system does not adequately ensurethe accuracy and integrity of data to support the safety, effectiveness,and quality of the drugs you manufacture. We acknowledge that you are using aconsultant to audit your operation and assist in meeting FDA requirements. Inresponse 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 theextent of the inaccuracies in data records and reporting. Yourinvestigation 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 thepotential effects of the observed failures on the quality of your drugs. Yourassessment should include analysesof the risks to patients caused by therelease of drugs affected by a lapse of data integrity, and risks posed byongoing 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 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 an all-inclusivelist. You are responsible for investigating these deviations, for determiningthe causes, for preventing their recurrence, and for preventing otherdeviations in all your facilities. If you are considering an action that is likely to lead to adisruption in the supply of drugs produced at your facility, FDA requests thatyou 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. FDA placed your firm on Import Alert 66-40 on July 6, 2016. Until you correct all deviations completely and we confirm yourcompliance with CGMP, FDA may withhold approval of any new applications orsupplements listing your firm as a drug manufacturer. Failure to correct these deviations may also result in FDAcontinuing to refuse admission of articles manufactured at Srikem LaboratoriesPvt. Ltd. Plot No. 17/24, MIDC Taloja, Navi Mumbai, MH 410208, into the UnitedStates under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Underthe same authority, articles may be subject to refusal of admission, in thatthe methods and controls used in their manufacture do not appear to conform toCGMP within the meaning 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 in writingwithin 15 working days. Specify what you have done since our inspection to correctyour deviations and to prevent their recurrence. If you cannot completecorrective actions within 15 working days, state your reasons for delay andyour schedule for completion. Carlos Gonzalez, 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 3005048741. Sincerely, /S/ Francis Godwin Acting Director Office of Manufacturing Quality Office of Compliance Center for Drug Evaluation and Research
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