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原创 2018-02-28 julia Julia法规翻译
Warning Letter 320-18-35
February 16, 2018Mr. T.G. Velumani, ChiefExecutive OfficerAlchymars ICM SM PrivateLimitedAdwave Towers C/4, III Floor,#17 South Boag RoadT. Nagar, Chennai 600 017, India
Dear Mr. Velumani:The U.S. Food and DrugAdministration (FDA) inspected your drug manufacturing facility, Alchymars ICMSM Private Limited at A-14 20 Complex, Alathur, Tamil Nadu, from September11 to 15, 2017.美国FDA于2017年9月11-15日检查了你们位于印度泰米尔纳德邦的AlchymarsICM SM Private Limited.生产场所。This warning letter summarizessignificant deviations from current good manufacturing practice (CGMP) foractive pharmaceutical ingredients (API).本警告信总结了原料药生产严重违反CGMP的行为。参见21CFR第210和211部分。Because your methods,facilities, or controls for manufacturing, processing, packing, or holding donot conform to CGMP, your API are adulterated within the meaning of section501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD C Act), 21U.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 October 6,2017, response in detail and acknowledge receipt of your subsequentcorrespondence.我们已详细审核了你公司2017年10月6日的回复并此告知已收到后续通信。During our inspection, ourinvestigators observed specific deviations including, but not limited to, thefollowing.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. Failureto have laboratory control records that include complete data derived from alllaboratory tests conducted to ensure your API complies with establishedspecifications and standards. 没有化验室检测记录，在其中包括为确保你们API符合既定质量标准所实施的所有化验室测试所生成的完整数据。Our investigator found thatyour firm was falsifying laboratory data. For example, the number ofcolony-forming units (CFU) found on (b)(4) plates for (b)(4)water point-of-use tests differed substantially from the number recorded onyour (b)(4) water report. For multiple points of use, your analystreported far fewer CFU than observed on the plate by our investigator. Inaddition, while you reported absence of growth on a selective media plate usedto detect objectionable microorganisms, our investigator observed growth onthis plate. This is concerning because you use(b)(4) water tomanufacture products, such as (b)(4) API, that are intended for use insterile injectable dosage forms.我们的调查人员发现你们公司伪造化验室数据。例如，在XX用水点检测XX碟上发现的菌落形成单位（CFU）数量与你们的XX水报告上所记录的数值有显著差异。有多个使用点，你们化验室所报告的数值都远低于我们调查人员在你们碟上看到的。另外，虽然你们报告说在一个用于检出致病菌的选择性培养基碟上未检出微生物生长，但我们调查人员却在该碟上看到了微生物生长。这种情况令人担忧，因为你们使用XX水生产用于无菌注射制剂的药品，例如XX原料药。We acknowledge your decisionto suspend production of (b)(4) and (b)(4) API based on your riskassessment, and your commitment to a third party data integrity assessment. Wealso acknowledge your commitment to conduct a risk analysis and data review fordistributed products, and to sanitize and validate the (b)(4) watersystem. We request that you notify FDA before resuming production of (b)(4)and (b)(4) API for U.S. supply.我们在此告知已收到你们基于你们的风险评估暂停XX和XX原料药生产的决定，以及你们承诺要聘请第三方进行数据完整性评估。我们也告知已收到你们承诺将对已销售产品进行风险分析和数据回顾，并对XX水系统进行消毒和验证。我们要求你们在恢复XX和XX原料药的美国市场供应前通知FDA。In response to this letter,provide your data integrity remediation efforts as requested in the DataIntegrity Remediation section of this letter below. In addition, provide thefollowing:在回复此函时，请按本函以下数据完整性弥补部分的要求提交你们的数据完整性弥补工作情况，提供以下资料：An independent assessment of your water system design, control, and maintenance;一份你们的水系统设计、控制和维护独立的评估A comprehensive corrective action and preventive action (CAPA) plan for improving design, control, and maintenance of your water system;一份改进你们水系统的设计、控制和维护的全面纠正预防措施（CAPA）计划Your (b)(4) water system validation report;你们XX水系统的验证报告A summary of improvements made to your water system design, as well as to your program for ongoing control and maintenance; 一份对你们水系统设计所做的改进总结，以及你们持续控制和维护的计划The total count and endotoxin limits that you currently use for this system. 你们当前用于此系统的总计数和内毒素限度
2. Failureto properly maintain equipment and to keep complete records of major equipmentmaintenance.未能对设备进行妥善维护，并保存主要设备维护的完整记录。Our investigator found damagedproduct-contact surfaces on your multi-product equipment. For example, themanhole gasket of (b)(4)111 was deteriorating and wrapped in peelingtape. A gasket on the (b)(4)102 was also cracked in one area and wrappedin peeling tape. 我们调查人员发现你们的多产品设备上与产品接触表面受损。例如，XX111的人孔垫圈损坏，包在剥落的胶带中。XX102的垫圈也有一个地方裂开了，也是包在剥落的胶带中。Your SOP/ENG/39-1, GasketManagement for Equipments and Pipelines which are in Direct Contact with theProduct, section 4.18, requires you to replace gaskets in critical areas,including gaskets for (b)(4)111 and (b)(4)102, (b)(4).Your firm was unable to provide gasket replacement records for this equipmentduring the inspection.你们的SOP/ENG/39-1“与产品直接接触的设备和管道垫圈管理”第4.18部分要求你们对关键区域的垫圈进行更换，包括XX111和XX102的垫圈。你们公司在检查期间未能提供此设备的垫圈更换记录。Furthermore, the most recentrecords of your firm checking the condition of the gaskets for (b)(4)102were from January 2017, more than (b)(4) before our inspection.还有，你们公司检查XX102垫圈情况的最近记录是从2017年1月开始的，在我们检查之前XX时长。This is a repeat observationfrom our February 2015 inspection. We also note that you have founddeteriorating gaskets to be the root cause for finished API particlecomplaints.这是2015年2月我们检查中发现的重复缺陷。我们也注意到你们已发现了老化的垫圈是成品原料药颗粒物投诉的根本原因。Your response is inadequate.You stated that the “involved gasket was immediately substituted” but did notevaluate all other gaskets on your manufacturing equipment. You indicated thatyou will update your procedure to require a supervisor walk-through to assessproduct contact surfaces, but did not include sufficient detail (e.g.,frequency of equipment inspection). You also failed to address the lack ofgasket maintenance records.你们的回复是不充分的。你们声称“所涉及的垫圈马上就被替换了”，但并未评估你们生产设备上所有其它垫圈。你们说你们会更新你们的程序，要求主管现场排查以评估产品接触表面，但并未包括足够详细的内容（例如，设备检查的频次）。你们也未解决缺少垫圈维护记录的问题。In response to this letterprovide a comprehensive assessment and corrective action and preventive action(CAPA) plan to address the adequacy of your maintenance program for allequipment. This systemic assessment and CAPA should also remediate yourmaintenance record deficiencies. In addition, provide procedures that specifythe frequency of gasket assessment and your preventive maintenance replacementrequirements.在回复此函时，请提交全面评估和纠正预防措施计划，解释你们所有设备维护计划充分性问题。此系统性评估和CAPA还应弥补你们的维护记录缺陷。此外，请提交程序写明垫圈评估的频率，以及你们的预防性维护更换要求。3. Failureof your quality unit to ensure that quality-related complaints are investigatedand resolved. 你们质量部门未能确保质量相关投诉经过调查，得到解决。Your quality unit did notthoroughly investigate customer complaints for (b)(4) API. For example,you classified the December 31, 2015, CC1/P/11 complaint about black spots infinished (b)(4) API as “minor and unjustified” without a thoroughreview. You did not perform a detailed review of production records orequipment cleaning and maintenance logs, even though equipment gaskets werefound to be the root cause of similar past complaints.你们质量部门并未彻底调查XX原料药的客户投诉。例如，你们产将2015年12月31日的CC1/P/11关于成品XX原料药中黑点的投诉分级为“轻微且未证实”，而未进行彻底审核。即使在过去类似投诉中发现设备垫圈是根本原因，你们仍未对生产记录和设备清洁和维护日志进行详细的审核。In addition, you classifiedthe April 20, 2015, CC1/P/01 complaint about out-of-specification results for (b)(4)moisture content as “minor and unjustified” without a thorough review.While you tested the retention samples for the complaint batch and threeprevious batches, your investigation lacked a review of production records,such as those for the API drying process.另外，你们将2015年4月20日的CC1/P/01关于XX水份OOS结果分级为“轻微且未证实”，而未进行彻底审核。虽然你们检测了投诉批的留样和之前的三个批次，但你们的调查缺乏对生产记录的审核，例如这些原料药干燥工艺。In your response you commit toan independent review of all investigations and to updating written procedureson deviations, complaints, and investigations. However, your response lackssufficient detail on how your firm intends to comprehensively remediate theinvestigation system.在你们的回复中，你们承诺将对所有调查进行独立审核，更新偏差、投诉和调查的书面程序。但是，你们的回复在你公司要如何全面弥补调查体系方面缺乏足够的细节。In response to this letter,provide a comprehensive independent review and remediation of your systems usedto ensure thorough, timely, and effective investigations of deviations,complaints, defects, out-of-specification results, and failures.在回复此函时，请提交一份全面的独立审核，以及你们用于确保彻底、及时及有效的偏差、投诉、缺陷、OOS结果和失败调查的体系的弥补措施。4. Failureto properly maintain buildings and facilities used in the manufacture ofintermediates and API. 未能适当维护用于中间体和原料药生产的厂房和设备。The equipment washroom in yourSection (b)(4) manufacturing block was found in a filthy condition withdamaged tiles and standing water. In addition, the handwashing stationsintended for the class-100,000 (ISO-8) areas in sections (b)(4) and (b)(4)of your facility were visibly dirty.我们发现你们XX生产区的设备清洁间肮脏、地砖破损、有积水。此外，你们工厂XX部分XX和XX10万级（ISO-8）区洗手间非常之脏。Your response commits toreconstructing these areas. However, you did not provide any detail on routinecleaning and preventative maintenance for these areas.你们的回复承诺说会重新修建这些区域。但是，你们并未提交关于这些区域的日常清洁和预防性维护的任何细节。In response to this letter,provide a comprehensive evaluation of your facility cleaning and maintenanceprogram. Please also provide your CAPA plan to improve routine cleaning andpreventative maintenance at your facility, including but not limited to yourequipment washrooms and handwashing stations.在回复此函时，请提交一份对你们工厂清洁和维护计划的全面评估。还请提交你们工厂改进日常清洁和预防性维护的CAPA计划，包括但不仅限于你们的设备清洗间和洗手间。5. Failureto provide personnel with adequate clean washing and toilet facilities. 未给员工提供足够的清洁清洗和如厕设施。Your handwashing stations wereinconveniently located and not fully functional. For example, the handwashingstations intended for the class-100,000 areas in sections (b)(4) and (b)(4)of your facility were in the equipment washrooms, accessible only to operatorswho had already put on gowns and gloves. Handwashing stations did not have hotwater, soap, or hand drying equipment. This is a repeat observation from ourFebruary 2015 inspection.你们的洗手间位置不方便，功能不齐全。例如，洗手间用于你们工厂XX和XX部分的10万级区，设置在设备清洁间内，只有穿戴了洁净服和手套的操作工才可进入。洗手间没有热水、肥皂，也没有干手设备。这是我们2015年2月检查中发现的重复缺陷。We acknowledge your commitmentto implement temporary handwashing stations and construct permanent stationswithin the gowning areas of the class-100,000 cleanrooms.我们告知你们已收到你们承诺要建立临时洗手间，并将在10万级洁净区更衣区建造永久的洗手间。In response to this letter,provide updated installation timelines and additional detail on hot wateravailability for these handwashing stations.在回复此函时，请提交更新后的安装时间表，以及这些洗手间内供应热水的其它细节。Repeat Deviations 重复偏差In a previous inspection datedFebruary 2 to 6, 2015, FDA cited similar CGMP deviations. In your responses tothe 2015 and 2017 inspections, you proposed specific remediation for thesedeviations. However, repeated deficiencies demonstrate that your facility’soversight and control over the manufacture of drugs is inadequate.在之前2015年2月2-6检查中，FDA发现了类似的CGMP偏差。在你们对2015年和2017年检查的回复中，你们都对这些偏差提出了具体的补救措施。但是，重复缺陷证明你们工厂对药品生产的监管和控制是不充分的。CGMP consultant recommended CGMP顾问建议Because you failed to correctrepeat deviations, we strongly recommend engaging a consultant qualified toevaluate your operations, and assist your firm in meeting CGMP requirements.The consultant should immediately and comprehensively assess your company’smanufacturing operations to ensure that systems and processes, and ultimately,the products manufactured, conform to FDA requirements. In particular, thisqualified third party should thoroughly assess and assist with remediation ofdata integrity, laboratories, investigations, the maintenance program, andquality oversight at your firm. Your use of a consultant does not relieve yourfirm’s obligation to comply with CGMP. Your firm’s executive management remainsresponsible for fully resolving all deficiencies and ensuring ongoing CGMPcompliance.由于你们未能纠正重复偏差，我们强烈建议你们使用一位有资质的顾问来评估你们的操作，协助你们公司符合CGMP要求。该顾问应立即全面评估你们公司的生产操作，以确保系统和工艺，以及最终，所生产的产品符合FDA的要求。尤其是，此具备资质的第三方应彻底评估和协助弥补数据完整性、化验室、调查、维护计划和你们公司的质量监管。你们使用顾问并不解除你们公司符合CGMP的义务。你们公司的高级管理层仍负有义务全面解决所有缺陷，确保持续CGMP符合性。Data Integrity Remediation 数据完整性补救Your quality system does notadequately ensure the accuracy and integrity of data to support the safety,effectiveness, and quality of the drugs you manufacture. In response to thisletter, provide the following.你们的质量体系未能充分确保用以支持你们所生产药品的安全性、有效性和质量的数据的准确性和完整性。在回复此函时，请提交以下资料：A. A comprehensiveinvestigation into the extent of the inaccuracies in data records andreporting, including results of the data review for products distributed to theUnited States.一份对数据记录和报告不准确程度的全面调查，包括销往美国的产品的数据核查结果B. A current riskassessment of the potential effects of the observed failures on the quality ofyour drugs. Your assessment should include analyses of the risks to patientscaused by the release of drugs affected by a lapse of data integrity, and risksposed by ongoing operations.一份所发现的失败对你们药品质量的潜在影响风险评估。你们的评估应包括受数据完整性问题影响的药品放行所引起的对患者的风险分析，以及继续生产所具有的风险。C. A management strategy foryour firm that includes the details of your global corrective action andpreventive action plan.一份对你们公司的管理策略，包括你们的全球纠正预防措施计划详细内容。Conclusion结论Deviations cited in thisletter are not intended as an all-inclusive list. You are responsible forinvestigating these deviations, for determining the causes, for preventingtheir recurrence, and for preventing other deviations in your facility.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，防止你工厂里其它偏差的发生。If you are considering anaction that is likely to lead to a disruption in the supply of drugs producedat your facility, FDA requests that you contact CDER’s Drug Shortages Staffimmediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on themost effective way to bring your operations into compliance with the law.Contacting the Drug Shortages Staff also allows you to meet any obligations youmay have to report discontinuances or interruptions in your drug manufactureunder 21 U.S.C. 356C(b) and allows FDA to consider, as soon as possible, whatactions, if any, may be needed to avoid shortages and protect the health ofpatients 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 alldeviations completely and we confirm your compliance with CGMP, FDA maywithhold approval of any new applications or supplements listing your firm as adrug 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 thesedeviations may also result in FDA refusing admission of articles manufacturedat Alchymars ICM SM Private Limited at A-14 20 Complex, Alathur, TamilNadu, 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).未能纠正这些偏差可能还会导致FDA依据FDCA第801(a)(3)条和21U.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 in writing within 15 working days. Specify what you havedone since our inspection to correct your deviations and to prevent theirrecurrence. If you cannot complete corrective actions within 15 working days,state your reasons for delay 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.govor mail your reply to:Ms. Marisa HeaynConsumer Safety OfficerU.S. Food and DrugAdministrationWhite Oak Building 51, Room435910903 New Hampshire AvenueSilver Spring, MD 20993USAPlease identify your responsewith FEI 3005216842.Sincerely,/S/ Francis GodwinActing DirectorOffice of ManufacturingQualityOffice of ComplianceCenter for Drug Evaluation andResearch