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Warning Letter WL: 320-15-04 CERTIFIEDMAIL RETURN RECEIPT REQUESTED December 19, 2014
Yonhui (William) Liu, GeneralManager 美国FDA给中国无锡一家API及制剂生产 Novacyl WuxiPharmaceutical Co. Ltd. 企业（诺化仕）的警告信 8 Guang Shi Xi Road Wuxi, Jiangsu,214185, China Dear Mr. Liu: During our October 14, 2013through October, 18, 2013 inspection of your pharmaceuticalmanufacturing facility, Novacyl Wuxi Pharmaceutical Co. Ltd. located at 8 GuangShi Xi Road Wuxi, Jiangsu, 214185, China, an investigator from the U.S. Foodand Drug Administration (FDA) identified significant deviations from currentgood manufacturing practice (CGMP) for the manufacture of active pharmaceuticalingredients (APIs) and significant violations of the CGMP regulations forfinished pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and211. These deviations and violations cause your APIs and drug products to beadulterated within the meaning of Section 501(a)(2)(B) of the Federal Food,Drug, and Cosmetic Act (the Act), 21 U.S.C. 351(a)(2)(B), in that the methodsused in, or the facilities or controls used for, their manufacture, processing,packing, or holding do not conform to, or are not operated or administered inconformity with, CGMP. 美国FDA于2013年10月14-18日对贵公司位于中国无锡的生产工厂进行了审计。审计过程中，审计官发现贵司的API生产与目前的GMP规范存在差异，并且成品药方面也存在明显违规行为，这些差异及违规导致贵司所生产的API和制剂成品在一定程度上存在参假行为。 Our inspection noted that yourfirm produces (b)(4) synthesized (b)(4) API and (b)(4) (a (b)(4) of (b)(4) and excipients). The (b)(4) is by definition an in-processmaterial for a finished drug product under Title 21, Code of FederalRegulations, section 210.3(b)(9), and therefore subject to the CGMP regulationsat 21 CFR 211.We have conducted a detailed review of your firm’s response datedNovember 06, 2013, and note that it lacks sufficient corrective actions. 审计过程中，我们注意到贵司生产的(b)(4) 。显然是成品的一种中间体物料，因此应遵守CGMP条例。我们对贵司于2013年11月6日的回复进行了仔细审核，注意到该回复仍缺乏足够整改行动。 Our investigator observedspecific deficiencies during the inspection of the API manufacturing facility,including, but not limited to, the following: 审计过程中，在API生产厂房，审计官发现了一些缺陷，包括，但不仅局限于以下内容： API: CGMP DEVIATION API：CGMP违规 1. Failure tomanage laboratory systems with sufficient controls to ensure conformance toestablished specifications and prevent omission of data. Our inspection revealed seriousdeficiencies related to your documentation practices, including missing rawdata. It is a basic responsibility of your quality unit to ensure thatyour firm retains the supporting raw data that demonstrates your APIs meetspecifications that they are purported to possess. 实验室系统无适当控制，确保遵守已建立的标准，防止数据遗失。 For example, during theinspection, our investigator found a chromatogram related to (b)(4), API in the trash, dated October15, 2013, which reported an additional chromatographic peak when compared tothe standard. During the inspection, your firm stated that the analystdiscarded the chromatogram because it was present in the blankinjection. However, the analyst was unable to retrieve the blankchromatogram from the system because it was overwritten by a subsequent injection. 例如，在审计过程中，审计官在垃圾桶中发现一份有关API(b)(4)的色谱图，日期为2013年10月15日，该图谱显示和标准相比，有一个额外的色谱锋面。审计过程中，贵司称由于色谱图谱是于空白注射时候产生的，所以分析人员才丢弃该图谱。然而，由于被随后注射所覆盖，分析人员无法从系统中检索到此份空白色谱图。 In addition, the inspectiondocumented that your firm made changes to integration parameters for the impuritiestest without appropriate documentation or justification. Your firm reliedupon hand written notes on a chromatogram discovered in a drawer at thelaboratory as the documentation for this change. Furthermore, your firmimplemented this change without an audit trail that would have captured thedate of the change and who made the change. 另外，审计文件显示对于杂质检测无合适的文件说明或定义。贵公司曾对集成参数进行过变更。作为此份变更的一个书面数据，在贵司实验室的一个抽屉中所发现的一份色谱图显示贵司仍依赖于手写备注。而且，贵司在无任何审计跟踪前提下就执行了此次变更，无变更生效日期及变更发起人等相关信息。 Other significant deficienciesnoted in your laboratory system include: 在贵司实验室系统中还发现其他明显的缺陷，包括： a) Failure to have a writtenprocedure for manual integration despite its prevalence. 对于人工集成，无书面程序，尽管已经非常广泛。 b) Failure to use separate passwordsfor each analyst’s access to the laboratory systems. 每位分析人员进入实验室系统的权限密码不是独立的。 c) Use ofuncontrolled worksheets for raw analytical data in your laboratory. 实验室原始分析数据所用到的工作表无控制。 d) Presence of many uncontrolledchromatograms, spreadsheets and notes of unknown origin found in a drawer. 在一个抽屉中，有许多未控制的色谱图，表格以及来源不明的注释。 The lack of controls on methodperformance and inadequate controls on the integrity of the data collectedraise questions as to the authenticity and reliability of your data and thequality of the APIs you produce. 由于方法操作方面缺少控制，并且数据收集完整性方面控制不充分，导致贵司所生产的API质量以及数据可靠性及真实性出现问题。 Your firm’s response, datedNovember 06, 2013, stated that your firm will create a validation program forall uncontrolled computer systems, create a new standard operating procedure(SOP), and retrain all analysts performing analytical tests. However,observations found during the most recent inspection regarding the inadequacyof your HPLC system raises questions regarding your ability to implementsustainable corrective and preventive actions, as previous commitments made tothe agency were not fulfilled. Please provide specific milestones and yourdetailed plan on how you intend to implement the appropriate correctiveactions. We will also encourage you to submit monthly reports to the agency ofyour progress. 贵司2013年11月6日的回复称：贵司为所有未受控制的计算机系统建立了一个验证程序，一个新的标准操作程序（SOP),并对所有分析人员的分析检测进行再配训。但是，在最近大部分审计过程中所发现的缺陷项，由于贵司HPCL系统不恰当导致贵司在持续执行整改预防措施能力方面出现问题。没有执行原先承诺。请提供详细的工作完成表以及如何正确执行整改行动的具体方案。同样，就贵司进展情况，我们希望能得到月度报告。 As part of your response, provide a complete validationplan for your laboratory computerized systems. This plan should include anaudit trail component and other appropriate controls to prevent deletion andoverwriting of data. In addition, include a retrospective review of the analytical data and batchrecords for all of the APIs distributed that remain within expiration, alongwith an evaluation of data that may have been generated to support a drugapplication, including any Drug Master File. This investigation shouldinclude a review of all APIs manufactured at your site. Furthermore,provide details of the systemic corrective actions taken to prevent recurrenceof these deficiencies. 作为贵公司回复的一部分，请提供一份有关贵司实验室计算机系统完整的验证计划。此份计划应包括审查跟踪部分以及其他的合适控制，以避免对数据的删除及更改。另外，也包括对所有已销售，仍在有效期内API分析数据和批记录的回顾性调查，以及支持药品申请或许已产生的评估性数据，包括药品主文件。此次调查还应该包括对贵司已生产所有API进行审核。另外，为避免这些缺陷的再次发生，请提供详细的，已执行的系统性整改措施。 Please note that a guidancedocument entitled “Q7 Good Manufacturing Practice Guidance for ActivePharmaceutical Ingredients” (ICH CGMP guidance), prepared under the auspices ofthe International Conference on Harmonization (ICH) of Technical Requirementsfor Registration of Pharmaceuticals for Human Use, describes current goodmanufacturing practice (CGMP) for the manufacture of APIs. The guidance isintended to help ensure that all APIs meet the standards for quality and puritythey purport or are represented to possess. FDA considers the expectationsoutlined in ICH Q7, as well as alternatives intended to accomplish the samegoals and provide an equivalent level of quality assurance, in determiningwhether a firm’s APIs have been manufactured, processed, packed, and heldaccording to current good manufacturing practice under section 501(a)(2)(B) [21USC 351(a)(2)(B)] of the Act. To obtain the ICH CGMP guidance document foryour reference, please refer to the following page of FDA’s website: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073497.pdf. FINISHED PRODUCT: CGMP VIOLATIONS 成品的CGMP违规 2. Your firm did not properly document or investigateout-of-specifications (OOS) and other discrepancies (21 CFR 211.192). 对OOS及其他差异，贵公司没有恰当地进行书面说明或调查。 For example, the inspection documented thatOOS Investigation #1203, related to the presence of metal particles in (b)(4), failed to determine the rootcause of the contamination or explain why the (b)(4) step was unable to prevent thecontamination. 例如，审计文件称OOS调查#1203，称(b)(4)中出现金属颗粒，但没有对该污染的根本原因进行判断或解释为何 (b)(4)步骤不能防止污染的发生。 3. Your firmfailed to establish laboratory controls that include scientifically sound andappropriate specifications, standards, sampling plans, and test proceduresdesigned to assure that components, drug product containers, closures,in-process materials, labeling, and drug products conform to appropriatestandards of identity, strength, quality, and purity (21 CFR 211.160(b)); and, 贵公司没有建立实验室控制，包括恰当的科学标准，规格，取样计划，以及检测过程，从而保证物料，药品容器，密封盖，工序间物料，标签，以及药品符合恰当的鉴别标准，浓度，质量以及纯度等； 4. Your firmdid not record all CGMP activities at the time these were performed. The lackof contemporaneous documentation of CGMP activities increases the likelihood ofrecording erroneous data (21 CFR 211.188). 贵公司没有记录所有已执行的CGMP行动。缺少同期登记CGMP活动的书面文件，增加数据记录错误发生的可能性(21 CFR 211.188)。 For example, your firm failed to ensuretesting documentation was complete and accurate. For example, on October15, 2013, our inspection revealed analysts working with unlabeled tubesreportedly of (b)(4) to perform the (b)(4) UV-Vis test. When enteringthe data onto the UV Spectrophotometer, the analyst entered “unknown” in thesample identification column for each sample where the lot number and samplenumber should have been recorded. In addition, examination of the (b)(4) UV-Vis test from September 02,2013, revealed that the analyst had entered “unknown” in the sampleidentification column for each sample. Later, we noted that the analyticalworksheet from September 02, 2013, had appropriate sample identifiers; however,the raw data on the worksheetcannot be properly linked to the sample preparations. In your response,you indicate that the analyst remembered the order in which the samples wereprepared and placed into the test tube rack. We are concerned that yourely on the memory of your employees, rather than on actual supportingdocumentation. A basic principle of CGMP is to record activities at thetime of performance to ensure that complicated activities and critical stepsare performed according to written procedures. Identifying samples undertest is essential to the integrity of the analysis. 例如，贵公司不能确保检测文件的完整性及正确性。例如，2013年10月15日，审计官发现分析人员工作时使用无标识试管，进行UV-Vis检测。 In addition, our inspectiondocumented multiple instances where the analysts did not record raw materiallot numbers during sample preparation, making it impossible to link the rawmaterials used to the appropriate test worksheet. This raises concernsabout the authenticity of the data that your laboratory testinggenerates. 另外，审计文件多个实例表明分析人员在样品配制过程中没有记录原辅料的批号，使其不能与所使用的原辅物料检测工作表相连接，从而导致对贵司实验室检测产生数据真实性的担忧。 Your firm’s response states thatyou will revise relevant test records and SOPs, and conduct training on these revisions. Yourdescribed corrective actions are insufficient to ensure that you can determinethe extent of your CGMP deficiencies and their effect on product quality. Theyare also insufficient to prevent recurrence of the deficient practices. 贵司回复称：贵司已修改了相关的检测记录和SOP，并对这些修改进行了培训。贵司所描述的整改行动不够充分，不能保证贵司可以确定贵司的CGMP缺陷程度及对产品质量的影响。同样，也不能防止这些缺陷的再发生。 The deviations and violationscited in this letter are not intended to be an all-inclusive list of deviationsand violations that exist at your facility. You are responsible forinvestigating and determining the causes of the deviations identified above andfor preventing their recurrence and the occurrence of otherdeviations. 贵司所存在的违规和缺陷并不仅局限于此封信件所提及的内容。贵公司有责任对其真正原因进行调查和判断。 SUMMARY总结 The above examples are seriousCGMP deficiencies and violations demonstrating that your quality system doesnot adequately ensure the accuracy and integrity of the data generated andavailable at your facility to support the safety, effectiveness, and quality ofthe APIs and drug products you manufacture. We strongly recommend that youhire a qualified third party auditor/consultant with experience in detectingdata integrity problems to assist you with coming into compliance with CGMPregulations and statutory authorities. In your response to this letter, providethe following to the Agency: 以上例子均为严重的CGMP缺陷与违规，说明贵公司的质量系统不恰当，不能保证产生数据的正确性与完整性，不能有效支持贵司生产API及成品的安全性，有效性及质量。我们强烈建议贵司聘请一位在数据完整性方面有着丰富检验，有资质的第三方审计官/顾问对贵司在CGMP规范及法定权限方面提供支持。在对此封信件的回复中，请贵司提供后续跟踪。 1. Acomprehensive evaluation of the extent of the deletion and destruction ofrecords. As part of your comprehensiveevaluation, provide a detailed action plan to investigate the extent of thedeficient documentation practices; 对记录的删除及破坏进行综合评估。作为综合评估的一部分，请提供一份详细的行动方案，对有缺陷的文件操作范围进行调查。 2. A riskassessment regarding the potential effect on the quality of APIs and drugproducts. As part of your risk assessment, determine the effects of yourdeficient documentation practices on the quality of the API and drug product releasedfor distribution; and 对API和药品质量有潜在影响的风险评估。作为风险评估的一部分，对贵司已放行销售的API及药品质量有影响的缺项性文件操作进行判断，并 3. A managementstrategy for your firm that includes details of your global corrective actionand preventive action plan. 贵公司的管理战略，包括详细的全球整改行动及预防方案 。 a) As part of your corrective actionand preventive action plan, describe the corrective actions you will take, such ascontacting your customers, recalling product, conducting additional testingand/or adding lots to your stability programs to assure stability, monitoringof complaints, or other steps to assure the quality of the product manufacturedunder the deficient and violative conditions discussed above. 作为贵司整改预防行动计划的一部分，请贵司描述在以上所提及的缺陷及违规环境下，贵司即将采取哪些整改行动，如与客户联系，召回产品，进行额外检测或在稳定性程序中增加批次，来确保稳定性及对投诉的监控，或其他确保产品质量的措施。 b) In addition, as part of yourcorrective action and preventive action plan, describe the preventiveactions you will take, such asrevising procedures, implementing new controls, training or re-trainingpersonnel, or other steps to prevent the recurrence of CGMP violations,including breaches of data integrity. 另外，作为贵司整改及预防行动计划的一部分，请描述贵司即将采取的预防措施，如修改程序，执行新的控制，对人员进行培训和再培训，或其他防止CGMP违规再发生及数据完整性违背方面的其他步骤。 If, as a result of receiving thiswarning letter or for other reasons, you are considering a decision that couldreduce the number of finished drug products or active pharmaceuticalingredients produced by your manufacturing facility, FDA requests that youcontact CDER's Drug Shortages Program immediately, as you begin your internaldiscussions, at drugshortages@fda.hhs.gov so that we can work with you on themost effective way to bring your operations into compliance with thelaw. Contacting the Drug Shortages Program also allows you to meet anyobligations you may have to report discontinuances in the manufacture of yourdrug under 21 U.S.C. 356C(a)(1),and allows FDA to consider, as soon as possible, what actions, if any, may beneeded to avoid shortages and protect the health of patients who depend on yourAPIs and drug products. Until all corrections have beencompleted and FDA has confirmed corrections of the deviations and violationsand your firm’s compliance with CGMP, FDA may withhold approval of any newapplications or supplements listing your firm as a drug product or an APImanufacturer. In addition, your failure to correct these deficiencies mayresult in FDA refusing admission of articles manufactured at Novacyl WuxiPharmaceutical Co., Wuxi, China into the United States under Section 801(a)(3)of the Act, 21 U.S.C. 381(a)(3). The articles may be subject to refusal ofadmission pursuant to Section 801(a)(3) of the Act, 21 U.S.C. 381(a)(3), inthat the methods and controls used in their manufacture do not appear toconform to CGMP within the meaning of Section 501(a)(2)(B) of the Act, 21 U.S.C.351(a)(2)(B). Within fifteen working days ofreceipt of this letter, please notify this office in writing of the specificsteps that you have taken to correct and prevent the recurrence of deviations,and provide copies of supporting documentation. If you cannot completecorrective actions within fifteen working days, state the reason for the delayand the date by which you will have completed thecorrections. Additionally, if you no longer manufacture ordistribute (b)(4) or (b)(4), provide the date(s) andreason(s) you ceased production. Please identify your response with FEI #3004117396. Please send your reply toDavid S.Jones, Compliance Officer, White Oak Building 51, Room 4220, 10903 New Hampshire Ave, Silver Spring, MD 20993-0002. Sincerely, /S/ Thomas Cosgrove Acting Director, Office of Manufacturing andProduct Quality Office of Compliance Center for Drug Evaluation andResearch
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发表于 2015-1-13 09:15:26
