被FDA认为是假药！海正收到FDA警告信（附全文）
医药新势力
前几日，海正药业对FDA的警告信内容发表过声明，详见《海正药业：关于FDA对台州工厂原料药检查出具警告信的公告》 FDA官网发布对浙江海正警告信，签署日期为2015年12月31日。英文原文下载：翻译件参见下面（部分英文内容略）。警告信全文翻译内容，。 FDA在-7日检查了你们在Zhejiang HisunPharmaceutical Co., Ltd., 46 Waisha Road, Jiaojiang District, Taizhou City,Zhejiang Province的生产场所。我们发现原料药的生产严重偏离了CGMP要求。 这些偏差导致你们的药品根据联邦食品药品和化妆品法案21 U.S.C. 351(a)(2)(B)第501(a)(2)(B)条，“其生产、加工、包装或存贮所用方法、设施或检测不符合GMP”，被认为是假药。 我们已经详细审核了你们于日给出的回复，也收到了之后的回复。 我们的调查员在检查中发现了一些问题，包括但不仅限于以下： 未能防止不经授权获取或更改数据，未能提供充分的控制以防止数据被篡改及数据遗失。 During the inspection, FDA investigators discovered a lack of basiclaboratory controlsto prevent changes to your firm’s electronically storeddata and paper records.Your firm relied on incomplete records to evaluatethe quality of your drugs and to determine whether your drugs conformed withestablished specifications and standards. 在检查中，FDA调查人员发现缺失了基本的化验室控制，无法防止对贵公司电子存贮数据和纸质记录的更改。贵公司依赖于不完整的记录来评估你们药品的质量，决定你们的药品是否符合既定的规格和标准。 Our investigators found that your firm routinely re-tested samples withoutjustification and deleted analytical data. We observed systemic datamanipulation across your facility, including actions taken by multiple analysts,on multiple pieces of testing equipment, and for multiple drugs. You areresponsible for determining the causes of these deviations, for preventingrecurrence, and for preventing other deviations from CGMP.我们的调查人员发现贵公司经常对样品进行复试，而没有相关论证，并且将分析数据进行了删除。我们在你们整个工厂都发现有数据造假现象，包括多个化验员在多种药品多个检测设备上所做的事情。贵公司有责任确定这些问题的原因，以防止同样问题再次发生，以及防止其它偏离CGMP的问题发生。 a.During the inspection, we reviewed the electronic logfor high performanceliquid chromatography (HPLC) system #36 and determinedthat the audit trail was disabled on February 6, 2014. One of youranalysts executed 80 HPLC injections for assay and impurity tests of validationstability batches (b)(4) of (b)(4) API. 在检查中，我们审核了36#HPLC系统的电子日志，确定日其审计追踪没有激活。贵公司一名化验员在当日进样80针，是某原料药某验证稳定性批次的含量和杂质检测。 Becausethe audit trail was disabled, neither your quality unit nor yourlaboratorystaff could demonstrate that records for these batches includedcomplete andunaltered data. All supporting raw data was discarded,including sample solution dilutions and balance weight printouts. Sampleanalyses were not recorded in the instrument use logbook. Test resultswere deleted from the hard drive and all supporting chromatograms werediscarded. Audit trail functions were re-enabled on February 8, 2014, andthe same analyses were repeated. You submitted the February 8th testresults to the FDA in March 2014 in support of Drug MasterFile (DMF) (b)(4).由于审计追踪被关闭，你们的质量部门和化验室员工都不能证明这些批次的记录包括的是完整未经伪造的数据。所有支持性原始数据均被弃去了，包括样品溶液稀释记录和天平称量打印纸。样品分析没有记录在仪器使用日志上。检验结果被从硬盘删除了，所有支持性色谱图均被废弃。审计追踪功能在日重新激活，然后重复了相同的样品检测。你们在2014年3月向FDA提交了2月8日的检测结果用以支持某原料药的DMF文件。 During the inspection, we asked the analyst who generated the datasubmitted to the FDA whether audit trails could be disabled. The analyststated that another employee, who was no longer with the company, had disabledthe audit trails. Your firm could not explain why the audit trail wasdisabled or why the original data was deleted, nor could you demonstratewhether the original results were within specification.在检查中，我们就审计追踪是否可以关闭的问题询问了实施检测获得FDA申报数据的化验员。化验员说是另一名化验员关闭的审计追踪功能，但该名化验员已经离开了公司。贵公司不能解释为什么审计追踪会被关闭，也不能解释为什么原始数据会被删除，更无法证明原始结果是否符合质量标准规定。 In your response, you assumed that the original raw data was deleted becausea systemsuitability failure invalidated the data. You acknowledged thatthe data shouldnot have been invalidated without an investigation of thelaboratory event.However, your response is inadequate. There is noevidence to supportinvalidation of the original data on the grounds of asystem suitability failurebecause your firm deleted all of the originalrecords associated with theseanalyses.在你们的回复中，你们假定初始的原始数据是因为系统适用性失败导致结果无效才被删除的。你们承认不应该没有经过化验室事件调查即行宣布数据无效。你们的回复不够充分。没有证据支持你们关于“初始的原始数据是因为系统适用性失败导致结果无效才被删除的”的说法，因为贵公司已删除了那些样品分析的所有原始记录。 b. While reviewing the electronic log for HPLC system#28, we determined that two of your analysts deleted portions of HPLC samplesequence
during assay, impurities, and identity testing for (b)(4)APIbatches (b)(4), and (b)(4).在审核28#HPLC系统时，我们确定有两名化验员删除了HPLC样品序列中的部分数据，这个序列是某原料药某批和某批的含量、杂质和鉴别测试。 Duringthe inspection, the investigator reviewed the data package that yourfirm usedfor batch release decisions for this drug. This data packageincluded resultsfrom 44 HPLC injections. However, the electronic audittrail from the instrumentused to generate these results showed that there werea total of 61 injections.Raw data for 17 of the 61 injections was deletedfrom the reported sequence asif the injections had never beenperformed. The investigator later discoveredthe missing data in a backupfolder.在检查期间，我们的调查人员审核了贵公司用于该药品批放行决策的数据包。该数据包括了44针HPLC进样结果，但是，用以产生这些结果的仪器上的电子审计追踪显示总共有61针。这61针中的17针原始数据被从报告序列中删除了，就好像没有进过这17针样似的。调查人员后来在一个备份文件夹里发现了这些失踪的数据。 You stated in your response that these specific API batches “were sold to[the]Chinese market” and that you planned to retest batches (b)(4) todetermine whether they are within specification. 你们在回复中声称这些特殊的原料药批号是“要销往中国市场的”，你们准备要对某批进行复测，以确定其是否符合质量标准。 You also stated in your response that the missing portions of the samplesequence were actually injections conducted for training, so product qualitywas not affected by the deletions. This response is inadequate, because,regardless of the reason for conducting the injections, your laboratory recordsmust retain all original raw data. 你们在回复中还声称样品序列中那些失踪的部分实际上是为了培训进的针，因此产品质量不受数据删除的影响。此回复是不充分的，因为不管出于什么原因进了针，你们化验室都必须保留所有初始的原始数据。 c.While reviewing the audit trail on HPLC system #28, wedetermined that one of your analysts performed trial HPLC injections duringassay and impuritiestesting for batches of (b)(4)API ((b)(4)and (b)(4)). These trial injectionswere performed on May 4-6,2014. The data for the sample set was deleted fromthesystem. Testing was not recorded in the instrument use logbook. Allsupporting electronic raw data was discarded. Testing results for thesebatches were then recorded on May 7, 2014, when the analyses were repeated usingHPLC system #32. 在审核28#HPLC审计追踪时，我们确定有一名化验室在某原料药某批和某批的含量和杂质测试中有试针。这些试针是在-6日进行。样品序列的数据被从系统中删除了。仪器使用日志中没有记录该检测。所有支持性电子原始数据均被弃去。这些批次的测试结果随后被记录在日，这天使用的是32#HPLC系统重复了该样品检测。 Duringour inspection, one of your analysts provided the original analysesworksheetsto review. According to this analyst, tests were repeatedbecause of poor columnefficiency. The analyst neither initiated aninvestigation of the laboratory event nor documented the original analyses inthe instrument use logbook. Theanalyst did not respond when we asked whythe initial chromatograms were deleted. 在我们的检查中，贵公司一名化验员提供了原始的检验记录供审核。根据此名化验员所述，重复测试是因为柱效太差。化验员没有启动化验室事件调查，也没有在仪器使用日志上记录原始检测信息。当我们质疑为什么会删除原始图谱时，这名化验员没有回答我们。 However, in your written response, you claimed that this analyst laterrecalled deleting the data (chromatogram) because column inefficiency may haveinvalidated the data. Your quality unit must review all pertinentanalytical data when making batch release decisions. When analysts deletenonconforming test results, the quality unit is presented with incomplete andinaccurate information about the quality of the products. Your responsedoes not demonstrate how your laboratory procedures prevent the deletion ofdata or how the quality unit ensures that the records relied upon for batchrelease and other quality review decisions are complete and accurate. 在你们的书面回复中，你们声称该名化验员后来回想起删除这些数据（图谱）是因为柱效差，可能会使得数据无效。你们质量部门在做出批放行决策时，必须审核所有可能的分析数据。如果化验员删除了不符合的测试结果，质量部门看到的是不完整不准确的产品质量信息。你们的回复没有说明你们化验室程序如何防止数据删除，以及你们质量部门如何确保其赖以放行批产品和做出其它质量审核决策的记录是完整准确的。 Our concerns about deletion of data are heightened by the significantnumber of customer complaints for subpotency and out-of-specification (OOS)impuritylevels from . We observed data deletion in your laboratoryrelated toassay and impurity levels during this time period. During theinspection, weasked to review your lab’s raw analytical data of the lotsassociated with fourof the 61 complaints. However, you were unable toprovide the raw data because it had been deleted. Without raw test datafor the lots associated with these complaints, your firm could not adequatelyinvestigate the complaints, nor could you expand your investigation todetermine whether other lots were affected by the same problems or takecorrective actions, such as recalling drugs if appropriate.在年大量关于含量不够和杂质超标（OOS）的客户投诉中，我们对于数据删除的担心更加增强了。我们发现在此期间你们化验室在删除含量和杂质相关数据的现象。在检查中，我们要求查看你们化验室在61个投诉中的4个投诉中相关批次的原始分析数据，但是，你们无法提供这些原始数据，因为它们都已经被删除了。没有这些投诉相关批次的原始检测数据，贵公司无法对客诉进行充分调查，也无法扩展你们的调查来确定是否有其它批次受到相同问题的影响，也无法采取纠正措施，例如必要时的产品召回。 We acknowledge your commitment to hire a third-party consultant, set upuser access restrictions, and upgrade computerized systems with audittrails. However, simply activating audit trail functions and institutingpassword controls are insufficient to correct the broad data manipulation anddeletion problems observed at your facility and to prevent theirrecurrence. 我们已收到贵公司的承诺。你们承诺将会聘请第三方顾问，设定用户权限限制，升级至具有审计追踪功能的电脑系统。但是，仅仅是激活审计追踪功能，设置密码控制是不足以纠正在贵工厂发现的大量存在的数据做假和数据删除问题，防止其再次发生的。 Your management is responsible for the assuring that the scope and extentof the third party audit is adequate, including a full evaluation ofsophisticatedelectronic systems and their potential formanipulation. Your management is also responsible for fully documentingand preserving records.贵公司高层管理有责任确保第三方审计的范围和深度是充分的，包括对复杂电子系统和其做假可能性的全面评估。贵公司高级管理层还有责任保证全面的文件记录和记录保存。 For more information about handling OOS results and documentation ofyourinvestigations, please refer to Investigating Out-of-Specification (OOS)Test Results for Pharmaceutical Production at
and Questions and Answers on Current GoodManufacturing Practices, GoodGuidance Practices, Level 2 Guidance—Records and Reports at 关于OOS结果处理，以及贵公司调查的文件记录的更多信息，请参见“药品OOS结果调查指南”和CGMP问答，二级指南---记录和报告。 In your response to this letter, provide the following:在贵公司对此函的回复中，应提供以下内容： A comprehensive investigation and evaluation. Describe yourmethodology. Results should include conclusions about the extent of dataintegrity deficiencies and their root causes, which may involve record control,contemporaneous recording, deletion of data, and other data integritydeficiencies. 一份全面的调查和评估。说明你们的方法。结果应包括数据完整性缺陷的广泛程度及其根本原因结论，这可能会涉及记录控制、同步记录、数据删除，以及其它数据完整性缺陷。 A risk assessment of how the observed deficiencies may affect thereliability and completeness of quality information available for yourdrugs. Also determine the consequences of your deficient documentationpractices on the quality of drugs released for distribution.一份风险评估，评估所发现的缺陷对你们产品可获得质量信息的可靠性和完整性的可能影响。还要确定你们有缺陷的文件记录做法对已放行销售的药品的质量产生的后果。 A management strategy that includes a detailed global corrective action and preventive action plan.
一份管理策略，其中包括详细的全球纠正和预防措施计划。 Describe the actions you will take, such as contacting your customers,recalling drugs, conducting additional testing and/or adding lots to yourstability programs, or other steps to assure the quality of your drugsmanufactured under the deficientconditions discussed above. 描述贵公司将要采取的行动，例如联系你们的客户、召回药品、实施附加测试和/或增加批次到你们的稳定性试验计划中，或其它措施来确保上述缺陷境况下你们生产的药品质量。 Describe the actions you will take, such as revising procedures,implementing new controls, training or re-training personnel, or other steps toprevent the recurrence of CGMP deviations, including breaches of dataintegrity.描述你们要采取的措施，例如修订程序、实施新的控制、人员培训或再培训，或其它措施来防止CGMP问题的再次发生，包括数据完整性问题。 2.Failure to conduct appropriate microbiological testingon API batches wheremicrobial quality is specified. 当原料药批次要求有微生物质量时，未能进行适当的微生物测试。 On March 2, 2015, we observed that all 14 culture media plates in incubator#6 were dried out and cracked, which compromised microbial growth promotion andaccurate enumeration. These plates were used to test multiple API batchesof (b)(4) and (b)(4) and (b)(4)).在日，我们发现在6#培养箱中的所有14个培养基碟已经干了并且都裂了，这种情况无法促进微生物生长及对其准确计数。这些碟子是用于测试多批原料药某批和某批。 Your investigation concluded that deformed glass plates caused the media tocrack. In your response, you claimed that the issue was isolated to the 14culture media plates and that you retested these (b)(4) batches. 你们的调查得出结论说玻璃碟变形导致培养基裂开。在你们的回复中，你们声明该问题和14个培养基碟不相干，然后你们复测了这些批次。 Yourresponse is inadequate because your investigation did not evaluate the(b)(4) other associated batches tested with culture media plates fromthe same lot containing deformed glass plates. In addition, we disagreewith your claim that these dried culture media plates were isolated to the 14plates we observed on March 2, 2015. On March 5, 2015, we observed twoadditional culture media plates in incubator SPX-150, SeriesNo. -0003, which also showed signs of drying out. 你们的回复是不充分的，因为你们的调查没有评估使用相同的变形玻璃碟进行测试的其它某相关批次。另外，我们不认同你们声明说这些干裂的培养基碟与我们在日发现的14只碟不相干。在日，我们发现在SPX-150，序号为No. -0003的培养箱中有另外2只培养基碟，也显示出干掉的迹象。 From 2012 to 2014, several of your customers complained that microbialresults were OOS when they tested your API upon receipt. In your response,you concluded that the percentage of customer complaints reporting OOSmicrobial test results was insignificant. You attributed the customers’OOS microbial results to test methods that differ from your own. 从年，你们的几个客户投诉说收到你们的原料药进行检测时发现微生物结果超标（OOS）。在你们的回复中，你们给出的结论是只有很少客户投诉微生物检测结果超标。你们将客户的微生物OOS结果归因于他们使用的检测方法与你们的方法有差异。 Your response lacks your findings and corrective actions from yourrecentinvestigation of dried out and cracked culture media plates. Forexample,you did not retest the batches that received OOS microbial complaints, even afterwe pointed out this deficiency. You lack scientific justification toconclude that your customers’ OOS findings are inaccurate or insignificant.你们的回复中没有说明你们最近对干裂培养基碟调查后发现的情况和纠正措施。例如，你们没有复测所收到的OOS微生物投诉批次，甚至在我们指出该缺陷后也没有复测。你们缺乏科学的论证来支持你们所说的“你们客户的OOS发现是不准确的或无意义的”结论。 In your response to this letter, provide the following:在贵公司对此函的回复中，请提供以下： An accelerated timeline for completing retroactive microbial testing of allpotentially-compromised batches via an independent laboratory, and a commitmentto respond with all results promptly. 一份时间表，通过独立的化验室加快完成追溯所有潜在受影响批次的微生物测试，承诺将对所有结果立即做出回应。 Your review of all microbial test methods to ensure they are suitable fortheir intended use.你们对所有微生物测试方法进行的审核，以确保这些方法均适合于其既定用途。 A detailed update on whether your firm has implemented any further riskmitigations, such as purchasing prepared culture plates from qualified outsidevendors.一份详细的更新，说明贵公司是否已实施任何进一步风险降低措施，例如，从经过确认的采购已制备好的培养基碟。 Your improved deviation and corrective action and preventive actionmanagement procedure.你们改进后的偏差和CAPA管理程序 Documentation of all changes implemented as a result of your review andremediation of these issues.在你们审核并弥补了这些问题后，所有实施变更的文件记录，
Access to information during inspection 检查期间获得资料的情况 We note that some records we requested during the inspection were notprovided in a timely manner. 我们注意到，在检查期间我们索取了一些记录，你们不能及时提供。 During the inspection, an analyst removed a USB thumb drive from a computercontrolling an HPLC. When asked to provide the drive, the analyst insteadexited the room with the thumb drive. After approximately 15 minutes,management provided our investigator with what they asserted was the USB thumbdrive in question. It is impossible to know whether management providedthe same USB thumb drive that the analyst had removed. 在检查期间，一名化验员从一台HPLC仪器控制电脑中拨出一个U盘。当我们要求提供这个U盘时，该化验员带着U盘离开了房间。在约15分钟之后，管理人员提供给我们调查人员一个U盘，他们说这就是当时被化验员带走的U盘。我们无法知道管理人员所提供的U盘是否正是该名化验员所拨出的U盘。 When an owner, operator, or agent delays, denies, limits, or refuses aninspection, the drugs may be adulterated under section 501(j) of the FD&CAct. We recommend that you review FDA’s guidance for industry Circumstancesthat Constitute Delaying,
Denying, Limiting, or Refusing a Drug Inspection at: 当企业主、操作员或代理延误、否定、限制或拒绝检查时，根据美国食品药品化妆品法案第501(j)部分规定，其药品将被作为假药处理。我们建议你们核对FDA行业指南“被认为是延误、否定、限制或拒绝药品检查的情形”。
Conclusion结论 Deviations cited in this letter are not intended as an all-inclusive list. Although we acknowledge and appreciate your significant efforts toimplement correctiveactions to date, FDA will conduct a follow-up inspectionfollowing the completeimplementation of global corrective actions. 在本函中引用的偏差并无意成为完整的问题清单。尽管我们收到并感谢你们到今天为止为所实施的纠正措施付出的巨大努力，但FDA将在你们完成全球纠正措施实施后进行跟踪检查。 If, as a result of receiving this warning letter or for other reasons, youareconsidering a decision that could reduce the number of drugs produced byyourmanufacturing facility, FDA requests that you contact CDER's DrugShortagesStaff immediately, as you begin your internal discussions, at drugshortages@fda.hhs.gov so that we can work with you on the most effective way to bring youroperations into compliance with the law. Contacting the Drug ShortagesStaff also allows you to meet any obligations you may have to reportdiscontinuances in the manufacture of your drug under 21 U.S.C. 356C(a)(1), andallows 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 yourproducts.如果因为收到本警告信或其它原因，贵公司考虑可能会决定减少贵生产场所药品生产量，FDA要求你们立即联系CDER药品短缺人员。当你们开始内部讨论时，请发邮件至上述邮箱，这样我们可以与你们一起以最有效的方式让你们回复符合法律要求的状态。联系药品短缺办公室也会让你履行所有可能义务，根据21 U.S.C. 356C(a)(1)要求报告药品生产中断情况，让FDA在可能时即行考虑需要采取何种措施（必要时）来避免短缺，保护依赖贵公司药品的患者健康。 Until you complete all corrections and FDA confirms your compliance withCGMP, FDA may with hold approval of any new applications or supplements listingyour firm as a drug manufacturer. 在贵公司完成所有纠正措施，FDA确认贵公司符合CGMP之前，FDA会暂停贵公司作为药品生产商所提交的所有新申报和增补申报。 Because of the findings of the FDA inspection described herein, your firmwas placed on Import Alert 66-40 on September 9, 2015. If you fail tocorrect thesedeviations, FDA may continue to refuse admission of articlesmanufactured atZhejiang Hisun Pharmaceutical Co., Ltd., 46 Waisha Road,Jiaojiang District,Taizhou City, Zhejiang Province, under Section 80l(a)(3) ofthe FD&C Act, 21U.S.C. 38l(a)(3) as the manufacturing methods and controlsdo not appear toconform to CGMP within the meaning of Section 501 (a)(2)(B) ofthe FD&C Act,21 U.S.C. 351 (a)(2)(B).鉴于FDA检查期间发现的问题，已于日将贵公司置于66-40进口禁令清单中。如果贵公司未能纠正这些问题，FDA将会根据联邦食品药品和化妆品法案21 U.S.C. 38 (a)(3)第801(a)(3)部分条款，拒绝许可所有在Zhejiang Hisun Pharmaceutical Co., Ltd., 46 Waisha Road, JiaojiangDistrict, Taizhou City, Zhejiang Province生产的产品，因为其生产方法和控制不符合联邦食品药品和化妆品法案21 U.S.C. 351 (a)(2)(B)第501(a)(2)(B)部分CGMP要求。 Within 15 working days of receipt of this letter, please notify thisoffice, inwriting, of the specific steps that you have taken to correct andprevent therecurrence of deviations detailed in this letter. 在收到此函15个工作日内，请书面通知以下办公室你们已采取的纠正和预防本函所列问题再次发生的详细措施。 If you cannot complete corrective actions within 15 working days, stateyour reasons for the delay and the date by which you will have completed thecorrections. If you no longer manufacture or distribute the drugs atissue, provide the date(s) and reason(s) you ceased production. Send yourreply to:如果你不能在15个工作日内完成纠正措施，请说明延误的原因，以及完成纠正措施的预计日期。如果你不再生产或销售受影响药品，请提交停产日期和原因。回复请发至：（地址信息略）翻译：julia朱玉姣 来自：蒲公英1.13央视焦点访谈对海正药业专题报道，CCTV1焦点访谈海正辉瑞。海正坚持了4年，从海正转到海正辉瑞继续亏本生产，能升价但不升价考虑更多的是消费者的心理，考虑更多的是国人健康与保障。包含海正辉瑞---甲强龙，美卓乐， 美特（美罗培南）， 海正力星（替加环素）这些紧急短缺廉价药。}