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Warning Letter 320-16-24 Via UPS Return Receipt Requested August 4, 2016 Mr. Jiang Xiao Yue CEO Zhejiang Medicine Co. Ltd. Xinchang Pharmaceutical Factory Floor 3, Building A Kechuangyuan 398 Mahuan Road, Binhaixincheng Shaoxing, Zhejiang 312366 China Dear Mr. Yue: The U.S. Food and Drug Administration (FDA)inspected your drug manufacturing facility, Zhejiang Medicine Co., Ltd.,Xinchang Pharmaceutical Factory, at 98 East Xinchang Dadao Road, Xinchang,Zhejiang, from June 15–18, 2015. FDA于2015年6月15-18日检查了你们位于浙江新昌的工厂。 This warning letter summarizes significant deviationsfrom current good manufacturing practice (C GMP) for active pharmaceuticalingredients (API). 此警告函总结了原料药偏离CGMP要求的重大缺陷。 Because your methods, facilities, or controls formanufacturing, processing, packing, or holding do not conform to CGMP, your APIare adulterated within the meaning of section 501(a)(2)(B) of the Federal Food,Drug, and Cosmetics Act (the FD&C Act), 21 U.S.C. 351(a)(2)(B). 由于你们生产、加工、包装或存贮的方法、设施或控制不符合CGMP要求，你们的原料药被认为是掺假药。 We reviewed your firm’s July 8, 2015, response indetail and acknowledge receipt of your subsequent responses. 我们仔细审核了你们公司于2015年7月8日发出的回复及随后回复。 Our investigators observed specific deviationsincluding, but not limited to, the following. 我们的调查员发现的具体问题包括但不仅限于： 1. Failure to havelaboratory control records that include complete data derived from all testsconducted to ensure compliance with established specifications and standards. 没有化验室控制记录，包括从所有为保证符合既定质量标准检测中产生的完整数据。 Your laboratory personnel conducted unofficial testingwithout appropriate documentation, justification, and investigation. 你们化验室人员实施了非正式测试，而没有适当的文件记录、论证和调查。 Our inspection found that analysts performed multiplegas chromatography (GC) analyses of (b)(4) samples for residualsolvents. Analysts performed these unofficial analyses and recorded them inseparate “R&D” folders before conducting the officially reported sampleanalyses. The original, unofficial analyses stored in separate R&D folderswere not part of the official quality control records for your API, and yourfirm did not consider the results of these unofficial analyses to evaluate thequality of your API or make batch release decisions for numerous batches ofAPI. 我们的检查发现化验员对XX样品残留溶剂进行了多次GC分析。化验室实施这些非正式分析并将它们记录在单独的“研发”文件夹中，然后再进行正式样品分析，报告结果。原始的非正式分析被存贮在单独的研发文件夹中，并不是你们原料药的正式QC记录的一部分，并且你们公司在评估你们原料药质量以及做出大量原料药批的批放行决策时并没有考虑这些非正检测的结果。 Our investigator reviewed chromatograms found in theR&D folders and noted that some displayed large unknown peaks that were notreported in the official records for the same samples. The presence of suchpeaks in the chromatograms may indicate the presence of unknown anduncharacterized impurities (including potential contaminants) in yourdrugs. 我们调查人员审核了在研发文件夹中发现的色谱图，注意到其中一些显示出很大的未知峰，而这些在相同样品的正式记录中并没有报告。这些峰出现在图谱中可能表示你们的药品中有未知未识别的杂质（包括潜在污染物）。 In your response, you stated that from April to July2013 you performed “pre-trial” sample analyses for residual solvent testing of (b)(4)batches to check system suitability. You also stated you were not testinginto compliance and attempted to attribute the unknown peaks found in your“pre-trial” sample analyses to operator error. FDA considers the use of anactual sample in test, prep, or equilibration runs as a means of disguisingtesting into compliance, a violation of CGMP. 在你们的回复中，你们声称自2013年4月-7月间，你们进行了XX批残留溶剂的“试测”样品分析，用以检查系统适用性。你们还声称你们并不是在实施符合性导向检测，然后试图将在你们“试测”样品分析中的未知杂质归因于操作人员错误。FDA认为在检测、准备或仪器平衡时使用一个实际的样品是掩盖符合性导向检测的方法，是违反CGMP要求的。 2. Failure to exercisesufficient controls over computerized systems to prevent unauthorized access orchanges to data, and failure to provide adequate controls to prevent omissionof data. 未能对计算机化系统实施充分的控制，以防止未经授权的进入或改变数据，未能提供足够的控制来控制数据删除。 Our investigator found that your GC system used totest for residual solvents in (b)(4) lacked controls to preventmanipulation, data deletion, and unauthorized access. For example, operatorsresponsible for generating CGMP records had full administrator rights to accessthe computers containing temporary data prior to routine transfer of the datato a server. All analysts shared a common login ID and password. Your use of universaladministrator privileges and a single common login/password meant that actionscould not be traced to specific individuals. Additionally, because the audittrail feature on the system’s software was not configured to create a filehistory for all activities executed by the user during analysis, yourelectronic data was exposed to manipulation and/or deletion withouttraceability. 我们调查人员发现你们用于XX批检测残留溶剂的GC系统缺乏控制，不能防止篡改、删除数据，以及未经授权的进入。例如，负责制作CGMP记录的操作人员有全部的计算机管理员权限在数据被常规地转移至服务器之前登录存有临时数据的计算机。所有化验员共用一个相同的登录帐号和密码。你们使用了通用的计算机管理员李娜，和单一通用的登录密码表示所做的操作无法追踪至具体的个人。另外，由于系统软件的审计追踪并没有进行参数设置，为分析期间用户实施的所有活动创建一个文件历史，你们的电子数据暴露于篡改和/或删除之下，并且没有可追踪性。 3. Failure to recordactivities at the time they are performed. 未在活动实施的同时进行记录。 During the inspection, our investigators observed (b)(4)different analysts pre-dating or backdating results in your API quality controllaboratory. Analysts were observed using pre-dated laboratory worksheets todocument system suitability testing for high performance liquid chromatography(HPLC) analyses for (b)(4) purity testing. The worksheets were datedfive days before the tests that they purported to document were actuallycarried out. Our investigators also observed analysts signing and datingmicrobiological testing laboratory worksheets five days before the test resultswould be available and backdating laboratory worksheets for impurities andcontent testing by four days. 在检查期间，我们的调查员发现XX不同的化验员将你们原料药QC实验室的结果提前或倒签日期。发现化验员使用提前写好日期的实验室记录表来记录HPLC的XX纯度检测系统适用性测试分析。检验记录日期是他们实际实施测试之前的5天的日期。我们调查人员还发现在微生物检验记录上，化验员在能够获得检验结果之前5天就签字并注明了日期，杂质和含量检测记录则是倒签了4天之前的日期。 Data Integrity Remediation 数据完整性弥补 Your quality system does not adequately ensure theaccuracy and integrity of data to support the safety, effectiveness, andquality of the drugs you manufacture. We strongly recommend that you retain aqualified consultant to assist in your remediation. In response to this letter,provide the following. 你们质量体系没有充分保证用以支持你们生产的药品的安全性、有效性和质量数据的准确性和完整性。我们强烈建议你们聘请一位有资质的顾问来协助你们弥补此问题。在回复此函时，请提供： A. A comprehensive investigationinto the extent of the inaccuracies in data records and reporting. Yourinvestigation should include: - 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.
- 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.
- 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.
- A comprehensive retrospective evaluation of the nature of the analytical testing 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.
B. A current risk assessment of thepotential effects of the observed failures on the quality of your drugs. Yourassessment should include analyses of the risks to patients caused bythe release of drugs affected by a lapse of data integrity and risks posed byongoing operations. C. A management strategy for yourfirm that includes the details of your global corrective action and preventiveaction plan. Your strategy should include: - 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.
- 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 data at your firm.
- 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.
- A status report for any of the above activities already underway or completed.
Conclusion Deviations cited in this letter are not intended as an all-inclusive list.You are responsible for investigating these deviations, for determining thecauses, for preventing their recurrence, and for preventing other deviations. If you are considering an action that is likely tolead to a disruption in the supply of drugs produced at your facility, FDArequests that you 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 theDrug Shortages Staff also allows you to meet any obligations you may have toreport discontinuances or interruptions in your drug manufacture under 21U.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 whodepend on your products. After you receive this letter, you have 15 working daysto respond to this office in writing. Specify what you have done since ourinspection to correct your deviations and to prevent their recurrence. If youcannot complete corrective actions within 15 days, state your completion dateand reasons for delay. Until you completely correct all deviations and weconfirm your compliance with CGMP, FDA may withhold approval of any newapplications or supplements listing your firm as an API manufacturer. Failureto correct these deviations may also result in FDA refusing admission ofarticles manufactured at Zhejiang Medicine Co., Ltd., Xinchang PharmaceuticalFactory, at 98 East Xinchang Dadao Road, Xinchang, Zhejiang, 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). Send your reply to: ChristinaAlemu-Cruickshank Consumer Safety Officer U.S. Food and DrugAdministration White Oak Building 51,Room 4359 10903 New HampshireAvenue Silver Spring, MD 20993 USA Please identify your response with FEI 3003631275. Sincerely, /S/ Francis Godwin Acting Director Office of Manufacturing Quality Office of Compliance Center for Drug Evaluation and Research Cc: Mr. Zhang Ding Feng Site Head Zhejiang Medicine Co.Ltd. Xinchang Pharmaceutical Factory 98 East Xinchang DadaoRoad Xinchang, Zhejiang312500 China
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发表于 2016-8-16 22:57:05
置顶卡
变色卡
发表于 2016-8-16 23:11:50
r如果员工要那样干，确实很难避免的！
