翻译：julia 来源：Julia法规翻译
Vital Laboratories Pvt Ltd Plant II 10/10/17
ViaUPS Warning Letter 320-18-01
October 10, 2017
Mr. Rajiv Bajaj
Director
Vital Laboratories Private Limited
Plot 1710 & A1 2208, Phase III GIDC
Vapi, Gujarat 396195
India
Dear Mr. Bajaj:
The U.S. Food and Drug Administration (FDA) inspectedyour drug manufacturing facility, Vital Laboratories Private Limited Plant-II,at Plot No.1710 & A1-2208, Phase III GIDC Estate, Vapi, Gujarat, from April3–6, 2017.
美国FDA于2017年4月3-6日检查了你们位于印度古吉拉特邦的生产场所Vital Laboratories Private Limited Plant-II。
This warning letter summarizes significant deviationsfrom current good manufacturing practice (CGMP) for active pharmaceuticalingredients (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 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 Cosmetic Act (FD&C Act), 21 U.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21 U.S.C. 351(a)(2)(B)被认为是掺假药品。
We reviewed your April 27, 2017 response in detail.
我们详细审核了你们公司2017年4月27日的回复。
During our inspection, our investigator observedspecific deviations including, but not limited to, the following.
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. Failure to ensure all productiondeviations are reported and evaluated, and that critical deviations areinvestigated and the conclusions are recorded.
未能确保报告及评估所有生产偏差，调查关键偏差并记录其结论。
Your firm failed to follow your written procedures forproduction and to report, evaluate, and investigate deviations from productionprocedures. For example, your (b)(4) batch records specify an in-processassay for (b)(4). You did not perform these in-process assay tests forat least five batches in 2016, but had no explanation for the failure toconduct these tests. Additionally, your (b)(4) batch records specify ayield reconciliation formula to (b)(4). Without any justification, youfailed to use the specified formula for at least three batches in2016.
你公司未能遵守自己的生产偏差报告、评估和调查程序。例如，你们的XX批记录显示XX有一个中控含量，但你们在2016年至少有5个批次并没有执行此中控含量测试，对未执行此测试也没有解释。此外，你们的XX批记录写明了XX的收率计算公式，但在2016至少有3个批次你们未经论证没有使用该指定公式。
In your response, you stated that the “for informationonly” in-process assay requirement for (b)(4) was “occasionallyperformed, without any rationale” because the (b)(4) in-process testprovided similar information and was within specifications for those batches.You also stated that you revised your master production records to remove thein-process assay test requirement: you only require it when(b)(4)values are out of specification. You also admitted that the (b)(4) yieldformula in the master production record was incorrect.
在你们的回复中，你们说XX的中控含量“仅供参考”，只是“偶尔执行，不需要理由”因为XX中控测试能提供类似的信息，并且这些批准都是在标准以内的。你们还说，你们会修订你们的主生产记录，删除此中控含量测试要求，你们只要求在XX值超出标准时才要求对该项进行测试。你们也承认主生产记录中的XX收率公式是不正确的。
Your response is inadequate. You did not review allyour production records to determine if other steps were “occasionallyperformed, without any rationale,” or if master batch record formulas for anyof your other drugs were incorrect.
你们的回复是不充分的。你们没有审核你们所有的生产记录以确定是否其它步骤是“偶尔执行，没有任何理由”，或者是否你们其它药品的主批记录公式是不正确的。
In your response to this letter, conduct and providethe results of a review of your firm’s production records to identify instancesof production deviations for all drugs distributed in the United States withinexpiry. Conduct a risk analysis to determine the product quality effects of anysuch identified failures, and indicate the specific steps you will take toinvestigate and respond to any critical deviations.
在你们对此函的回复中，请对你们公司的生产记录进行审核，识别出所有销售至美国的药品生产偏差的情况，并提交结果。进行风险分析以确定所有此类识别出的失败对产品质量的影响，写明你们将采取的具体调查措施，以及对关键偏差所做出的响应。
2. Failure to adequately documentthe completion of each significant step in the batch production records withsignatures of the persons performing and directly supervising or checking eachcritical step in the operation.
未能充分记录批生产记录中每个重要步骤的完成情况，连同其执行人员和直接监管或对操作中每个关键步骤检查的人员签名。
Your batch production records omitted signature fieldsto document who performed, directly supervised, and checked each critical stepin your manufacturing process. For example, the batch production record for (b)(4)batch (b)(4), Section E, Packing Details, indicates a grossweight of (b)(4), a tare weight of (b)(4), and a calculated netweight of (b)(4) for “Drum No. 4.” The correct calculated net weightshould be (b)(4). There are no signatures to identify who performed theweighing operation and who subsequently verified it. We also observed that the“done by” and “checked by” fields in many of your other batch productionrecords were completed by the same person. During the inspection, you statedthat it was general practice for supervisors to initial or sign for operators.
你们的批生产记录里没有记录执行、直接监管和检查你们生产工艺中每个关键步骤的人员签字的地方。例如，XX批XX产品的批生产记录，第E部分，包装详情，显示有一个XX的毛重、XX的净重、第4桶XX的计算净重。正确的计算净重应为XX。这里没有签名来识别出是谁执行的称重操作，又是谁在之后对此进行核查。我们还发现在你们的很多其它批生产记录中，“操作人”和“复核人”都是由同一个完成的。在检查期间，你们声称一般都是由主管代替操作人员签名或首字母签名。
In your response, you stated that you revised your (b)(4)batch records to include space for operators and verifiers to sign. Youexplained that supervisors were signing for operators because the operators’“hands were dirty” and your corrective action and preventive action (CAPA) wasto provide operators with gloves. Additionally, you noted that your batchrecords were in English but many of your operators only understand Hindi. Thus,you proposed bilingual English and Hindi batch records to improve operatorunderstanding and compliance.
在你们的回复中，你们声称你们修订了你们的XX批记录，在其中放进了操作人员和复核人员签名的地方。你们解释说主管代替操作人员签名是因为操作人员的“手很脏”，你们的CAPA是为操作人员提供手套。另外，你们提到你们的批记录是英文，而你们许多操作人员只懂印地语，因此，你们拟采用双语批记录来改进操作人员的理解水平和合规性。
Your response is inadequate. Your revision of thebatch record for (b)(4) was insufficient because you did not review allbatch records for all of your drugs to identify any additional critical steps(besides weighing) that may have been inadequately performed, documented, andreviewed or checked. Your CAPA of providing gloves to operators and proposal togenerate bilingual batch records did not directly address the observeddeficiency of supervisors signing records on behalf of operators who performedcritical steps.
你们的回复是不充分的。你们对XX批记录的修订是不足够的，因为你们并没有审核所有的药品批记录中是否还有其它的关键步骤（除了称重）可能会执行、记录、审核和检查不充分。你们的CAPA是提供手套给操作人员，并拟制作双语批记录，并未直接解决所发现的主管代替关键步骤操作人员签字的缺陷。
In your response to this letter, provide the resultsof a retrospective investigation of batch records for all of your APIdistributed to the U.S. that are within expiry. Your review should identify anyinstances in which your batch records indicate inadequate performance,documentation, or review of critical steps in the operation, and should includea risk assessment to determine the impact on the quality of your API for anysuch identified instances. Also provide the specific actions you have taken toensure that current and future batch records for all products are adequate andsigned correctly, such as establishing a documented system of regular, periodicquality unit audits of your batch records.
在你们对此函的回复中，请提交对所有你们销售至美国仍在有效期的原料药的批记录回顾性调查的结果。你们的审核应识别出你们批记录中所有显示关键操作步骤中表现、文件记录和审核的情形，应包括一份风险评估来确定此类识别出的情形对你们API质量的影响。还要提交你们为确保当前和未来所有产品批记录内容充分签字正确所采取的措施，例如建立一个书面的体系，由质量部门对你们批记录进行常规定期审计。
3. Failure to adequately investigateand document out-of-specification results and implement appropriate correctiveactions. 未能充分调查和记录OOS结果并实施适当的纠正措施。
Your firm ignored aberrant analytical test resultsrather than investigating them, determining the root cause, and implementingappropriate corrective actions. You relied on these out-of-specification (OOS)results to assign “expiration dates” to your API. For example, our investigatorreviewed your 48-month stability gas chromatography (GC) test results for (b)(4)content in (b)(4) validation batches (b)(4), (b)(4),and (b)(4).
你们公司忽略了异常分析结果，没有对其进行调查以确定根本原因并实施适当的纠正措施。你们依据这些OOS结果来制订你们原料药的“有效期”。例如，我们调查人员审核了你们XX产品验证3个验证批次的48个月稳定性XX含量GC检测结果。
Our investigator observed that all three chromatogramsfor these batches displayed an unknown peak at an earlier retention time thanthe internal standard peak. The unknown peak did not appear in the internalstandard blank run. Prior to our inspection, you did not initiate aninvestigation into this OOS result, nor did your firm determine the root causeor assess the effects of the unknown peak on the quality of your drugs.Instead, you reviewed, approved, and used the stability data for these batchesto determine the “expiration date” for your commercial (b)(4) APIbatches.
我们的调查人员发现这些批次的所有3个色谱图均在保留时间靠右前的地方显示有未知峰，但并不是内标峰。该未知峰在内标空白中并没有。在我们调查之前，你们并没有启动对此OOS结果的调查，也没有确定根本原因，或评估此未知峰对你们药品质量的影响。相反，你们审核、批准、使用了这些批次的这些稳定性数据来确定你们商业批次XX原料药的“有效期”。
In your response, you stated that you performed aretrospective investigation, and determined that the unknown peak was due to“injector contamination” of (b)(4) precipitation in the needle of the GCinjector. You concluded that the unknown peaks were isolated, and did notreflect systemic product quality deviations or affect the reported values of (b)(4)or labeled expiration dates. You revised your procedures to require chemists todocument and investigate OOS results, and stated that you would purchase new GCequipment.
在你们的回复中，你们声称你们进行了回顾性调查，确定未知峰是因为GC进样针中XX沉淀物对“进样器污染”所造成的。你们得出结论说未知峰是孤立的情况，不能反映出系统的产品质量偏差，或对XX报告值及所标示有效日期的影响。你们修订了你们的程序，要求化验员记录和调查OOS结果，并声称说你们会购买新的GC仪器。
Your response is inadequate. You did not expand thescope of your investigation to determine if other drugs tested on the same GCequipment were affected by similar “injector contamination” events. You alsofailed to explain why you neglected to investigate these aberrant test resultsin the first instance, or relied on OOS results to assign “expiration dates” toyour API.
你们的回复是不充分的。你们没有将你们调查的范围进行扩展，以确定是否有其它在同一台GC仪器上的受试药品受到类似“进样器污染”的影响。你们也没有解释为什么你们没有在第一时间对些异常测试结果进行调查，而是依赖于这些OOS结果来为你们原料药给定“有效期”。
In your response to this letter, provide yourinvestigation report and risk analysis for all drugs tested on the affected GCequipment since 2015. Indicate the steps you will take for any analytical testresults you identify as having been affected by needle contamination orcarryover. Also provide your revised stability program to indicate how you willensure that your “expiration dates” are based only on analytical data thatmeets scientifically valid and appropriate specifications.
在你们的回复中，请提交你们自2015年以来在这台受到影响的GC仪器上所检测的所有药品的调查报告和风险分析。说明你们对于受到进样针污染或残留影响的所有分析结果要采取的措施。也请提交你们修订后的稳定性计划来说明你们要如何确保你们的“有效期”只基于符合科学有效和适当标准的分析数据来制订。
4. Failure of your quality unit toadequately perform annual product reviews. 你们质量部门未能充分实施年度产品回顾。
We reviewed your annual product reviews (APR) formultiple products and observed a variety of deficiencies. For example, thestability data from your 2016 (b)(4) APR was identical to the dataincluded in your 2015 APR for the same API. Your 2016 (b)(4) APR alsoincluded stability data that could not have been generated at the time pointsprovided in the APR. Your 2016 APR for (b)(4)also included multipleerrors. For example, the mean values for product quality attributes such aswater content, impurities, and optical rotation exceed the maximum values.Product quality tables of numerical minimum values also reported maximum valuesas “not detected.” In another instance, mean values were reported for a singlebatch.
我们审核了你们多个产品的年度产品回顾（APR），发现了大量的缺陷。例如，你们2016年XX产品APR的稳定性数据与2015年APR同一原料药的稳定性数据是相同的。你们的XX产品2016年APR中包括有在APR所提供的时间点不可能生成的数据。你们的2016年XX产品APR里面还有多个错误。例如，产品质量属性如水份、杂质和旋光的平均值超出了最大值。产品质量表中最小数字值也报告最大值为“未检出”。另一个地方，平均报告的是一个批号。
Such reporting errors are repeat deviations from FDA’s2013 inspection of this site.
这些报告错误是该场所2013年FDA检查中重复问题。
In your response, you attributed these APR errors topersonnel using the previous year’s APR as a template. You revised yourprocedures to include a blank template. You also stated that “all the error wastranscription error and review error by all managers of concerned departments.”You indicated that you would avoid such errors in the future by usingenterprise resource planning to compile QMS data online.
在你们的回复中，你们将这些APR错误归罪于使用之前年度APR作为模板的人员。你们修订了你们的程序，在其中包括了一个空白模板。你们还声称“所有错误均是相关部门经理的抄录错误和审核错误”。你们说你们在未来通过使用企业资源规划来汇整QMS在线数据以避免此类错误。
Your response is inadequate. You did not explain howyour use of an enterprise resource planning system will prevent APR errors inthe future. Further, you did not perform a retrospective review of all APR toensure that there were no errors that may have compromised or obscured indiciaof drug quality.
你们的回复是不充分的。你们并未解释在未来你们使用企业资源规划系统如何来防止APR错误。另外，你们也没有对所有APR进行回顾性审核，以确保其中没有错误，这些错误可能会使得药品质量受损或标记模糊。
In your response to this letter, conduct a retrospectivereview of all APR for the past three years, and provide a tabular summary ofyour review. Also provide annotated copies of your revised 2015 and 2016 (b)(4)and (b)(4) APR, referencing the underlying data along with copies of therecords containing the underlying data.
在你们对此函的回复中，请对过去3年所有APR进行回顾性审核，提交一份你们审核的是表格式总结。也请提交你们修订后的2015年和2016年XX产品和XX产品APR，对基础数据的引用以及包括基础数据的记录的副本。
Repeat deviations at multiple sites多场所重复偏差
FDA cited similar CGMP deviations at other facilitiesin your firm’s network. Specifically, when FDA inspected Vital LaboratoriesPrivate Limited Plant-I (formerly known as Vital Healthcare Private Limited) inVapi, Gujarat, in 2015, it was classified as unacceptable for drugmanufacturing as a result of observations that were similar to those observedduring Plant-II’s inspection. These repeated failures at multiple sitesdemonstrate that your company’s oversight and control over the manufacture ofdrugs is inadequate.
FDA在对你们公司旗下其它场所检查中发现有类似的CGMP偏差。具体来说，2015年在吉拉特邦一厂区检查时，该工厂因发现与此次二厂类似偏差而被列为不可接受。多个工厂重复失败的情况证明你们公司药品生产的监管和控制是不足够的。
Your executive management remains responsible forfully resolving all deficiencies and ensuring ongoing CGMP compliance. Youshould immediately and comprehensively assess your company’s globalmanufacturing operations to ensure that systems, processes, and ultimately,manufactured products, conform to FDA requirements.
你们的执行管理人员对于全面解决所有这些缺陷负有义务，应确保持续的CGMP合规性。你们应立即全面评估你们公司的全球生产操作，以确保系统、工艺以及最终生产的产品符合FDA要求。
CGMP consultant recommendedCGMP顾问建议
Based upon the nature of the violations we identifiedat your firm, we strongly recommend engaging a consultant, qualified as setforth in 21 CFR 211.34, to assist your firm in meeting CGMP requirements. Youruse of a consultant does not relieve your firm’s obligation to comply withCGMP. Your firm’s executive management remains responsible for fully resolvingall deficiencies and ensuring ongoing CGMP compliance.
基于我们所发现的你们公司的违规情况，我们强烈建议你们聘请顾问，顾问应符合21 CFR 211.34要求。帮助你们公司符合CGMP要求。聘请顾问并不能免除你们公司符合CGMP的义务。你们公司的高层管理人员仍负有全面解决所有缺陷以及确保持续CGMP符合性的责任。
Conclusion结论
Deviations cited in this letter are not intended as anall-inclusive list. You are responsible for investigating these deviations, fordetermining the causes, for preventing their recurrence, and for preventingother deviations in all your facilities.
在此函中所引用的偏差并不是全部。你们有责任对这些偏差进行调查，确定原因，防止所有场所中这些偏差的再次发生，防止其它偏差的发生。
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, at[email protected], 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.
如果你们正在考虑可能会导致你们工厂所生产的药品供应中断的措施，FDA要求你们立即通过上述邮箱联系CDER药物短缺办公室，使得FDA可以与你们一起，以最高效的方式将你们的运行带回符合的轨道。与药物短缺办公室联系还能让你们完成所你们所承担的报告你们药品生产中断的义务，使得FDA尽可能快地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 all deviations completely and weconfirm your compliance with CGMP, FDA may withhold approval of any newapplications or supplements listing your firm as a drug 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 these deviations may also result inFDA refusing admission of articles manufactured at Vital Laboratories PrivateLimited Plant-II, at Plot No.1710 & A1-2208, Phase III GIDC Estate, Vapi,Gujarat 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21 U.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 officein writing within 15 working days. Specify what you have done since ourinspection to correct your deviations and to prevent their recurrence. If youcannot complete corrective actions within 15 working days, state your reasonsfor 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 [email protected] or mail your reply to:
请将你们的电子回复发送至上述邮箱或者以下邮箱。
William Yang, PhD
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 FEI3007474872.
Sincerely,
/S/
Thomas J. Cosgrove
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
