FDA警告信：印度Vital Laboratories

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.