翻译：Julia 来源：Julia法规翻译
Dear Mr. Ye:
The U.S. Food and Drug Administration (FDA)inspected your drug manufacturing facility, Teva Pharmaceutical and Chemical(Hangzhou) Co. Ltd., 1889 Jingliu Road, Xiaoshan, Hangzhou, Zhejiang, Chinafrom September 26 to 29, 2016.
美国FDA于2016年9月26-29日检查了你们位于杭州萧山的泰华医药化工有限公司生产场所。
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。
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 October 21, 2016 response in detailand acknowledge receipt of your subsequent correspondence.
我们详细审核了你们公司2016年10月21日及之后的回复。
During our inspection, our investigator observedspecific deviations including, but not limited to, the following.
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 establishwritten procedures to monitor the progress and control the performance ofprocessing steps that may cause variability in the quality characteristics ofyour API.
未能建立书面程序以监控工艺步骤进程及表现，因此可能会导致你们API的质量特性的波动。
Our inspection found that approximately 10 percent of (b)(4)API batches produced at your facility from December 2014 to September 2016failed to meet the (b)(4) impurity limit. During this period, anadditional 10 percent of batches yielded out-of-trend (OOT) results for (b)(4).You have reprocessed rejected out-of-specification OOS batches but failed toimplement effective corrective and preventive actions (CAPA) to correct processdesign and control flaws that lead to excessive formation of this impurityduring processing.
我们检查发现你工厂自2014年12月至2016年9月生产的约有10%的某API批次不符合某杂质限度要求。在此期间，同一产品另有10%批次质量超趋势（OOT）。你们对OOS批准进行了返工，但未实施有效的CAPA来纠正工艺设计，控制工艺中导致此杂质过量生产的工艺瑕疵。
According to your response, a new root cause analysisfound that impurity failures appear to be related to insufficient control of (b)(4).You committed to monitor (b)(4) specific process parameters in the newprocess performance qualification batches of (b)(4) API and the first (b)(4)commercial batches. However, these proposed parameters differ from the“critical process parameters” monitored by your firm in the last three years.They also do not include all of the parameters that you categorized as“critical and significant” in the most recent process qualification study. Yourresponse does not commit to monitor future batches for all parameters thatimpact quality, and may contribute to the failure of a batch of intermediatesor API to meet specifications.
根据你们的回复，在新的根本原因分析中发现杂质失败貌似与对XX控制不充分有关。你们承诺会在该API新的工艺性能确认批次及首次XX商业批次中监测该特定工艺参数。但是，这些所提出的参数并不是你们公司在过去三年所监测的“关键工艺参数”。他们也不包括所有的你们在最近工艺确认研究中定为“关键和重要”的参数。你们的回复没有承诺在将来监测所有影响质量、可能会与中间体或API不符合质量标准有关的参数。
Your response is also inadequate because it did notinclude the risk assessment and related scientific rationale to ensure thatcontrols implemented for all batches will detect upstream processing variationand ensure final API quality. You also acknowledged in March 2017correspondence that additional lots have failed since you resumed commercialmanufacture of (b)(4) API. Recurrence of product quality failuresfollowing the completion of your investigation and process re-qualificationindicate that your root cause analysis and CAPA were ineffective.
你们的回复不充分还因为其中未包括风险评估以及相关的科学合理性，以确保对所有批次所实施的控制能检出上游工艺波动，确保最终API质量。你们在2017年3月的信函中告知我们自从你们恢复某API的商业生产以来，又有一些批次不合格。在你们完成调查和工艺再确认之后，产品质量又发生不合格表明你们的根本原因分析和CAPA是无效的。
In response to this letter:
在回复此函件时：
Provide an updated investigation into the root cause(s) of (b)(4) OOS results and an improved CAPA plan. Include provisions to ensure CAPA effectiveness.
请提交更新后的某OOS结果根本原因调查，以及改进后的CAPA计划。包括确保CAPA有效性的条款。
Specify if the presumed root causes for failures were actually observed in the failed (b)(4) batches.
说明在不合格的XX批次中是否实际观察到了所假定的根本不合格原因。
Describe why some finished (b)(4) API batches yielded OOS results for the bis-ether impurity, but passed testing for this same impurity at the (b)(4) stage.
说明为什么有些某API批次产生二醚杂质OOS结果，但却能通过在某工艺步骤中该相同杂质的检测。
List the past and current process parameters for (b)(4) API. Explain their role in the process, the potential impact on quality, the limits used, and your justification if you plan to cease monitoring and controlling any parameter during commercial batch manufacture.
列出过去和现在的某API工艺参数。解释在工艺中各参数的作用、对质量的潜在影响、所使用的限度以及如果你们计划停止在商业批次生产中监测和控制任一参数时你们的论证。
Explain your systems for incorporating reprocessing activities into Drug Master Files.
解释你们将返工活动整合入DMF文件的系统。
Provide procedures that ensure that reprocessed lots and process performance qualification lots are included in your stability program.
提供程序确保返工批次和工艺性能确认批准被放入你们的稳定性计划中。
