發(fā)布日期：2017-04-28
昨夜，F(xiàn)DA官網(wǎng)掛出對(duì)仿制藥巨頭梯瓦制藥中國蕭山工廠的警告信，缺陷包括關(guān)鍵工藝參數(shù)未監(jiān)控、產(chǎn)品質(zhì)量反復(fù)不合格、根本原因分析和CAPA無效、未能建立一個(gè)科學(xué)合理的取樣計(jì)劃、工藝驗(yàn)證取樣不合理、未描述持續(xù)工藝確認(rèn)計(jì)劃如何確保質(zhì)量屬性持續(xù)符合并且批批一致
具體如下：
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.
FDA于2016年9月26-29日檢查了你們位于杭州蕭山的梯瓦醫(yī)藥化工有限公司生產(chǎn)基地。
This warning letter summarizes significant deviationsfrom current good manufacturing practice (CGMP) for active pharmaceuticalingredients (API).
本警告信概述了原料藥生產(chǎn)嚴(yán)重違反CGMP的行為。
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).
由于你們?cè)纤幍纳a(chǎn)、加工、包裝或保存的方法、場(chǎng)所或控制不符合CGMP要求，你們的原料藥根據(jù)FDCA的501(a)(2)(B)以及21 U.S.C.351(a)(2)(B)被認(rèn)定為摻假。
We reviewed your October 21, 2016 response in detailand acknowledge receipt of your subsequent correspondence.
我們?cè)敿?xì)審閱了你們公司于2016年10月21日及之后的回復(fù)。
During our inspection, our investigator observedspecific deviations including, but not limited to, the following.
我們的檢查人員發(fā)現(xiàn)的具體問題包括但不僅限于以下：
1. Failure to establishwritten procedures to monitor the progress and control the performance of processing steps that may cause variability in the quality characteristics ofyour API.
未能建立書面程序以監(jiān)控工藝步驟進(jìn)程及表現(xiàn)，因此可能會(huì)導(dǎo)致你們API的質(zhì)量特性的波動(dòng)。
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.
我們檢查發(fā)現(xiàn)你工廠自2014年12月至2016年9月生產(chǎn)的約有10%的某API批次不符合某雜質(zhì)限度要求。在此期間，同一產(chǎn)品另有10%批次質(zhì)量超趨勢(shì)（OOT）。你們對(duì)OOS批準(zhǔn)進(jìn)行了返工，但未實(shí)施有效的CAPA來糾正工藝設(shè)計(jì)，控制工藝中導(dǎo)致此雜質(zhì)過量生產(chǎn)的工藝瑕疵。
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.
根據(jù)你們的回復(fù)，在新的根本原因分析中發(fā)現(xiàn)雜質(zhì)失敗貌似與對(duì)XX控制不充分有關(guān)。你們承諾會(huì)在該API新的工藝性能確認(rèn)批次及首次XX商業(yè)批次中監(jiān)測(cè)該特定工藝參數(shù)。但是，這些所提出的參數(shù)并不是你們公司在過去三年所監(jiān)測(cè)的“關(guān)鍵工藝參數(shù)”。他們也不包括所有的你們?cè)谧罱に嚧_認(rèn)研究中定為“關(guān)鍵和重要”的參數(shù)。你們的回復(fù)沒有承諾在將來監(jiān)測(cè)所有影響質(zhì)量、可能會(huì)與中間體或API不符合質(zhì)量標(biāo)準(zhǔn)有關(guān)的參數(shù)。
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.
你們的回復(fù)不充分還因?yàn)槠渲形窗L(fēng)險(xiǎn)評(píng)估以及相關(guān)的科學(xué)合理性，以確保對(duì)所有批次所實(shí)施的控制能檢出上游工藝波動(dòng)，確保最終API質(zhì)量。你們?cè)?017年3月的信函中告知我們自從你們恢復(fù)某API的商業(yè)生產(chǎn)以來，又有一些批次不合格。在你們完成調(diào)查和工藝再確認(rèn)之后，產(chǎn)品質(zhì)量又發(fā)生不合格表明你們的根本原因分析和CAPA是無效的。
In response to this letter:
在回復(fù)此函件時(shí)：
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.
請(qǐng)?zhí)峤桓潞蟮哪砄OS結(jié)果根本原因調(diào)查，以及改進(jìn)后的CAPA計(jì)劃。包括確保CAPA有效性的條款。
Specify if the presumed root causes for failures were actually observed in the failed (b)(4) batches.
說明在不合格的XX批次中是否實(shí)際觀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.
說明為什么有些某API批次產(chǎn)生二醚雜質(zhì)OOS結(jié)果，但卻能通過在某工藝步驟中該相同雜質(zhì)的檢測(cè)。
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.
列出過去和現(xiàn)在的某API工藝參數(shù)。解釋在工藝中各參數(shù)的作用、對(duì)質(zhì)量的潛在影響、所使用的限度以及如果你們計(jì)劃停止在商業(yè)批次生產(chǎn)中監(jiān)測(cè)和控制任一參數(shù)時(shí)你們的論證。
Explain your systems for incorporating reprocessing activities into Drug Master Files.
解釋你們將返工活動(dòng)整合入DMF文件的系統(tǒng)。
Provide procedures that ensure that reprocessed lots and process performance qualification lots are included in your stability program.
提供程序確保返工批次和工藝性能確認(rèn)批準(zhǔn)被放入你們的穩(wěn)定性計(jì)劃中。
2. Failure to establish a sampling plan based on scientifically-sound sampling practices.
未能建立一個(gè)科學(xué)合理的取樣計(jì)劃
Our investigator documented deficiencies in your validation sampling plan for (b)(4) API. You did not conduct adequate monitoring and testing during process performance qualification stage to evaluate whether product quality was uniform throughout each batch. You only assessed water content at the drying step for homogeneity.
我們的檢查員發(fā)現(xiàn)了你們對(duì)XX API的驗(yàn)證取樣計(jì)劃的缺陷。你們?cè)诠に囆阅艽_認(rèn)階段沒有進(jìn)行充分的監(jiān)測(cè)和檢驗(yàn)以評(píng)價(jià)每一批次的產(chǎn)品質(zhì)量是否一致。你們只在干燥步驟評(píng)估了水分含量的均勻性。
In your response, you acknowledged that a higher level of sampling during the revalidation of the manufacturing process revealed some inter-batch variability in residual solvents and particle size distribution of (b)(4).
在你們的回復(fù)中，你們確認(rèn)了在生產(chǎn)工藝再驗(yàn)證期間的一個(gè)高水平的取樣顯示XX的殘留溶劑和粒度分布存在一些批內(nèi)差異。
Your response is inadequate because it did not describe how your continued process verification program assures that quality attributes continue to be met batch-to-batch, as well as uniformly throughout each batch. Regarding uniformity, using only (b)(4) samples for attributes that may significantly vary within a batch is insufficient to ensure that your process remains in an ongoing state of control.
你們的回復(fù)是不充分的，因?yàn)闆]有描述你們的持續(xù)工藝確認(rèn)計(jì)劃如何確保質(zhì)量屬性持續(xù)符合并且批批一致。關(guān)于一致性，僅僅使用XX樣品來確認(rèn)可能在批內(nèi)顯著變異的屬性是不足以確保你們的工藝保持在一個(gè)持續(xù)受控狀態(tài)的。
In response to this letter:
回復(fù)此函：
· Specify how you will improve batch sampling of (b)(4) API to ensure that you detect intra- and inter-batch variability during commercial manufacturing.
詳細(xì)說明你們將如何改善XX API的批取樣來確保你們可以在商業(yè)生產(chǎn)過程中發(fā)現(xiàn)批內(nèi)和批間變異。
· evaluate other API produced by your firm for adequacy of sampling plans.
· 評(píng)價(jià)貴司生產(chǎn)的其他API取樣計(jì)劃的充分性。
· Provide overall quality system improvements to ensure all sampling performed by your firm is representative and able to detect non-uniformity of the quality attributes that may vary within a batch.
· 提供質(zhì)量體系的總體改善以確保貴司執(zhí)行的所有取樣都能具有代表性并能夠檢測(cè)到可能發(fā)生變異的質(zhì)量屬性的不一致性。
來源：新浪醫(yī)藥新聞
