【技术交流】欧洲药品管理局签发生物技术产品工艺验证指南草案-一个分析

EMA issues Draft Guideline on Process Validationfor Biotechnological Products - anAnalysis

欧洲药品管理局签发生物技术产品工艺验证指南草案-一个分析

    Ina news in the GMP Newsletter last week we alreadybriefly reported about the EMDraft Guideline of Process Validation forbiotechnological products and alsoannounced the following more detailedanalysis.

在上周GMP通讯的新闻中，我们的已经简要报道关于欧洲药品管理局生物技术产品工艺验证指南草案，并也宣布后续更详细的分析。

    Asalready mentioned then the draft is the secondvalidation document EMApublishes within short time. EMA published the finaldocument on a revision ofits "old" Note for Guidance only at the endof February. The newtitle of this "general" guideline on processvalidation forauthorisation purposes is: Guideline on Process Validation forfinishedproducts - information and data to be provided in regulatorysubmissions. Thedraft on process validation for biotechnologically manufacturedactivepharmaceutical ingredients describes the required data to be submittedfor themarketing authorisation or variation of biotechnology-derived proteinsused asactive substance in the manufacture of medicinal products. Processvalidationcan be based on a traditional approach, on a "modern"(enhanced)approach or on a combination of both (called "hybridapproach" in thegeneral EMA Guideline on Process Validation). In theexecutive summary thefollowing requirement is made: Regardless of the approachfollowed, the datashould cover information relating to the evaluation and theverification of themanufacturing process.

    正如已经提到的，该文件草案是欧洲药品管理局在很短的时间内发布的第二个验证文件。 欧洲药品管理局在2月底发布的最后文件仅仅是对“老”指南注释文件的修订。该“总”指南以授权为目的的工艺验证的新标题是：制剂产品工艺验证指南-在药政申报中需要提供的信息与资料。生产原料药的生物技术工艺验证草案描述了在在药品生产中用做原料药的生物技术衍生蛋白质上市授权或变更申报所要求的数据。工艺验证可基于一个传统方式、“现代”（增化）方式，或两者组合（在欧洲药品管理局总的工艺验证指南中称为“混合方式”） 。在摘要做出如下规定：无论用什么方式，数据应包括生产工艺评价与确证相关信息。

    Inthe introduction process validation is defined as inthe ICH Q7 document. Butit is mentioned that process validation activitiescontinue through thelifecycle of the product and its process. At this pointexpress reference ismade once more to the data on the evaluation andverification of themanufacturing process. Then the terms process evaluation andprocessverification are defined. Process evaluation should provide evidencethat the processand each process step have been appropriately designed and arecontrolled toobtain a product of the intended quality. This can also beperformed at smallscale. Process verification studies should then confirm thatthe finalmanufacturing process is able to produce an active substance orintermediatemeeting its predetermined acceptance criteria, on an appropriatenumber ofconsecutive batches produced with the commercial process and scale.Thedocument then refers to the requirements of EU Good ManufacturingPractices(GMP) for the activities after approval (maintenance in a state ofcontrol).

    在介绍工艺验证中用了在ICH-Q7文件中的定义。但需要提及的是工艺验证活动是在产品与其工艺生命周期持续的活动。在这一点上，多次明确提到了生产工艺的评价与确证数据。随后，定义了工艺评价与工艺确证。工艺评价应提供该工艺及每个工艺步骤已经恰当地设计并受控来获得预期质量的产品的证据。其这也可以在小规模上进行。工艺验证研究应随后用商业化工艺与规模生产的恰当数量的连续批次确认最后的生产工艺有能力生产符合预定验收标准的原料药或中间体。该文件使批准或的活动（保持受控状态）参考了欧洲药品生产质量管理规范（GMP）要求。

    Under"scope" it is indicated that the documentapplies to recombinantproteins and polypeptides, their derivatives, andproducts of which they arecomponents (e.g. conjugates), as defined in ICH Q6B.The principles that areoutlined in the document may also apply to otherbiological products such asvaccines or blood products, as appropriate. Todetermine applicability in suchcases, manufacturers should consult with theappropriate regulatoryauthorities. For evaluation of viral safety, reference ismade to ICH Q5A.

    在“范围”中指出，该文件适用于按照ICH-Q6B定义的重组蛋白质与多肽、其衍生物，以及其作为成分的产品（例如，结合物）。如果恰当，在文件中所列出的原则也可能适用于其它生物制品，诸如疫苗和血液制品。这样的情况下要确定适用性，生产企业应与适当的监管部门咨询。对于病毒安全性的评价，参考了ICH-Q5A。

Aslegal basis Directive 2001/83/EC(introduction, Chapter 4, Part II of Annex I)is indicated.

已经表示第2001/83/EC号法令作为法律依据（附件I的简介、第四章、第II部分）。

Thechapter process development indicatesexpressly that process development is nota part of validation. Naturally, itcomprises an essential role in defining thecriteria and conditions to beaddressed as part of process validation. Insofar,manufacturing processdevelopment should identify the inputs (e.g. processparameters) and outputs(e.g. quality attributes) for each process step.According to the text,documented prior knowledge and risk assessment can behelpful.

本章的工艺开发中标明，工艺开发不是验证的一部分。当然，起在工艺严正部分即将解决的定义标准与条件起重要作用。在这个范围内，生产工艺开发应识别每一个工艺步骤的输入（例如，工艺参数）与输出（例如，质量属性）。根据本文件，已经文件化的先前知识与风险评估可有所帮助。

Thechapter process validation refersonce again to the contents of process evaluationand process verification ofwhich process validation normally consists. Datafrom small scale studies couldreduce data requirements for processverification (e.g. reduced number ofvalidation batches) and/or impact oncontrol strategy (e.g. alternative approachto end product testing) if therelevance for the commercial scale batch size canbe demonstrated. Expressreference is made to the fact that controls used inprocess validationactivities are expected to go beyond the routine controlsystem as described inthe authorisation documentation.

工艺验证章节再次指出了通常包括在验证工艺中的工艺性评价与工艺确证的内容。如果与商业规模批次大小的相关性可以得到证明，小规模研究数据可能降低工艺确证需求数据（例如，减少验证批次数量），和/或，控制策略的影响（例如，对最终产品测试的替代方法）。明确提到了期望在工艺验证活动中使用的控制高于在授权文件中描述的日常控制系统。

Interestingly,it is mentioned by way ofconclusion that process evaluation and verificationactivities are ofteninvestigated in the same "studies". Then it isnot necessary to make aclear difference between these activities as long asthey are appropriatelypresented so that they can be justified.

有趣的是，其以结论的方式提到，工艺评价与确证活动经常在同一个“研究”调查。那么其没有必要在这些活动之间进行显著区别，只要他们得到适当展示，其可以是合理的。

Inthreesub-chapters process evaluation, process verification and ongoingprocessverification are addressed. A summary of these three sub-chapters aspart of acomplete analysis of the draft is available in the ECA websitemembers' area.

在三个小节中描述了工艺评价、工艺确证与进行中工艺确证。这三个小节的总结作为草案的完整分析的一部分可在ECA网站会员的区找到。

Thedraft of the "Guideline onprocess validation for the manufacture ofbiotechnology-derived activesubstances and data to be provided in theregulatory submission" can becommented on until end of October.

直到十月底可提交对“生物技术衍生原料药制造工艺验证及在药政提交中即将提供数据指南”草案的评论。

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