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ECA新闻:检查员工艺验证备忘—详细分析
2018-05-30 15:27:00 作者: 来源:国际药物制剂网 文字大小:[][][]
Inspectors Aide Memoire on Process Validation - a Detailed Analysis

检查员工艺验证备忘—详细分析

With the Annex 15 revision, the issue of process validation became significantly more complicated. What is the authoritys view on process validation nowadays? In order to reacha uniform approach, the German Central States Authority (ZLG - Zentralstelleder L?nder für Gesundheitsschutz bei Arzneimitteln und Medizinprodukten) hasissued a new aide memoire on process validation.

随着附录15的修订,工艺验证的问题显然变得更为复杂。官方目前在工艺验证方面的观点又是怎样的呢?为了达成一致方法,德国中央药监局(ZLG)刚发布了一份工艺验证的新备忘。

The 47-page document describe show the general principles of validation and QRM should be applied to process validation. These general principles are/will be described in additional aide memoires.

这份47页的文件描述了验证通则和QRM要如何应用于工艺验证。这些通则目前已经或者将来会在其它备忘里描述。

The introduction discusses the innovation caused by the revision of Annex 15. Process validation is a lifecycle model now and starts with the development of a process (process design). The control strategy which accompanies the process routine and which is repeatedly confirmed during ongoing process verification is very important.The introduction also covers the three (new) validation approaches (traditional, continuous process verification, hybrid) as well as the increased importance of risk assessment, which is now required for all phases of the product life cycle.

引言部分讨论了由于附录15修订而引起的创新。工艺验证现在是一个从工艺开发开始(工艺设计)的生命周期模式。伴随工艺常规操作并在持续工艺确认中重复确认的控制策略是非常重要的。引言还包括了3个(新的)验证方法(传统的、持续工艺确认、混合的)以及风险评估日益增加的重要性。目前产品生命周期的各个阶段均需要有风险评估。

The subchapter on Process development as a basis for process validation introduces new terms such as quality target product file, critical and non-critical quality attributes as well as critical and non-critical process parameters and material attributes. Scale-up and pilot batches have special significance in this aide memoire. Furthermore, the approaches to development (minimal/empirical approach and the extended QbD approach) known from ICH Q8 are explained and advantages and disadvantages are discussed. Because of the poor knowledge so far with QbD processes, the aide memoire recommends to consult experts (e.g. assessors) for the inspection of such processes,depending on the expertise of the GMP inspectors.

“工艺开发作为工艺验证的基础”子章节介绍了新的术语,如质量目标产品文件、关键和非关键质量属性以及关键和非关键工艺参数和物料属性。放大和中试批次在此备忘中具有特殊的重要性。还进一步解释了ICH Q8里了解的开发的方法(最小/经验方法和延伸QbD方法),讨论了其优缺点。由于对QbD工艺截止目前知之甚少,备忘建议根据GMP检查员的专业背景应此类工艺的检查咨询专家(例如评审人员)。

The subchapter on acceptable approach to process validation describes the three validation approaches. For traditional validation based on the minimal development approach, there is explicit mention that a three-batch initial validation is possible in the future as well. The number and extent of the batches should be based on a risk analysis in that case. An initial validation with less than three batchesis deemed possible depending on the experience with similar processes. Regarding GMP inspections, the aide memoire advises inspectors to examine those aspects that are not part of the approval documentation. Ongoing process verification is only examined during GMP inspections.

可接受的工艺验证方法子章节描述了3种验证方法。对基于最小开发方法的传统验证,明确提到3批起始验证在未来也是可能的。这此情形下的验证批次数量和程度应基于风险分析。批次少于3批的初始验证依类似工艺的经验也是有可能的。关于GMP检查,备忘建议检查员检查这些不是批准文件的内容。持续工艺确认则只是在GMP检查中会进行查验。

The aide memoire demands the following GMP requirements on process validation:

备忘提出了以下在工艺验证方面的GMP要求:

GMP-compliant requirements within the QA system

QA体系内GMP合规要求

Performance according to requirements

依要求实施

Appropriate and scientifically sound validation design

适当和科学合理的验证设计

The quality manual should contain a declaration of voluntary undertaking of the management on the provision of resources. There is explicit mention of the fact that process validation is also obligatory for subcontractors. Nineteen minimum requirements for an approach to process validation are listed, which should be included in anSOP or validation master plan. The required entries in a validation master plan (6 entries) are also mentioned. One of the six entries is the description of a bracketing approach, where applicable.

质量手册应包括自愿承担资源管理的声明。这里明确提到工艺验证也是承包商的义务。文中列出了工艺验证方法的19个最低要求,这些应包括在SOP或验证主计划中。也提到了验证主计划中所需的条款(6项)。6项中有一项是括号方法的描述(适用时)。

An individual subchapter describes the staff responsibilities regarding process validation. It specifies the heads of production and of quality control, the qualified person, QA units,the validation team and external consultants.

有一个子章节描述了员工在工艺验证方面的职责。其中具体说到了生产负责人和质量负责人、QP、QA部门、验证团队和外部顾问。

The organisational procedure and documentation of a process validation are rather briefly described with emphasis on consecutive validation batches and references in the documents in order to clearly allocate them to validation projects. The requirements for performing a process validation are discussed in ten points.  

文中对工艺验证的公司程序和文件的讲解相对简短,侧重在持续验证批次和参考文献,以清楚指出其在验证项目中的位置。实施工艺验证的要求在10点中进行了讨论。

The topic of risk assessment is discussed in greater extent in the aide memoire. It is interesting to note that the aide memoire demands the quantification of risk levels for this purpose. Possible examples such as risk priority numbers, but also categorisation into other/major/critical are named. Regarding the latter categorisation, non-formalised risk management tools can be used as well.

备忘中对风险评估主题的讨论颇为深入。有意思的是备忘要求在此中将风险水平量化。文中列出了可能的例子如风险优先数,但也有其它/主要/关键归类。关于归类,也并没有非正式风险管理工具可使用。

Then twenty-two points are described as being required for a validation protocol and an individual subchapter explains bracketing requirements. Very modern, the subchapter on batch size also addresses continuous production and batch size range. Regarding the latter, a bracketing approach is expected. The aide memoire states that it is not necessary to run the process out of the limits during a process validation. However, predictable variations of the production process (e.g. different active ingredient batches, different machines, varying process parameters or stand and hold times, variation of the environmental conditions, shift operation) should be considered. The importance of sampling plans is explained, but a random statistical sample is not explicitly requested. Eleven minimum requirements are also listed. The document specifically mentions release of validation batches and especially releases before the completion ofa validation (e.g. during a concurrent validation).

然后提出了22点验证方案要求,有一个单独的子章节解释了括号法要求。很现代化的是,批量的子章节也讲解了连续生产和批量范围。对于后者则要求采用括号法。备忘说没有必要在工艺验证中超出限度来执行工艺。但是应考虑可预期的生产工艺波动(如不同活性成分批次、不同设备、工艺参数波动或放置和保存时长、环境条件波动、轮班操作)。文中解释了取样计划的重要性。文件特别提到了验证批次放行,特别是验证完成之前的放行(例如,同步验证中)。

The ongoing process verification (OPV) will replace a periodic revalidation according to the aide memoire. The purpose of the OPV is to provide information on the process performance in the course of a monitoring programme. That requires amonitoring plan and periodic reports. The scope of the programme must be defined risk-based. In the context of an OPV, trend analyses are requested in particular. Depending on the necessity of reliable statements, the aide memoire also addresses statistical methods and indices regarding OPV.

依备忘的说法,持续工艺确认(OPV)将取代定期再验证。OPV的目的是在监测程序中提供工艺性能信息。这就要求制订一份监测计划以及定期制作报告。计划的范围必须基于风险定义。在OPV中,特别要求进行趋势分析。根据是否需要可靠性声明的情况,备忘也讲了OPV的统计学方法和指数。

In a separate subchapter, process changes and technology transfers are discussed. The very extensive chapter 2 ends with an excursus on QbD-associated process management and process control. In this subchapter, information on design space, PAT, SPC and real time release testing (RTRT) are in turn described in further subsections. The subsection on SPC also discusses process performance and capability indices in great detail.

在单独的子章节中,讨论了工艺变更和技术转移。超级全面的第2章是以QbD相关工艺管理和工艺控制附记结束的。在此子章节中,细分为子章节依次描述了设计空间、PAT、SPC和实时放行测试(RTRT)信息。SPC子章节也超级详细地讨论了工艺性能和能力指标。

Finally, a third chapter lists definitions and abbreviations.

最后,第三章列出了定义和缩略词。

Conclusion: The new aide memoire on process validation displays the current view of the authority on process validation and is highly readable for that reason alone, but also because of its partially specific requirements. Participants of the event Process Validation in the light of therevised Annex 15 and FDA Requirements on 25/26 April 2018 in Frankfurt/Germany will exclusively receive an English-language translation.

结论:该工艺验证新备忘展示了官方对工艺验证当前的观点,单就此点来讲就具有高度可读性,但其可读性同时也部分来自其详细的要求。参与ECA于2018年4月25-26日在德国法兰克福会议即可获得该文的独家英文翻译稿。
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