分享|WHO验证指南（2016版）解读
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At the end of 2015, the WHO adapted its Appendix 7 to the latest technological standards. Appendix 7 provides support with regard to non-sterile process validation. Now, further changes to WHO guidelines are in sight. One of these changes concerns the guideline on process validation which is currently available as a draft and can be commented on until July, 12th 2016. Please find here an analysis of this draft.
2015年底，WHO采纳了其最近技术标准附录7。附录7为非无菌工艺验证提供了支持。现在，WHO指南有了进一步变化。变化之一是关于工艺验证的指南，现在草案已发布，征求意见截止日期为2016年7月12日。这里是对此草案的一些分析。
The draft contains 21 pages divided into 13 chapters and one part with references.
草案包括21页，分为13章和参考文献。
The guideline serves as a sort of umbrella guideline and should replace in the future Annex 4 of the WHO Technical Report Series No. 937 from 2006. In so far, the draft refers to other guidelines about the topic validation which will thus have to be updated too as subordinated guidelines (Appendices). The following appendices are named:
该指南是类似伞样的指南，将来会替代2006年WHO技术报告第937号中的附录4。到目前为止，草案提到了其它关于验证专题的指南，而这些指南作为附属指南（附录）也将必须进行更新。其中列出了以下附录：
Appendix 1 Validation of HVAC systems (currently already available as a revised draft)附录1 HVAC系统的验证（现在修订后的草案可以获取）
Appendix 2 Validation of water systems for pharmaceutical use (will be replaced by cross-reference to WHO Guidelines on water for pharmaceutical use for consideration in qualification of water purification systems)附录2 制药用水系统的验证（将通过对WHO制药用水指南水纯化系统确认考虑的交叉索引被替代）
Appendix 3 Cleaning Validation附录3 清洁验证
Appendix 4 Analytical method validation附录4 分析方法验证
Appendix 5 Validation of computerized systems附录5 计算机化系统验证
Appendix 6 Qualification of systems and equipment附录6 系统和设备的确认
The introduction describes validation as an essential part of GMP and GCP. Validation also includes qualification and a lifecycle comprising an 'ongoing review' for continuous improvements. The necessity, scope and depth of validation activities should be based on quality risk management principles.
概述中将验证描述为GMP和GCP的基本部分。验证也包括确认和持续改进“持续审核”的生命周期。验证活动的必要性、范围和深度应基于质量风险管理原则。
The following resources are listed:
列出了以下资源：
Time 时间
Finances 资金
Personnel (multidisciplinary team).
人员（多学科团队）。
So far, a summary of the introduction.
以下是简单介绍。
The chapter “Scope“ points out that the draft describes an overall validation concept which could be applicable to the manufacture and control of starting materials and finished pharmaceutical products. The qualification aspects included in the document could also apply to premises, equipment, utilities and systems.
“范围”一章指出草案描述了总体验证概念，它可以应用于原料和制剂的生产和控制。确认方面包括在文件中，也可以应用于设施、设备、公用设施和系统。
Made up of three pages, the glossary is very extensive. It is interesting to see that this chapter offers a definition for the terms 'Commissioning' and “Good Engineering Practice”. The definition for process validation is very close to that of the FDA. Performance qualification is described as applicable to equipment and systems. In the context of systems, the term “process validation” could also be used. There is also a own definition for the term “validation“ (“Action of proving and documenting that any process, procedure or method actually and consistently leads to the expected results”). The term “retrospective validation“ is not listed but the term “revalidation“ - also in the sense of a periodic (re)validation.
术语有3页，它非常广泛。有意思的是看到此章提供了关于术语“调试”和“良好工程规范”的定义。对工艺验证的定义与FDA非常接近。性能确认则被描绘为适用于设备和系统。在系统的上下文中，术语“工艺验证”也可以使用。还有一个自己定义的术语“验证”（“证明和文件记录所有工艺、程序或方法实际并一致地获得预期结果的活动”）。术语“回顾性验证”现在没有列出了，而“再验证”—也是定期（再）验证的意思。
Chapter 4 addresses the relationship between validation and qualification. “Qualification and validation are essentially the same” whereby qualification is normally used in relation to equipment and utilities, and validation in relation to systems and processes.
第4章讲了验证和确认之间的关系。“确认和验证0本质上是一样的”，但确认一般用于设备和公用系统，而验证则用于系统和工艺。
Chapter 5 “Validation” and its subchapter “Approaches to validation” include some interesting requirements. Where appropriate, statistical calculations should be used to deliver the scientific proof that the process, systems and other related aspects are appropriately validated. Moreover, the senior management is explicitly spoken to with respect to the availability of resources. Both the management and the persons responsible for quality assurance should be actively involved in the validation activities as well as in the authorization of protocols and reports. Regarding the topic risk management which should be used, it is referred to a specific WHO guideline. Where necessary, worst-case tests or so-called 'challenge tests' should be performed like for example stress load tests and volume verification tests in computer systems.
第5章“验证”及其子章节“验证方法”包括一些有意思的要求。适当时，统计学计算应用于传递科学证据证明工艺、系统和其他相关方面经过适当的验证。还有，明确说明了高级管理层负责保证资源。管理层和QA负责人应主动参与验证活动，以及方案和报告的批准。当讲到需要应用的风险管理时，指南引用了具体的WHO指南。必要时，应进行最差条件测试或所谓的“挑战试验”，如在计算机系统中增加负载测试，以及容量核查。
The documents needed to accompany the validation activities (Chapter 6) include among other things protocols and reports as well as a validation master plan. By means of own (superordinate?) plans, it should be ensured that a validation review is available which guarantees the maintenance of the validated status. The next chapters look at the validation master plan, protocols and reports.
验证活动所需的文件（第5章）包括方案和报告以及验证主计划。通过自己的（上级？）计划，应保证对验证都有审核，确保维持验证状态。下几章讲的是验证主计划、方案和报告。
A validation master plan – concise and clear - should be available (Chapter 7). However, 28 minimum requirements are listed. One should notice that this high number is mainly due to the fact that for the qualification activities each sub item is respectively listed for the qualification of premises, equipment, utilities. The same applies to the validation activities (cleaning, process, analytical methods, and computerised systems). The validation master plan should be regularly reviewed and the GMP status should be kept up-to-date.
应该制订有验证主计划---简洁明了（第7章）。其中列出了28个最低要求内容。公司要注意数字大主要是因为对于确认活动来说，每个设施、设备、公用系统确认的子项目都相应地列入了。这同样适用于验证活动（清洁、工艺、分析方法和计算机化系统）。验证主计划应定期审核，GMP状态应保持更新。
The minimum requirements concerning the validation and qualification protocols are fairly detailed too (15 items). Chapter 8 also points out that there should be a description of how results should be analysed (including statistical analyses where appropriate).
关于验证和确认方案的最低要求也很详细（15项）。第8章还指出应该描述结果要如何分析（适当时包括统计学分析）。
Also in the following Chapter 9 on qualification and validation reports, the focus of reporting is put on statistical analyses where possible. The final approval of reports should be done by the quality assurance department.
在后面的第9章确认和验证报告里，主要讲的可能时统计学分析的报告。报告最终应由质量保证部门来批准。
Chapter 10 Qualification 第10章 确认
Made up of almost 3.5 pages, Chapter 10 (Qualification) is relatively extensive. It suggests that there are different approaches to qualification. The V-Model for Direct Impact Systems is given as an example. Yet, the model presents abbreviations which are not explained (e.g. UAT). “Normally” – quoting the text – ?qualification should be completed before process validation is performed”. 'Normally', qualification should begin with user requirement specifications (URS). Depending on the object considered, the following steps are: FAT, SAT, DQ, IQ, OQ, PQ. According to the document though, major equipment and critical systems may require at least URS, DQ, IQ, OQ, PQ. Now, there may be some equipment which only requires IQ and OQ when those two qualification stages already indicate the performance of the equipment. It is explicitly mentioned that a qualification stage should be completed before the next one can start. An own paragraph addresses computerised systems requiring user and functional requirements specifications, design and configuration specifications. Stress tests are also required for those systems. Apart from that, it is referred to the respective WHO on computerised system validation. Not as clearly as in Annex 15, it is pointed out that the URS should be the starting point for the next qualification stages. Each qualification stage FAT, SAT, DQ, IQ, OQ, PQ is then addressed whereby FAT and SAT are listed as “should be” provisions where appropriate. In the course of OQ, worst-case studies are required and when measurements are made with a statistical approach, they should be described. Test results and continuous process verification (continued process verification is likely to be meant) should be collected over an appropriate period of time and /or within periodic reviews and monitoring to demonstrate that the equipment operates consistently.
第10章（确认）总共有近3页半，内容相对广泛。它建议了不同的确认方法。例如，直接影响系统采用V型方式。这种模型代表意思没有解释（例如，UAT）。“一般”—引用其中方案—“确认应在工艺验证之前完成”。“一般”，确认应从用户需求规范（URS）开始。根据考虑的对象不同，可以考虑以下各步：FAT、SAT、DQ、IQ、OQ、PQ。根据文件要求，主要设备和关键系统应该要求至少有URS、DQ、IQ、OQ、PQ。现在，可能有些设备只要求IQ和OQ，如果这样就能显示设备的性能的话。指南中明确提到每一个确认阶段应在下一个开始之前完成。一个WHO自己的段落说明了计算机系统系统要求用户和功能性要求标准，设计和参数设置标准。讲了这些系统也需要的测试。除此之外，还引用了相关的WHO关于计算机化系统验证的文件。指南不像附录15那么明确，它指出URS应是下一个确认阶段的起始点。对于FAT、SAT、DQ、IQ、OQ、DQ的各个确认阶段则是这么说，适当时，FAT和SAT应列为“应做”的项目。对于OQ，要求做最差情形研究，如果使用了统计学方法做测试，则要描述该统计学方法。应收集适当时间段和/或定期审核和监测测试结果和持续工艺核查来证明设备操作是一致的。
The subchapter “Requalification” expressly mentions that full requalification is not required for the replacement of parts but a 'like for like' replacement. Where items of equipment haven’t been used for a longer period of time, requalification may have to be considered.
子章节“再确认”提到在更换部件时并不需要全面再验证，但采用相似的全设备替代时则需要。如果设备很长时间没有使用，则必须考虑再确认。
Another subchapter on revalidation points out that where periodic revalidation is performed, this should be done within defined cycles. Periodic revalidation should be considered when small process changes occur over a longer period of time. The frequency and extent of revalidation should be determined on a risk-based approach taking into account historical data.
另一个再验证的子章节指出如果实施定期再验证，则需要在指定的周期内进行。如果在很长时间内有一些小的工艺变更发生，则考虑进行定期再验证。再验证的频次和深度应基于风险方法结合历史数据来决定。
Within one paragraph only, the subchapter “Process validation” addresses the new approach and lapidary refers to other process validation guidelines. Another paragraph is dedicated to the traditional process validation and expressly underlines the necessity of validation when applying the traditional approach (e.g. through product quality reviews).
子章节“工艺验证”只有一个子章节，讲了其它工艺验证指南里的新方法和传统方法。另一个段落专门讲的是传统工艺验证和应用传统工艺验证方法时验证的前提条件（例如，通过产品质量审核）。
Chapter 11 and 12 第11章和第12章
The contents of Chapter 11 (Change Management – only 3 paragraphs) and Chapter 12 (Deviation Management, just one paragraph) are relatively low compared to Chapter 13 on calibration and verification which is considerably more extensive (one page). Here, the text highlights the necessity of regular calibration with traceable calibrated measuring devices. IQ is considered as appropriate qualification stage for calibration and verification of equipment. Whether devices or instruments should be calibrated should be based on an impact or risk assessment.
第11章的内容（变更管理---仅3个段落）和第12章（偏差管理，只有一段）相比于第13章校正和核对的内容（1页）要少许多。这里，强调了定期校正，并且可以追溯到校正的测量器具的必要性。IQ被认为是设备校正和核查的一个适当的确认阶段。不管是装置还是仪器，其校正均应基于其影响性或风险评估。
Conclusion: 结论
Although this guideline has been thought as superordinate guideline for other validation and qualification guidelines, it has – in its current draft status – relatively little relation to the validation lifecycle approach as required in Annex 15 and FDA’s process validation guideline. There are no references to development which represents the basis for a modern validation approach. Still, periodic revalidation is basically required. Interestingly, references to the application of statistical methods – where appropriate – recur again and again. Another interesting aspect is the mention of “GEP” and “Commissioning“ in the glossary whereby no further explanation is given as for the V-Model. In the course of qualification tests, conditional approvals (as mentioned in Annex 15) are not intended. The specification according to which a 'like for like' replacement requires requalification is very interesting. This is a contrast to PIC/S’s document “PI 006-3, Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation” in which a 'like-for-like' replacement normally doesn’t require requalification. All in all, a closer alignment with other process validation guidelines would be preferable.
尽管此指南作为其它验证和确认指南的附属指南，它---在现在草案状态下---与附录15和FDA工艺验证指南中所要求的验证生命周期方法的联系还是相对较少。其中没有引用代表现代验证方法基础的发展。定期再验证仍然是基本要求。有意思的是，再三讲到统计学方法的应用---适当时。另一个有意思的方面是在术语中提到了“GEP”和“调试”，而对V模型没有给出进一步解释。在确认测试中，有条件批准（在附录15中提到）是不允许的。根据指南的意思，“相似设备”替换需要进行再验证很有意思。这与PIC/S的“PI 006-3，验证主计划、安装和运行确认、非无菌工艺验证、清洁验证的建议”是相反的，在该份文件中说“相似设备”的替换一般并不需要进行再验证。总而言之，如果此指南能够与其它工艺验证指南一致将会更好。
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