附录15和FDA工艺验证指南：与FDA预期的异同

julia朱玉姣

GMP News
28/10/2015

Annex 15 and FDA Process Validation Guideline: Similarities/differences from the FDA perspective

附录15和FDA工艺验证指南：与FDA预期的异同

The "new" FDA Process Validation Guidance has been in force since January 2011. The revised Annex 15 has been valid since 1 October 2015. At a Conference in September 2015 which was co-sponsored by the FDA, Grace McNally, Senior FDA Official reported about similarities and differences between the two documents from the perspective of the FDA.

“新”的FDA工艺验证已于2011年1月实施。修订后的附录15在2015年10月1日生效。在2015年9月的会议上，FDA提出了倡议， GRACE MCNALLY, FDA的资深官员报告了FDA角度所诠释的这两份文件的异同。

First to the similarities: both documents address a process validation life cycle and quality risk management across all stages of the life cycle. For Grace McNally there is also comparability with regard to a science-based process development and to the development of process understanding as the basis for stage 2 in accordance with the FDA Process Validation Guideline, resp. with the actual process validation in the sense of Annex 15. Prospective validation is favoured in both documents. Only in special cases one concurrent validation is possible, but is never favoured as a routine procedure. The FDA also sees similarities between the Annex 15 and the FDA Process Validation Guideline relative to the need for a rationale for determining the number of samples for PPQ/process validation, as well as in determining the number of PPQ - / validation runs. And this rationale should include, for example, the process variables and the complexity and experience with the process. For the FDA there are further similarities with regard to statistical methods and analyses as part of the process validation: mentioned are PAT, multivariate SPC, statistical methods regarding variability and process capabilities, trend analyses and methods for measuring/evaluating process stabilities and capabilities. Moreover, the authority considers stage 3 in the process validation life cycle (continued/ongoing process verification) as comparable. An exception is mentioned below in the differences. Finally, the requirements for change control in both FDA Process Validation Guideline and the revised Annex 15 are also similar from the perspective of the FDA.

首先是相同的地方：两份文件均强调了工艺验证的生命周期和各阶段的质量风险管理。对于GRACE MCNALLY，在基于科学工艺研发和根据FDA工艺验证指南，将工艺理解发展作为第二阶段的基础，相对于附录15中实际工艺验证的含义是具有可比性。前验证在两份文件中都是受到青睐的。仅有在特殊情形下，可以进行同步验证，但绝不能作为常规程序来用。FDA还看到附录15和FDA工艺验证指南中同样要求在决定PPA/工艺验证样品数量，以及决定PPQ-/验证批次时要有合理性。该合理性应包括，例如，工艺变量和工艺复杂性及工艺经验。对于FDA来说，关于统计学方法和分析作为工艺验证的一部分也有相同之处：提到了PAT、多变更SPC、关于变化和工艺能力的统计学方法、趋势分析和测量/评估工艺稳定性和能力的方法。另外，官方认为工艺验证生命周期的第三阶段（持续工艺确认）也是可比的。例外情况在下面的不同之处里提到。最后，在FDA看来，两份文件中对于变更控制的要求也是相似的。

But what are now the differences between the FDA Process Validation Guidelines and the revised Annex 15?

那么现在FDA工艺验证指南和修订后的附录15之间有哪些不同之处呢？

As one difference the Annex 15 asks to also list non-critical attributes and parameters in the validation protocol. The FDA Process Validation Guideline only requires the specification of critical quality attributes and critical process parameters. The FDA sees another difference in the number of validation batches. Annex 15 refers to the minimum number of 3, whereas the FDA Process Validation Guideline does not mention a number. For the FDA there is another difference in terms of process validation approaches. In Annex 15 three approaches are mentioned (traditional, continuous process verification, hybrid), while the FDA Process Validation Guideline makes no distinction. Further, the requirements for statistics also differ in the two documents. This topic is emphasized more in the FDA Process Validation Guideline. The FDA even recommends that a statistician should create the data collection plans and should also be consulted with regard to the use of statistical methods. This requirement goes beyond what is stated in the FDA Process Validation Guideline. It "just" recommends someone with statistical knowledge. The FDA also sees differences regarding the subject of sampling in the stage 3 of the process validation life cycle (continued/ongoing process verification). The FDA Guideline demands a higher number of samples (comparable to stage 2) - at least until sufficient data exist to assess variability. There is no such demand for an increased number of samples in the ongoing process verification in Annex 15. In addition, it addresses transport, packaging operations and cleaning validation, while the FDA Guideline addresses processes in general. Also, Annex 15 mentions more details with regard to transfer, bracketing and qualification. However, the FDA Process Validation Guideline does not address the qualification stages DQ IQ, OQ as such, but mentions similar requirements.

一个不同之处是附录15要求在验证方案中也列出非关键性属性和参数。FDA工艺验证指南只要求关键质量属性标准和关键工艺参数。FDA还看到另一个不同之处是验证批数的不同。附录15要求最少3批，而FDA工艺验证指南不再提具体批次了。在FDA看来，还有另一个不同之处是关于工艺验证方法的。在附录15中，提到了三种方法（传统方法、持续工艺确认和混合法），而FDA工艺验证指南则没有做出区别。另外，关于统计学的要求也有差异。该问题在FDA工艺验证指南中强调的很多。FDA甚至推荐说统计人员应创建数据采集计划，还应该问统计员需要使用什么统计方法。这个要求已经超出了FDA工艺验证指南内容的范围了。它“只是”推荐具有统计学知识的人员。FDA还看到关于工艺验证生命周期（持续工艺确认）第三阶段的取样目的的差异。FDA指南要求更多样品（相比于第二阶段）---至少直到有足够的数据来评估变动性。在附录15中则没有对持续工艺确认中提出增加样品数量的要求。另外，它还讲了运输、包装操作和清洁验证，而FDA指南只是讲了工艺。还有，附录15提到更多关于转移、分组法和确认的更多详细内容。而FDA工艺验证指南并没有提到DQ、IQ、OQ确认阶段，但提到了类似的要求。

Conclusion 结论
There is (gratifying) much conformity between the FDA Process Validation Guideline and the revised Annex 15. A better match with the FDA Guideline was also one of the reasons for the revision of Annex 15.

FDA工艺验证和修订后的附录15之间有许多（令人高兴的）相通性。更好地契合FDA指南也是附录15修订的原因之一。

But there are also differences, and companies that want to operate both in the US market and in Europe have to be aware of these differences. The recommendation that a statistician should create the data collection plans and should be consulted with regard to the use of statistical methods is somewhat surprising. This requirement goes beyond what is stated in the FDA Process Validation Guideline. Here "just" someone with statistical knowledge is recommended. On the other hand this emphasizes the FDA's increased focus on statistics in the field of process validation. Information on knowledge of statistics cannot be found in Annex 15.

但它们还是有许多不同之处，想在同时销售到美国市场和欧洲市场的公司必须知道这些差异。关于要统计员创建数据采集计划以及要向统计员咨询使用统计方法的建议就让人很惊奇。该要求超出了FDA工艺验证指南所述内容的范围。这里“只有”推荐具有统计学知识的人员。另一方面，这里强调的是FDA增加了对工艺验证领域的统计学关注。关于统计学的知识信息则在附录15中没有。

julia朱玉姣

GMP News
28/10/2015

Annex 15 and FDA Process Validation Guideline: Similarities/differences from the FDA perspective

附录15和FDA工艺验证指南：与FDA预期的异同

The "new" FDA Process Validation Guidance has been in force since January 2011. The revised Annex 15 has been valid since 1 October 2015. At a Conference in September 2015 which was co-sponsored by the FDA, Grace McNally, Senior FDA Official reported about similarities and differences between the two documents from the perspective of the FDA.

“新”的FDA工艺验证已于2011年1月实施。修订后的附录15在2015年10月1日生效。在2015年9月的会议上，FDA提出了倡议， GRACE MCNALLY, FDA的资深官员报告了FDA角度所诠释的这两份文件的异同。

First to the similarities: both documents address a process validation life cycle and quality risk management across all stages of the life cycle. For Grace McNally there is also comparability with regard to a science-based process development and to the development of process understanding as the basis for stage 2 in accordance with the FDA Process Validation Guideline, resp. with the actual process validation in the sense of Annex 15. Prospective validation is favoured in both documents. Only in special cases one concurrent validation is possible, but is never favoured as a routine procedure. The FDA also sees similarities between the Annex 15 and the FDA Process Validation Guideline relative to the need for a rationale for determining the number of samples for PPQ/process validation, as well as in determining the number of PPQ - / validation runs. And this rationale should include, for example, the process variables and the complexity and experience with the process. For the FDA there are further similarities with regard to statistical methods and analyses as part of the process validation: mentioned are PAT, multivariate SPC, statistical methods regarding variability and process capabilities, trend analyses and methods for measuring/evaluating process stabilities and capabilities. Moreover, the authority considers stage 3 in the process validation life cycle (continued/ongoing process verification) as comparable. An exception is mentioned below in the differences. Finally, the requirements for change control in both FDA Process Validation Guideline and the revised Annex 15 are also similar from the perspective of the FDA.

首先是相同的地方：两份文件均强调了工艺验证的生命周期和各阶段的质量风险管理。对于GRACE MCNALLY，在基于科学工艺研发和根据FDA工艺验证指南，将工艺理解发展作为第二阶段的基础，相对于附录15中实际工艺验证的含义是具有可比性。前验证在两份文件中都是受到青睐的。仅有在特殊情形下，可以进行同步验证，但绝不能作为常规程序来用。FDA还看到附录15和FDA工艺验证指南中同样要求在决定PPA/工艺验证样品数量，以及决定PPQ-/验证批次时要有合理性。该合理性应包括，例如，工艺变量和工艺复杂性及工艺经验。对于FDA来说，关于统计学方法和分析作为工艺验证的一部分也有相同之处：提到了PAT、多变更SPC、关于变化和工艺能力的统计学方法、趋势分析和测量/评估工艺稳定性和能力的方法。另外，官方认为工艺验证生命周期的第三阶段（持续工艺确认）也是可比的。例外情况在下面的不同之处里提到。最后，在FDA看来，两份文件中对于变更控制的要求也是相似的。

But what are now the differences between the FDA Process Validation Guidelines and the revised Annex 15?

那么现在FDA工艺验证指南和修订后的附录15之间有哪些不同之处呢？

As one difference the Annex 15 asks to also list non-critical attributes and parameters in the validation protocol. The FDA Process Validation Guideline only requires the specification of critical quality attributes and critical process parameters. The FDA sees another difference in the number of validation batches. Annex 15 refers to the minimum number of 3, whereas the FDA Process Validation Guideline does not mention a number. For the FDA there is another difference in terms of process validation approaches. In Annex 15 three approaches are mentioned (traditional, continuous process verification, hybrid), while the FDA Process Validation Guideline makes no distinction. Further, the requirements for statistics also differ in the two documents. This topic is emphasized more in the FDA Process Validation Guideline. The FDA even recommends that a statistician should create the data collection plans and should also be consulted with regard to the use of statistical methods. This requirement goes beyond what is stated in the FDA Process Validation Guideline. It "just" recommends someone with statistical knowledge. The FDA also sees differences regarding the subject of sampling in the stage 3 of the process validation life cycle (continued/ongoing process verification). The FDA Guideline demands a higher number of samples (comparable to stage 2) - at least until sufficient data exist to assess variability. There is no such demand for an increased number of samples in the ongoing process verification in Annex 15. In addition, it addresses transport, packaging operations and cleaning validation, while the FDA Guideline addresses processes in general. Also, Annex 15 mentions more details with regard to transfer, bracketing and qualification. However, the FDA Process Validation Guideline does not address the qualification stages DQ IQ, OQ as such, but mentions similar requirements.

一个不同之处是附录15要求在验证方案中也列出非关键性属性和参数。FDA工艺验证指南只要求关键质量属性标准和关键工艺参数。FDA还看到另一个不同之处是验证批数的不同。附录15要求最少3批，而FDA工艺验证指南不再提具体批次了。在FDA看来，还有另一个不同

质量小兵

学习一下，谢谢分享。

longxiatom

谢谢 学习中

Jason

不错的法规分享知识

friendly521

路过看看学习学习

glm1024

统计学以后越来越受到重视了

红茶.

要统计员创建数据采集计划以及要向统计员咨询使用统计方法——这句话有点瘆人啊。

尼采

感谢分享   

尼采

感谢分享   

centrel

Annex 15 工艺验证规定为三批次的话，申报的成本又要增加了。

赵旭锋

让统计员或者说有统计基础的人来创建数据采集计划和决定使用统计方法的建议是很有必要的。这个估计以后会成为一个很重大的变化

赵旭锋

红茶. 发表于 2015-10-29 08:21
要统计员创建数据采集计划以及要向统计员咨询使用统计方法——这句话有点瘆人啊。

不瘆人，挺好的一个建议，看来还要好好学学统计啊，尤其是抽样和数据分析

wct0526

学习一下，谢谢分享。

胜利者

学习

xhf123456

学习一下，谢谢分享。

北重楼

统计学在处理数据和趋势分析上是有不可替代的作用。不过我记得好像国内稳定性研究都是用文字表达自己的产品是稳定的，最多说说检验结果范围，很少使用统计学处理呀，是不是也要使用呀