【WHO】ECA News WHO公布工艺验证草案 20140521

GMP News

21/05/2014

WHO publishes Draft on Process Validation

WHO公布工艺验证草案

Dated April 2014 the WHO published a proposal for a revision of appendix 7 (non-sterile process validation) as a supplementary to the Guidelines on Good Manufacturing Practices. The reason given for the revision is compliance with actual GMP requirements. Explicitly mentioned are quality risk management principles and quality by design principles with references to WHO and ICH requirements. The text is mainly applicable to non-sterile finished pharmaceutical dosage forms. According to the draft similar approaches may be applicable to active pharmaceutical ingredients (APIs) and sterile products. The WHO now also puts the focus of validation on the life-cycle of process validation which consists of:

2014年4月，WHO公布了GMP指南附录7的修订意向（非无菌工艺验证）。修订是为了符合实际的GMP要求，其是明确提到质量风险管理原则和质量源于设计原则，以及对WHO和ICH要求的引用。文件主要适用于非无菌制剂。根据草案，类似的方法也适用于原料药和无菌药品。WHO现在也关注生命周期的工艺验证，其中包括

product and process development

产品和工艺研发

validation of the commercial manufacturing process

商业生产工艺的验证

And以及

maintaining the process in a state of control.

保持工艺受控

A risk-based approach and the use of in-line, on-line and/or at-line controls is recommended expressly.

推荐基于风险的方法，使用在线控制。

The 16-pages-draft consists of 7 chapters and the references:

这份16页的草案包括7个章， 以及参考文献

1. Background and scope 背景和范围

2. Glossary 术语

3. Introduction 介绍

4. Process design 工艺设计

5. Process qualification 工艺确认

6. Continued process verification 持续工艺确认

7. Change control 变更控制

References参考文献

Glossary 术语

A part of the terms in the glossary has been taken over verbatim from the ICH Guidelines and the FDA Process Validation Guidance. It is striking that the term process validation is quoted in the glossary still in the old version ("documented evidence that a process..."). The reference to the life-cycle approach is missing completely here. The matrix approach can be found as a term but without any further explanations.

术语中的有些词是从ICH指南和FDA工艺验证指南照搬的，引人注目的是所引用的术语“工艺验证”仍来自于旧版本（“书面证据证明一个工艺……”）。生命周期方法的引用则完全没有。矩阵方法被作为了一个术语，但并没有进一步的解释。

Introduction 介绍

In the introduction reference is made once more to the new approach pointing out critical steps and parameters. A risk assessment approach should be followed to determine the extent of variations in the starting materials and in the process. The aim is that the manufacturing process is under control before a product is placed on the market. The following words which are put in brackets are highlighted using a yellow background: "Clarify under control?".

在介绍部分，再次引用了指出关键步骤和参数的新方法。要求采用一个风险评估的方法来决定起始物料和工艺变更的程度，目的是保证生产工艺在产品上市前受控。以下文字被放在一个以黄色为背景高亮显示的括号中：“说明受控？”。

Flow diagrams are recommended as being very helpful within the scope of a process validation and may be amended as part of the validation documentation. When applying a quality risk management, the steps preceding and following that operation should also be considered. Process performance verification is also referred to as part of the validation in the introduction without the term being clarified, however.

流程图被推荐作为工艺验证范围内非常有用的工具，可能会被增补作为验证文件的一部分。在采用质量风险管理时，也要考虑操作前后的步骤。工艺性能确认也在“介绍”中被引用，作为验证的一部分，但并没有对术语进行解释。

Generally, the validation should cover all manufactured strengths of a product. But a matrix approach may be acceptable based on appropriate risk assessment. The term matrix approach is listed in the glossary. It is not defined, however (see above). The extent of validation at each manufacturing site should also be based on risk assessment.

一般来说，验证应包括一个品种所有生产的剂量。但是，基于适当的风险评估，采用矩阵方法进行验证也是可以接受的。术语表中列出了矩阵的解释，但并没有进行定义（见上）。各工厂验证的深度也可以基于风险评估来决定。

Different approaches to process validation are addressed in the introduction. Traditional process validation consists of prospective and concurrent validation. Reference is made furthermore to the 3-step- process (process design, process qualification and continued process verification). The combination of traditional process validation and the 3-step-process is mentioned as further possibility. A table illustrates once more the different phases of the new approach. Process validation with its 3 steps accompanies almost the complete product life-cycle, and change control and GMP in general, too.

在介绍中说明了工艺验证的不同方法。传统工艺验证包括前验证和同步验证。这里引用了3段式（工艺设计、工艺确认和持续工艺确认）。提到可以将传统工艺验证和3段式进行结合。给出了一个表格来说明新方法的不同阶段。工艺验证的3段基本包括了完整的产品生命周期，和变更控制以及常规GMP。

Process design 工艺设计

The chapter Process design indicates that he focus of validation now also includes development under the life-cycle approach. In the draft process design is understood as: design of experiments, process development, clinical manufacturing, pilot scale batches and technology transfer. At the stage of the process design framework conditions are developed (such as selection of materials and of the manufacturing process and so on) that will then lead to a control strategy.

工艺设计这章说明了草案对验证的关注现在也包括了生命周期方法中的研发。在草案中，工艺设计被理解为：实验设计、工艺研发、临床生产、中试批次和技术转移。在工艺设计框架阶段，对工艺条件进行研究（例如，选择物料，选择生产工艺等等），然后导出控制策略。

It is expressly mentioned that some process validation studies may be conducted on pilot-scale batches (corresponding to at least 10% or 100 000 units whichever is the greater). In case of smaller batch size it may be necessary to determine production-scale validation data.

文字中提到，一些工艺验证研究可能是在中试批次上进行的（对应至少10%或10万剂单位，取大者）。如果批量更小，则需要决定生产批量验证数据。

Process qualification and continued process verification should in any case always be linked to process design and the batches used for bioequivalence testing.

不论什么情况下，工艺确认和持续工艺确认应总是与工艺设计相链接，与用于生物等效性测试的批次相比较。

Generally, reference is made to an appropriate documentation.

一般来说，要参照适当的文件。

A development report and/or a technology transfer document, formally reviewed and approved by research and development personnel is required. A further "approval" ("formally accepted") of the documents is required to be carried out by manufacturing, engineering and quality personnel. Then examples are given for the content of such documents. Mentioned are, inter alia, specification of approved suppliers but also bills of (starting) materials.

研发报告和/或技术转移文件，应由研发人员进行正式审核和批准，还要由生产、工程和质量人员对文件进行进一步“批准”（“正式接受”）。草案给了一个例子说明文件的内容，其中提到，上述内容以外，批准供应商的质量标准，（起始）物料的帐单。

Process qualification 工艺确认

Process qualification requires that personnel, premises, utilities, support systems and equipment should be appropriately qualified before processes are validated. As concerns the qualification of equipment (DQ, IQ, OQ, PQ) reference is made to Annex 2 of the document no. 970.

工艺确认要求人员、厂房、设施、支持系统和设备在工艺验证前均应进行适当确认。关于设备的验证(DQ, IQ, OQ, PQ)，草案参考了第970号文件附件2.

Interestingly, the draft mentions the manufacture of at least three batches as traditional approach. But now it is indicated expressly that the number of batches to be manufactured should be based on risk assessment. Examples for points to be taken into consideration are variability of materials, product history, where the product is being transferred from. The stage at which the product is considered to be validated and the basis on which that decision was made should be defined. This includes a justification for the number of batches used based on the complexity and expected variability of the process.

有意思的是，草案提到作为传统方法，至少要有3批生产。但现在，草案说生产批次应基于风险评估来确认。要考虑的因素例如，物料变化、产品历史、产品转移自哪里。要界定产品在什么阶段进行验证，基于什么做出决定，这包括论述如何基于工艺复杂性或工艺预期变更来决定验证的批次。

It is remarkable how much in detail (16 points) the contents of a validation protocol are addressed. Fortunately, no timetable is required in the validation protocol. A validation report should reflect the validation protocol. It is also welcome that a dual validation protocol report can be used if they are designed to ensure clarity and if sufficient space for recording of results is available. And, naturally, deviations should be clearly addressed and examined.

引人注意的是，草案中详细列出了验证方案的很多（16条）内容。幸运的是，在验证方案中并没有要求有时间表。一个验证报告应根据验证方案来制作。如果验证方案和验证报告的设计可以保证内容的清晰性，如果有足够的空间允许记录验证的结果，那么也可以使用一份验证方案来直接填写作为报告（方案报告两用式）。当然，偏差要进行清楚的说明和检查。

A risk assessment should be performed for the change in batch size from scale up to commercial batch size.

如果批量从中试放大到商业批量，则应对变更进行风险评估，

It is explicitly mentioned that the process should be verified on commercial-scale batches prior to marketing of the product. Results of relevant quality attributes, for example of incoming materials or IPC material, should be collected. Extensive in-line and/or online and/or at-line controls should be used to monitor process performance and product quality in a timely manner. Process analytical technology applications (PAT) and multivariate statistical process control (MSPC) can also be used. It is enigmatic why parts of this chapter are highlighted in yellow.

草案清楚地提到工艺应在产品上市前对商业批量的批次进行确认。相关质量属性的结果，例如进厂物料或中控物料，应进行收集。应采用广泛的在线控制对工艺性能和产品质量以及时的方式进行监控，也可以使用工艺分析技术工具PAT和多变统计工艺控制MSPC。让人不解的是本章不知什么原因多部分是用黄色高亮显示的。

Continued process verification 持续工艺确认

The continued process verification aims at providing evidence that a state of control is maintained. According to the draft scope and extent of process verification will be influenced by a number of factors including:

持续工艺确认的目标是提供证据证明能维持在受控的状态。根据草案，工艺确认的范围和深度是受到许多因素影响的，包括

prior development and manufacturing knowledge from similar products and/or processes;

之前类似产品和/或工艺中所获得的研发和生产知识

the extent of process understanding gained from development studies and commercial manufacturing experience;

在研发和商业生产经验中获得的对工艺理解的程度

the complexity of the product and/or manufacturing process;

产品和/或生产工艺的复杂性

the level of process automation and analytical technologies used;

所使用的工艺自动化和分析技术的水平

process robustness and manufacturing history since point of commercialization as appropriate.

工艺耐受性和商业化开始的生产历史

Manufacturers should describe the appropriateness of the verification strategy in a protocol. Process parameters and material attributes that will be monitored as well as the validated analytical methods that will be employed should be listed.

生产商应在方案中描述确认策略的适用性。要监控的工艺参数和物料属性，以及将要使用的验证过的分析方法均要在方案中列出。

The following should be defined:

应对以下内容进行界定

the number of batches to be monitored;

要监控的批次数

the type of testing to be performed in the course of monitoring;

在监控过程中所进行的测试类型

the acceptance criteria to be applied;

采用的可接受标准

the evaluation of the data.

对数据的评估

Furthermore, any statistical models or tools used should be described. There is also a reference to continuous processing stating that the stage where the commercial process is considered to be validated should be defined clearly if continuous processing is employed.

另外，要描述所用的所有统计学模式或工具。如果采用了连续生产工艺，要验证商业化生产工艺时，要说明哪一步是连续的。

The draft states that periods of enhanced sampling and monitoring may help to increase process understanding as part of continuous improvement. Process trends (such as the quality of incoming materials) should be assessed in order to verify the validity of the original process validation or to identify required changes to the control strategy.

草案说明了增加取样和监控可能有助于增加对工艺的了解，作为持续改进的措施之一。工艺趋势（例如进料质量）应进行评估，以确认原始工艺验证的有效性，或识别控制策略是否需要进行变更。

The extent and frequency of continued process verification should be reviewed periodically and modified if appropriate.

持续工艺确认的深度和频次应进行周期性审核，在必要时进行修订。

Change management 变更管理

The life-cycle of a product should be accompanied by an accompanying change management. This is valid also for existing systems or processes. Sufficient data should be generated to demonstrate that the changed process will result in a product of the desired quality, consistent with the approved specification.

一个药品的生命周期应伴随着所有的变更管理。对于已经存在的系统或工艺，这也同样有效。要生成足够的数据来证明变更后的工艺会使得一个药品达到预期的质量，与批准的质量标准保持一致。

Furthermore, the necessity of a thorough documentation and a regulatory approval, where appropriate (variation), is stated.

另外，说明了必要时（变更）需要进行完整的文件记录和法规批准。

Changes that might require revalidation are addressed very comprehensively:

对需要进行再验证的变更进行了综合解释

changes in the master formula, methods, starting material manufacturer;

主要配方、制备方法、起始物料生产商变更

changes in the equipment or instruments (e.g. addition of automatic detection systems);

设备或仪器（例如增加自动检测系统）变更

changes in equipment calibrations and preventive maintenance carried out;

设备校正和预防性维护变更

production area and support system changes (e.g. a new water treatment method);

生产区域和支持性系统变更（例如，新的水处理方法）

changes in the manufacturing process (e.g. mixing times, drying temperatures);

生产工艺（例如，混合时间、干燥温度）变更

process transfers;

工艺转移

unexpected changes (e.g. those observed during self-inspection or during routine analysis of process trend data);

非预期的变更（例如，在自检中发现的，或在常规工艺趋势数据的日常分析中发现的）

changes to standard operating procedures (SOPs);

标准操作规程变更

changes to cleaning and hygiene programmes.

清洁和卫生程序变更

References 参考文献

There can be found many "old friends" among the listed references:

参考文献中，我们看到很多“老朋友”

EMA Guideline on Process Validation (still in the draft from 2012)

EMA工艺验证指南（2012年起仍在起草中）

FDA Guidance for Industry, Process Validation (2011)

FDA行业指南，工艺验证（2011）

ICH Guidelines Q8-10

ICH指南Q8-10

3 further WHO documents

3个WHO文件

The deadline for comments was strikingly short. It ended already at the end of April. The document containing the incorporated comments will be presented at the forty-ninth meeting of the WHO Expert Committee in October 2014. You can find the document in the ECA Website Members' Area.

征求意见的时间短的令人震惊，已经在4月底结束了。结合了意见的文件将在2014年10月呈交WHO专家委员会第49次会议。你可以在ECA网站成员区域找到这份文件。

Conclusions 结论

The draft of the document is oriented strongly towards the FDA Guidance on Process Validation. The validation life-cycle for example is directly comparable with the life-cycle requested by the FDA. Hence, the qualification of apparatuses is part of the process qualification as is the case in the FDA Guidance. (Unfortunately) there are almost no indications as to the handling of legacy processes. Only one statement in the chapter Change management includes existing systems and processes. There is still mentioning of the traditional approach with 3 validation batches but the number of validation runs is to be defined on the basis of a risk assessment. Parts of the sometimes very detailed requirements concerning the content of the validation protocol and concerning changes which might trigger a revalidation are interesting. Some rudiments from the developing stage (such as comments) indicate that the review prior to the publication of the draft was not really optimal. The deadline for comments was surprisingly short.

文件草案向FDA工艺验证指南靠近。例如，生命周期验证与FDA所要求的生命周期具有直接可比性。因而，仪器确认成为工艺确认的一部分，而在FDA指南中。（非常不幸地）几乎没有关于如何处理遗留工艺的指导，仅在“变更管理”中有一个声明，包括了已有系统和工艺。草案中仍然提到了传统方法的3个验证批次，但验证轮次将由基于风险的评估来确定。有意思的是，对于验证方案的内容、哪类变更可能引起再验证讲的很详细。有些起草阶段（例如征求意见）的草率情况表明草案在公布前的审核并不严格。征求意见的限期短的出人意料。

哇，好帖天天有

谢谢分享~~~