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清洁验证:质量风险管理方法

近日,ASME发布了E3106-18<基于科学和基于风险的清洁工艺开发和验证标准指南>,该指南对清洁验证作出了较为全面的要求,解读如下:


With the implementation of the ICH Q9 document, risk management has become mandatory in almost all GMP areas. This also applies to cleaning validation. Now, what can a quality risk management approach look like in cleaning validation? The American Society of Testing and Material (ASTM) has recently issued a guideline on this.

随着ICH Q9文件的实施,风险管理已成为几乎所有GMP领域的强制性要求。这同样包括清洁验证。现在,质量风险管理方法在清洁验证中的作用是什么?美国测试与材料协会(ASTM)最近发布了一份指南。


The document entitled Standard Guide for Science-Based and Risk-Based Cleaning Processes Development and Validation, labelled E3106-18, comprises 9 pages with 10 chapters. The first chapter Scope starts pointing out that the Guide applies a life cycle approach to cleaning validation, from development to validation up to cleaning process verification. This approach can be applied to all dosage forms, to active substances and also to cleaning during clinical supply production.

该文件标题为<基于科学和基于风险的清洁工艺开发和验证标准指南>,标记为E3106-18,共9页,共10章。第一章范围指出,本指南采用生命周期方法进行清洁验证,从开发到验证再到清洁过程确认。该方法可应用于所有制剂,活性物质以及临床试验样品生产的清洁。


The first 2.5 pages deal both with the scope and referenced documents (Chapter 2) as well as definitions (Chapter 3). Chapter 4 (Significance and Use) refers to ICH Q8, 9, 10 and 11 and the FDA Process Validation Guidance. In Chapter 5, the use of cleaning development process and validation based on science, risk and statistics is recommended.

前2.5页包括范围和参考文献(第2章)以及定义(第3章)。第4章(重要性和用途)引用了ICH Q8,9,10和11以及FDA工艺验证指南。在第5章中,建议使用基于科学,风险统计学的清洁开发过程和验证。


Chapter 6 Risk Assessment

第六章风险评估


The 3.5-page Chapter 6 addresses risk assessment. The following points should be taken into account in the risk assessment:

3.5页的第6章讨论了风险评估。风险评估应考虑以下几点:


  • Acceptable daily exposure (ADE) values, if available

    可接受的日暴露值(ADE),如有

  • The threshold of toxicological concern (TTC) concept

    毒理学阈值(TTC)

  • Microbiological contaminations

    微生物污染

  • Equipment design

    设备设计

  • Handling errors

    处理错误


In the risk analysis, the aspects mentioned above are assigned to a risk. This assignment should also include:

在风险分析中考虑上述方面。还应包括:


  • The development of the cleaning process

    清洁工艺的开发

  • A design review of the facility and equipment

    设施和设备的设计审查

  • A review of the cleaning processes and

    清洁工艺的审查,以及

  • Selection of the analysis method.

    分析方法的选择


The risk analysis should also include risk reduction. An important point of the risk analysis is the characterisation of the process residues (solubilities, adhesion behaviour) and the influence of instrument design (material, dead ends, drainability) on the cleanability. If possible, historical data of cleaning results should be integrated. Great importance is attached to the development of the cleaning process. This development should include laboratory studies, the determination of the cleaning parameters and the ion of cleaning agents. Existing cleaning SOPs should also be subjected to a risk analysis. Equipment for cleaning should also have a suitable design. Interestingly, the Guide suggests Design of Experiment (DoE) to optimize the cleaning processes and even a Cleaning Design Space. Manual cleaning should also be considered with a risk analysis (are there differences between different people?). Regarding automated cleaning systems, the risk of cross-contamination by the system itself should be considered in the risk analysis.

该风险分析还应包括风险降低。风险分析的一个重点是工艺残留物的特性(溶解度,粘附性)以及设备设计(材质,死角,排水性)对清洁的影响。如有可能,应结合清洁结果的历史数据。清洁工艺的开发非常重要。这一开发应包括实验室研究,清洁参数的确定和清洁剂的选择。现有的清洁SOP也应进行风险分析。清洁设备也应该有合适的设计。有趣的是,指南建议设计实验(DoE)以优化清洁过程甚至是“清洁设计空间”。还应考虑人工清洁并进行风险分析(不同人之间是否存在差异?)。关于自动清洁系统,在风险分析中应考虑系统本身的交叉污染风险。


Of course, the grouping of processes and equipment should also be based on a risk analysis. These groupings can then also serve as a basis for factors in the DoE mentioned above. Also the times in which devices may stand dirty before they are cleaned (Dirty Hold Time) and the time in which the plant may stand clean (Clean Hold Time) should be considered on the basis of a risk analysis. Where there is no influence on the cleanability due to the holding times, no qualification activities - in this case called qualification activities - have to be carried out. If these hold times are exceeded, a new term is used: expired equipment hold time (EEHT). Particular emphasis is placed on monitoring the success of training with manual cleaning.

当然,工艺和设备的分组也应该基于风险分析。然后,这些分组也可以作为上述DoE所考虑因素的基础。还应根据风险分析考虑设备在清洁之前可能的污染时间(“脏的保持时间”)和设备洁净时间(“干净的保持时间”)。如果保持时间对清洁效果没有影响,则不需要进行任何确认活动 - 在这种情况下称为确认活动。如果超过这些保持时间,则使用新术语:“超过设备保持时间”(EEHT)。特别强调需要监测人工清洁培训的成功


The result of all risk analyses should finally lead to a Cleaning Control Strategy, which has to be evaluated regularly.

所有风险分析的结果应最终形成“清洁控制策略”,并应定期评估。


The next item Sampling covered in the chapter Risk Analysis is very extensive. Of course, a risk analysis should also determine the sampling strategy (representative sampling locations, number and methods). This risk analysis should also include statistical considerations. Somewhat surprisingly, in the case of process residues with low risk and a fully visible surface, even visual evaluations based on a risk analysis are considered sufficient for cleaning validation. Interestingly, this assessment is cited with reference to Annex 15. A direct sampling (swab) before an indirect sampling (rinse) is considered to be preferable. Of course, the choice should also be based on a risk analysis. Fourier Transform Infrared (FTIR), Near Infrared (NIR), Raman, fluorescence and UV spectroscopy are mentioned as possible methods for surface scanning sampling as part of a cleaning verification. Sampling techniques require recovery rates and extensive training of samplers. Statistical techniques are recommended to determine the accuracy, precision and robustness of the sampling technique. The ion of the analytical method (specific or non-specific) should also be based on science and risk. A master plan for cleaning should form the basis for the cleaning control strategy.

风险分析一章中另一个项目是“取样”。当然,风险分析还应确定取样策略(代表性的取样位置,数量和方法)。此风险分析还应包括统计学考虑。令人惊讶的是,在工艺残留物风险较低并且清洁表面完全可见的情况下,基于风险分析的目视评估被认为足以用于清洁验证。有趣的是,该评估引用了附录15(EU GMP)。直接取样(擦拭)相比间接取样(冲洗)被认为是优选的。当然,选择也应该基于风险分析。文件提到傅里叶变换红外(FTIR),近红外(NIR),拉曼,荧光和UV光谱作为清洁确认表面扫描取样的可能方法。取样技术需要回收率和“取样人员”的广泛培训。建议使用统计技术来确定取样技术的准确性,精确性和稳健性分析方法(专属或非专属)的选择也应基于科学和风险。清洁主计划应成为清洁控制策略的基础。


In the risk assessment (evaluation), the cleaning data should be evaluated against the acceptance criteria of the risks. The risk assessment should already consider risk reduction if the risks are too high. The evaluation of cleaning data can be done via maximum safe surface residue (MSSR) based on ADE data. According to the Guide, microbiological data can be collected using a comparable procedure.

在风险评估(评价)中,应根据风险的接受标准评估清洁数据。如风险过高,风险评估应该考虑降低风险。清洁数据的评估可以通过“基于ADE数据的最大安全表面残留(MSSR)”来完成。根据“指南”,可以使用类似的程序收集微生物数据。


The actual risk-reducing measures, if necessary, are described in chapter 7 on risk control. Possible reduction measures with regard to significance, probability of occurrence and detectability are listed in a separate table. Routine monitoring should also be developed as part of risk control. Routine monitoring could also take the form of statistical process control (SPC). Process analytical technologies (PAT) for the development, analysis and control of the cleaning process, up to continuous monitoring or even parametric releases of the equipment are also recommended. The results of risk-reducing measures should be documented in terms of risk acceptance.

第7章风险控制中描述了实际的风险降低措施。关于重要性,发生概率和可检测性的可能降低措施列在单独的表中。还应制定日常监测作为风险控制的一部分。日常监测也可以采用统计过程控制(SPC)的形式。还建议使用过程分析技术(PAT)来开发,分析和控制清洁过程,连续监测甚至参数放行。风险降低措施的结果应书面化以接受风险。


Chapter 8 deals with the Risk Review. Based on a risk analysis, cleaning and cleaning monitoring results should be evaluated regularly. On this basis, the review cycles can be adjusted if necessary. There is an indication when a new product is introduced. Using the toxicological data as a basis, the integration of this new product into the existing cleaning system should be considered.

第8章谈及“风险回顾”。根据风险分析,应定期回顾清洁和清洁监测结果。在此基础上,必要时可以调整回顾周期。当引入新产品时应进行风险分析。使用毒理学数据作为基础,应考虑将该新产品放到现有清洁体系中。


Chapter 9 on risk communication points out that risk communication involves the exchange of information on cleaning risks and their control. This concerns the various parties involved. The company itself, various companies among themselves, contract manufacturers, regulatory authorities, etc. are mentioned. Contents of the information exchange should be

第9章风险沟通指出,风险沟通涉及清洁风险及其控制的信息交流。这涉及各个方面。公司内部,不同公司间,合同制造商,监管机构等都被提及。信息交换的内容应该是:


  • Severity (ADE/PDE)

    严重性(ADE / PDE)

  • Probability (experience from the past)

    可能性(过去的经验)

  • Detectability (analytical methods)

    可检测性(分析方法)

  • Controls (cleaning procedures and agents)

    控制(清洁程序和清洁剂)


and always with a view to patient risk.

并始终考虑到患者的风险。


Chapter 10 includes a keyword index.

第10章包括关键字索引。


Conclusion: The guide shows the implementation of a life cycle approach based on quality risk management with regard to the development, validation and control of cleaning. New terms and abbreviations not yet listed in regulatory documents are somewhat irritating. The integration of modern methods, such as DoE and PAT for cleaning validation is also very future-oriented. What is surprising is the clear statement, with reference to Annex 15, that after a risk analysis, visual cleanability can also be regarded as the sole cleaning validation criterion. Whereby the corresponding passage in Annex 15 on visual cleanings is: It is generally unacceptable that this criterion is used alone. Does this really correspond to the interpretation of the ASTM Guide?   

结论:该指南显示了基于质量风险管理的生命周期方法的实施,涉及清洁的开发,验证和控制。尚未列入监管文件的新术语和缩写有些令人费解。结合“现代”方法,如DoE和PAT,用于清洁验证,也可能是未来的趋势。令人惊讶的是,参考(EU GMP)附录15的明确声明,在风险分析之后,目视干净也可被视为唯一的清洁验证标准。因此,附录15中关于目视干净的相应段落是:单独使用该标准通常是不可接受的。这是否真的符合ASTM指南的解释?

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