ECA新闻：清洁验证：质量风险管理方法可能是什么样的？

罗伊鲱

09.01.2019

Cleaning Validation: What can a Quality Risk Management Approach Look Like?
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。这也适用于清洁验证。现在，质量风险管理方法在清洁验证中的作用是什么？美国材料与试验协会（ASTM）最近发布了一项指导原则。
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.
题为《基于科学和风险的清洁工艺开发和验证的标准指南》的文件，标号E3106-18，包括9页共10章。第一章范围开始指出，本指南将生命周期方法用于清洁验证，从开发到验证再到清洁工艺验证。该方法可应用于所有剂型、活性物质以及临床供应生产期间的清洁。
The first 2.5 pages deal both with the scope and referenced documents (Chapter 2) as well as definitions (Chapter 3). Interestingly, some of the definitions still contain discussion subpoints which further interpret the respective definition point. 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页涉及范围和参考文献（第2章）以及定义（第3章）。有趣的是，一些定义仍然包含进一步解释了各自定义点的讨论子点。第4章（意义和用途）参考了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、风险和统计数据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。在风险评估中应考虑以下几点：
•        Acceptable daily exposure (ADE) values, if available
•        可接受的每日暴露（ADE）值（如果有）
•        The threshold of toxicological concern (TTC) concept
•        毒理学关注（TTC）概念的阈值
•        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，上述方面被指定为风险。该赋值还应包括：
•        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核
•        A review of the cleaning processes and  审核清洁工艺和
•        Selection of the analysis method.  选择分析方法。
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 selection 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.
风险分析还应包括降低风险。风险分析的一个重点是表征工艺残留物（溶解度、粘附行为）以及仪器设计（材料、肓端、排水能力）对可清洁性的影响。如果可能，应整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。清洁用设备也应有合适的设计。有趣的是，该指南建议实验设计（DoE）以优化清洁工艺甚至是“清洁设计空间”。手动清洁也应考虑风险分析（不同的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中的因素的基础。此外，设备在清洁之前保持肮脏的时间（“脏保持时间”）和设备保持清洁的时间（“清洁保持时间”）应在风险分析的基础上加以考虑。如果由于保持时间对可清洁性没有影响，则不必进行任何确认活动——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：“过期设备保持时间”（EEHT）。特别强调通过手动清洁监测培训的成功与否。
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该最终导致“清洁控制策略”，这必须定期评估。
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 selection 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.
风险分析一章中涵盖的下一项采样非常广泛。当然，风险分析还应确定取样策略（代表性取样位置、数量和方法）。此风险分析还应包括统计学考虑。有些令人意外的是，在工艺残留物低风险和完全可见表面的情况下，甚至基于风险分析的视觉评估也被认为足以进行清洁验证。有趣的是，该评估参考引用附件15。间接取样（冲洗）之前的直接取样（拭子）被认为是优选的。当然，选择也应该基于风险分析。作为清洁验证的一部分，提到傅里叶变换红外（FTIR）、近红外（NIR）、拉曼、荧光和UV光谱法作为表面扫描采样的可能方法。取样技术需要回收率和“取样器”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（特异或非特异的）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.
在风险评估中，应根据风险的接受标准评估清洁数据。如果风险过高，风险评估应该已经考虑降低风险。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.
如有必要，实际的减少风险措施将在第7章风险控制中予以说明。关于重要性，发生概率和可检测性的可能减少措施列在单独的表中。还应制定常规监测作为风险控制的一部分。常规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，直至设备的连续监测甚至参数释放。风险降低措施的结果应记录在风险接受方面。
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章涉及“风险回顾”。根据风险分析，应定期评估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。在引入新产品时有一个指示。使用毒理学数据作为基础，应考虑将这种新产品整合到现有的清洁系统中。
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
关于风险沟通的第9章指出，风险沟通涉及清洁风险及其控制的信息交流。这涉及有关各方。公司本身、各种公司、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)  概率（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 very well. New terms and abbreviations not yet listed in regulatory documents are remarkable. The integration of "modern" methods, such as DoE and PAT for cleaning validation is future-oriented. Interesting is the section regarding the visually clean-criterion as a solely acceptance criteron in cleaning validation with reference to Annex 15. Concerning this the EMA Q&A document could as the circumstances require help to discuss this with GMP inspectors.
结论：该指南非常好地显示了关于清洁的开发、验证和控制的基于质量风险管理的生命周期方法的实施。尚未列入监管文件的新术语和缩写非常引人注目。用于清洁验证的“现代”方法（例如DoE和PAT）的整合是面向未来的。有趣的是参考附件15将视觉清洁标准作为清洁验证的唯一验收标准的章节。有关这一点，EMA问答文件可作为环境要求帮助与GMP检查员讨论。
The Standard Guide for Science-Based and Risk-Based Cleaning Processes Development and Validation with the label E3106-18 can be purchased on the ASTM website.
《基于科学和风险的清洁工艺开发和验证的标准指南》标号E3106-18，可在ASTM网站上购买。

http://www.gmp-compliance.org/gm ... -approach-look-like

罗伊鲱

CLEANING VALIDATION WITH RISK ASSESSMENT
Bangkok, Thailand
July 26 2017
Jairaj (Jai) Mehta, Consultant,
Promoting the Quality of Medicines

晓坏坏_z9Z5D

了解一下  

syhorchid

了解一下

冷雪清风

https://www.ouryao.com/thread-467377-1-1.html，这个链接里可以下载。

罗伊鲱

https://www.sterislifesciences.c ... ess-parameters.ashx

清晨的太阳

前来学习，补充知识