近日，ASME發(fā)布了E3106-18《基于科學和基于風險的清潔工藝開發(fā)和驗證標準指南》，該指南對清潔驗證作出了較為全面的要求，解讀如下：

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.

隨著ICH Q9文件的實施，風險管理已成為幾乎所有GMP領(lǐng)域的強制性要求。這同樣包括清潔驗證。現(xiàn)在，質(zhì)量風險管理方法在清潔驗證中的作用是什么？美國測試與材料協(xié)會（ASTM）最近發(fā)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.

該文件標題為《基于科學和基于風險的清潔工藝開發(fā)和驗證標準指南》，標記為E3106-18，共9頁，共10章。第一章范圍指出，本指南采用生命周期方法進行清潔驗證，從開發(fā)到驗證再到清潔過程確認。該方法可應用于所有制劑，活性物質(zhì)以及臨床試驗樣品生產(chǎn)的清潔。

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頁包括范圍和參考文獻（第2章）以及定義（第3章）。第4章（重要性和用途）引用了ICH Q8,9,10和11以及FDA工藝驗證指南。在第5章中，建議使用基于科學，風險和統(tǒng)計學的清潔開發(fā)過程和驗證。

Chapter 6 Risk Assessment

第六章風險評估

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

3.5頁的第6章討論了風險評估。風險評估應考慮以下幾點：

• 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

  毒理學閾值（TTC）

• Microbiological contaminations

  微生物污染

• Equipment design

  設(shè)備設(shè)計

• Handling errors

  處理錯誤

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

在風險分析中考慮上述方面。還應包括：

• The development of the cleaning process

  清潔工藝的開發(fā)

• A design review of the facility and equipment

  設(shè)施和設(shè)備的設(shè)計審查

• A review of the cleaning processes and

  清潔工藝的審查，以及

• Selection of the analysis method.

  分析方法的選擇

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.

該風險分析還應包括風險降低。風險分析的一個重點是工藝殘留物的特性（溶解度，粘附性）以及設(shè)備設(shè)計（材質(zhì)，死角，排水性）對清潔的影響。如有可能，應結(jié)合清潔結(jié)果的歷史數(shù)據(jù)。清潔工藝的開發(fā)非常重要。這一開發(fā)應包括實驗室研究，清潔參數(shù)的確定和清潔劑的選擇?，F(xiàn)有的清潔SOP也應進行風險分析。清潔設(shè)備也應該有合適的設(shè)計。有趣的是，指南建議設(shè)計實驗（DoE）以優(yōu)化清潔過程甚至是“清潔設(shè)計空間”。還應考慮人工清潔并進行風險分析（不同人之間是否存在差異？）。關(guān)于自動清潔系統(tǒng)，在風險分析中應考慮系統(tǒng)本身的交叉污染風險。

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.

當然，工藝和設(shè)備的分組也應該基于風險分析。然后，這些分組也可以作為上述DoE所考慮因素的基礎(chǔ)。還應根據(jù)風險分析考慮設(shè)備在清潔之前可能的污染時間（“臟的保持時間”）和設(shè)備潔凈時間（“干凈的保持時間”）。如果保持時間對清潔效果沒有影響，則不需要進行任何確認活動 - 在這種情況下稱為確認活動。如果超過這些保持時間，則使用新術(shù)語：“超過設(shè)備保持時間”（EEHT）。特別強調(diào)需要監(jiān)測人工清潔培訓的成功。

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

所有風險分析的結(jié)果應最終形成“清潔控制策略”，并應定期評估。

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.

風險分析一章中另一個項目是“取樣”。當然，風險分析還應確定取樣策略（代表性的取樣位置，數(shù)量和方法）。此風險分析還應包括統(tǒng)計學考慮。令人驚訝的是，在工藝殘留物風險較低并且清潔表面完全可見的情況下，基于風險分析的目視評估被認為足以用于清潔驗證。有趣的是，該評估引用了附錄15（EU GMP）。直接取樣（擦拭）相比間接取樣（沖洗）被認為是優(yōu)選的。當然，選擇也應該基于風險分析。文件提到傅里葉變換紅外（FTIR），近紅外（NIR），拉曼，熒光和UV光譜作為清潔確認表面掃描取樣的可能方法。取樣技術(shù)需要回收率和“取樣人員”的廣泛培訓。建議使用統(tǒng)計技術(shù)來確定取樣技術(shù)的準確性，精確性和穩(wěn)健性。分析方法（專屬或非專屬）的選擇也應基于科學和風險。清潔主計劃應成為清潔控制策略的基礎(chǔ)。

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.

在風險評估（評價）中，應根據(jù)風險的接受標準評估清潔數(shù)據(jù)。如風險過高，風險評估應該考慮降低風險。清潔數(shù)據(jù)的評估可以通過“基于ADE數(shù)據(jù)的最大安全表面殘留（MSSR）”來完成。根據(jù)“指南”，可以使用類似的程序收集微生物數(shù)據(jù)。

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章風險控制中描述了實際的風險降低措施。關(guān)于重要性，發(fā)生概率和可檢測性的可能降低措施列在單獨的表中。還應制定日常監(jiān)測作為風險控制的一部分。日常監(jiān)測也可以采用統(tǒng)計過程控制（SPC）的形式。還建議使用過程分析技術(shù)（PAT）來開發(fā)，分析和控制清潔過程，連續(xù)監(jiān)測甚至參數(shù)放行。風險降低措施的結(jié)果應書面化以接受風險。

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章談及“風險回顧”。根據(jù)風險分析，應定期回顧清潔和清潔監(jiān)測結(jié)果。在此基礎(chǔ)上，必要時可以調(diào)整回顧周期。當引入新產(chǎn)品時應進行風險分析。使用毒理學數(shù)據(jù)作為基礎(chǔ)，應考慮將該新產(chǎn)品放到現(xiàn)有清潔體系中。

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章風險溝通指出，風險溝通涉及清潔風險及其控制的信息交流。這涉及各個方面。公司內(nèi)部，不同公司間，合同制造商，監(jiān)管機構(gòu)等都被提及。信息交換的內(nèi)容應該是：

• Severity (ADE/PDE)

  嚴重性（ADE / PDE）

• Probability (experience from the past)

  可能性（過去的經(jīng)驗）

• Detectability (analytical methods)

  可檢測性（分析方法）

• Controls (cleaning procedures and agents)

  控制（清潔程序和清潔劑）

and always with a view to patient risk.

并始終考慮到患者的風險。

Chapter 10 includes a keyword index.

第10章包括關(guān)鍵字索引。

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?   

結(jié)論：該指南顯示了基于質(zhì)量風險管理的生命周期方法的實施，涉及清潔的開發(fā)，驗證和控制。尚未列入監(jiān)管文件的新術(shù)語和縮寫有些令人費解。結(jié)合“現(xiàn)代”方法，如DoE和PAT，用于清潔驗證，也可能是未來的趨勢。令人驚訝的是，參考（EU GMP）附錄15的明確聲明，在風險分析之后，目視干凈也可被視為唯一的清潔驗證標準。因此，附錄15中關(guān)于目視干凈的相應段落是：單獨使用該標準通常是不可接受的。這是否真的符合ASTM指南的解釋？