近日，WHO發布清潔驗證指南草案修訂稿，名為：在清潔驗證中，使用基于健康的暴露限（HBEL）時應考慮的要點。
該指南初稿于今年5月發布，之后基于收集到的反饋意見形成了本版本。WHO表示，將在9月21日前再次收集反饋意見，之后的修訂稿將在今年10月份召開的第55屆WHO 藥物制劑專家委員會（ECSPP）會議上進行報告。
本指南主要涵蓋了：
在清潔驗證中，基于藥理和毒理學數據的HBEL時應考慮的要點，即如何基于風險和科學的方法。
就審查多產品設施中和清潔驗證的當前狀態和方法時，需要考慮的要點。
該指南正文分為五個部分，分別是：（1）介紹和背景、（2）范圍、（3）術語、（4）傳統方法和（5）新方法。
PharmLink指南組將對全文主要內容進行翻譯和連載，供大家參考。
1.Introduction and background 介紹和背景
The World Health Organization (WHO) has published the guideline entitled Good manufacturing practices for pharmaceutical products: main principles in the WHO Technical Report Series, No. 986,Annex 2, 2014 (1).
世界衛生組織（WHO）已發布指南，標題為“藥品的GMP：WHO技術報告叢書的主要原則”，第986號，附件2，2014（1）。
The WHO Supplementary guidelines on good manufacturing practice: validation were published in 2006 and were supported by seven appendices. The main text and its appendixes were revised between 2006 and 2019. Appendix 3, relating to cleaning validation , was not updated at that time. Its revision, however, was discussed during an informal consultation held in Geneva, Switzerland, in July 2019. The outcome of the discussion was presented to the WHO Expert Committee on Specifications for Pharmaceutical Products (ECSPP) meeting in October 2019. The ECSPP acknowledged the importance of harmonization in regulatory expectations with regards to cleaning validation approaches. The Expert Committee recommended a “Points to consider” document be prepared in order to describe the current approaches used in cleaning validation and highlighting the complexities involved in order to establish a common understanding. A revision of the relevant appendix would then be considered by the Expert Committee thereafter.
世界衛生組織“GMP補充指南：驗證”于2006年發布，并有七個附錄作為支持。正文及其附錄在2006年至2019年之間進行了修訂。關于清潔驗證的附錄3當時尚未更新。但是，在2019年7月在瑞士日內瓦舉行的非正式磋商中討論了其修訂版。討論的結果已提交給2019年10月的WHO 的ECSPP會議。ECSPP認識到就清潔驗證方法而言，協調在監管預期中的重要性。專家委員會建議編寫一份“考慮要點”文件，以描述清潔驗證中使用的當前方法，并強調其中涉及的復雜性，以建立共識。此后，專家委員會將考慮對相關附錄進行修訂。
Many manufacturers produce products in multi-product facilities where there is a risk of contamination and cross-contamination. Some of the main principles of good manufacturing practices (GMP) include the prevention of mix-ups and the prevention of contamination and cross-contamination. It is therefore important that manufacturers identify all risks for contamination and cross-contamination and identify and implement the appropriate controls to mitigate these risks.
許多生產商會在多產品設施中生產多個產品，存在污染和交叉污染的風險。GMP的一些主要原則包括防止混淆，防止污染和交叉污染。因此，重要的是，生產商必須確定所有污染和交叉污染的風險，并確定并實施適當的控制措施，以減輕這些風險。
These controls may include, for example, technical and organizational measures, dedicated facilities, closed systems, cleaning and cleaning validation.
這些控制措施可能包括，例如，技術和管理措施、專用設施、封閉系統，清潔和清潔驗證。
It is strongly recommended that manufacturers review their existing technical and organizational measures, suitability of cleaning procedures and appropriateness of existing cleaning validation studies.
強烈建議生產商審查其現有的技術和管理措施、清潔程序的適用性，以及現有清潔驗證研究的適當性。
Technical controls, such as the design of the premises and utilities (e.g. heating, ventilation and air-conditioning {heating, ventilation and air conditioning (HVAC)}, water and gas), should be appropriate for the range of products manufactured (e.g. pharmacological classification, activities and properties). Effective controls should be implemented to prevent cross-contamination when air is re-circulated through the HVAC system.
技術控制，例如場所和公用系統的設計（例如，HVAC、水和氣），應適合所生產產品的范圍（例如，藥理學分類、活動和屬性）。當空氣通過HVAC系統再循環時，應執行有效的控制措施，以防止交叉污染。
Organizational controls, such as dedicated areas and utilities, dedicated equipment, procedural control, and campaign production, should be considered where appropriate as a means to reduce the risk of cross-contamination.
應酌情考慮管理控制措施，例如專用的區域和公用系統、專用設備、程序控制和周期生產，以減少交叉污染的風險。
It should be noted that the above examples are described in more detail in other documents. The focus of this document is on Health-Based Exposure Limits (HBELs) setting in cleaning validation
應當注意，上述示例在其他文檔中有更詳細的描述。本文檔的重點是清潔驗證中基于健康的暴露限（HBEL）設置。
2.Scope范圍
This document provides points to consider for a risk and science-based approach when considering HBELs, based on pharmacological and toxicological data, in cleaning validation.
本文檔提供了：在清潔驗證中，基于藥理和毒理學數據的HBEL時應考慮的要點，即基于風險和科學的方法。
This document further provides points to consider when reviewing the current status and approaches to cleaning validation in multiproduct facilities.
本文檔還提供了：就審查多產品設施中和清潔驗證的當前狀態和方法時，需要考慮的要點。
The principles described in this document may be applied in facilities where active pharmaceutical ingredients (APIs), investigational medical products (IMP), vaccines, human and veterinary medical products are manufactured. The principles may also be considered, where appropriate, in facilities where medical devices are manufactured.
本文檔中描述的原理可能適用于：生產活性藥物成分（API）、研究醫療產品（IMP），疫苗、人和獸用醫療產品的設施。在適當的情況下，也可以在生產醫療器械的設施中，考慮這些原則。
This document should be read in conjunction with the main GMP text and supplementary texts on validation.
該文檔應與GMP主要文本和驗證補充性文本一起閱讀。
3.Glossary 術語
adjustment factor (safety factors). A series of modifying or safety factors are applied to take into account the fact that data from toxicological studies of differing types and durations in differing species have been used.
調整系數（安全系數）：對于來自不同物種的、不同類型和持續時間的毒理學研究數據，應用了一系列修正或安全因子。
cleanability. The ability of a cleaning procedure to effectively remove material, cleaning agent residue and microbial contamination
清潔性：清潔程序能夠有效去除物料、清潔劑殘留和微生物污染的能力。
cleaning validation. Documented evidence to establish that cleaning procedures are removing residues to predetermined levels of acceptability, taking into consideration factors such as batch size, dosing, toxicology and equipment size.
清潔驗證：證明清潔程序可將殘留清除至預定可接受水平的書面證據，同時考慮到諸如批量、劑量、毒理學和設備規格等因素。
contamination. The undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter, into or on to a starting material or an intermediate or pharmaceutical product during handling, production, sampling, packaging, repackaging, storage or transport.
污染：在處理、生產、取樣、包裝、分包裝、存儲或運輸工藝中，化學或微生物雜質或異物非希望地引入到起始物料、中間體或藥品之中或之上。
cross-contamination. Contamination of a starting material, intermediate product or finished product with another starting material or product during production.
交叉污染：在生產工藝中，起始原料、中間體或成品與另一種起始原料或產品的相互污染。
Health Based Exposure Limits (HBELs)
See definition of Permitted Daily Exposure (PDE)
基于健康的暴露限（HBEL）：參閱允許的每日暴露量（PDE）的定義
margin of safety. The margin of safety is the difference between the cleaning acceptance limit based on HBEL and the process residue data.
安全邊際：基于HBEL的清潔可接受極限與工藝殘留數據之間的差異。
maximum safe carryover (MSC). The maximum amount of carryover of a residual process residue (API, cleaning agent, degradant, and so forth) into the next product manufactured without presenting an appreciable health risk to patients..
最大安全殘留（MSC）：殘留物（API、清潔劑、降解劑等）的最大殘留量，其進入所生產的下一個產品，而不會給患者帶來明顯的健康風險。
maximum safe surface residue (MSSR). The MSSR is the maximum amount of process residue that can remain on equipment surfaces and still be safe to patients. The MSSR is mathematically calculated dividing the Maximum Safe Carryover (MSC) by the total area of contact (MSC/Total).
最大安全表面殘留（MSSR）：MSSR是最大工藝殘留量，其可以保留在設備表面上、且對患者仍是安全的。MSSR是通過數學計算得出的，將最大安全殘留（MSC）除以接觸的總面積（MSC / Total）。
permitted daily exposure (PDE). PDE represents a substance-specific dose that is unlikely to cause an adverse effect if an individual is exposed at or below this dose every day for a lifetime.
允許的每日暴露量（PDE）:PDE代表一種特定于物質的劑量。個體一生中，每天以該劑量或低于該劑量的劑量接觸，不太可能造成不利影響。
point of departure. The dose at which a significant adverse effect is first observed, or the lowest- observed-adverse-effect level (LOAEL).
出發點：在該劑量下，首次觀察到明顯不良反應，或可觀察到的最低不良反應水平（LOAEL）。
verification. The application of procedures to provide evidence through chemical analysis (e.g. after a batch or campaign) to show that the residues of the previous product and cleaning agents, where applicable, have been reduced below the scientifically set maximum allowable or maximum safe carryover level.
確認：對程序的應用，通過化學分析提供證據（例如在批或周期生產后），以表明先前產品和清潔劑的殘留（如適用）已減少至最大允許或最大安全殘留水平以下，這些限度是基于科學而設定的。
4. Historical approach傳統方法
For details on the historical approaches in cleaning validation, see the WHO Technical Report Series, No. 1019, Annexure 3, Appendix 3, 2019.
有關清潔驗證的傳統方法的詳細信息，請參閱WHO技術報告系列，第1019號，附件3,2019年附錄3。
The acceptance criteria for cleaning validation recommended in historical GMP texts did not account for HBELs.
傳統上，在GMP文本中建議的清潔驗證可接受標準中，未考慮HBEL。
A limit based on HBELs should still be established. Historically established limits may be used as alert limits when these are more stringent than HBELs.
應建立基于HBEL的限度。當傳統限度比HBEL更為嚴格時，可以將其用作警戒線。
Where the historical approach cannot be satisfactorily justified, and in view of the risks of contamination and cross-contamination, the new approaches, as described below, should be prioritized and implemented.
如果不能令人滿意地證明傳統方法是正確的，考慮到污染和交叉污染的風險，則應優先考慮和實施如下所述的新方法。
5.New approaches 新方法
Historical cleaning validation approaches often merely showed that using a defined cleaning procedure achieved an objective of meeting historical limits. In many instances, no development work or cleanability studies were done nor was consideration given to toxicological data for establishing limits for cleaning residues.
傳統上，清潔驗證方法通常僅表明使用定義的清潔程序，可以達到滿足傳統限度的目的。在許多情況下，沒有進行開發工作或清潔能力研究，也沒有考慮毒理學數據，來確定清潔殘留物的極限。
Manufacturers should ensure that their cleaning procedures are appropriately developed and that their cleaning validation provides scientific evidence that residues of identified products that can be manufactured in shared facilities are removed to safe levels, providing a high margin of safety to patients. Control measures should be implemented to mitigate the risks of contamination and cross- contamination.
生產商應確保正確制定其清潔程序，并進行清潔驗證，以提供科學證據，針對在共享設施中生產的特定產品，證明其殘留被清除到安全水平，為患者提供了很高的安全系數。應采取控制措施，以減輕污染和交叉污染的風險。
This approach should include at least the following points (which are further described in the text below):
該方法至少應包括以下幾點（下文將進一步描述）：
• risk assessment to identify hazards, analyse risks, and to identify risk controls;
•風險評估，以識別危害、分析風險，并確定風險控制措施；
• cleaning procedure development studies including cleanability studies, where applicable (e.g. new products or cleaning procedures);
•清潔程序開發研究，包括清潔能力研究（如適用）（例如新產品或清潔程序）；
• determination of technical and organizational controls;
確定技術和管理控制；
• HBELs setting;
HBEL設置；
• selection of appropriate analytical procedures; and
選擇適當的分析程序；
• cleaning process control strategy.
清潔工藝控制策略。
Manufacturers should describe and implement their policy and approaches, including the points mentioned above, in a document such as a master plan.
在諸如主計劃之類的文件中，生產商應描述并實施其政策和方法，包括上述要點。
Genotoxic and carcinogenic substances, degradants and other contaminants should be identified and their risks evaluated. Appropriate action should be taken where required .
應當確定遺傳毒性和致癌物質、降解物和其他污染物，并評估其風險。需要時，應采取適當的措施。
5.1 Documentation 文件化
Risk management principles, as described by WHO and other guidelines on quality risk management (10), should be applied to assist in identifying and assessing risks. The appropriate controls should be identified and implemented to mitigate contamination and cross-contamination.
應采用世衛組織和其他質量風險管理指南所述的風險管理原則，以幫助識別和評估風險。應確定并實施適當的控制措施，以減輕污染和交叉污染。
The policy and approaches in cleaning and cleaning validation require that good scientific practices should be applied (including the use of appropriate equipment and methods). This should be described in a cleaning validation master plan. Development studies, cleaning and cleaning validation should be performed in accordance with predefined, authorized standard operating procedures, protocols and reports, as appropriate. Records should be kept.
清潔和清潔驗證的政策和方法要求應采用良好的科學實踐，包括使用適當的設備和方法。這應該在清潔驗證主計劃中進行描述。應根據預定義和批準的標準操作程序、草案和報告，進行開發研究、清潔和清潔驗證。記錄應保存。
The design and layout of documents, and the reporting of data and information, should be in compliance with the principles of good documentation practices and should also meet data integrity requirements .
文檔的設計規劃、以及數據和信息的報告，應符合良好文檔規范的原則，并且還應滿足數據完整性要求。
5.2 Equipment 設備
Cleaning validation should cover direct product contact surfaces. Non-contact surfaces should be included in cleaning validation where these have been identified as areas of risk.
清潔驗證應覆蓋產品的直接接觸表面。如果非接觸表面已被確定為風險區域，則應將其包括在清潔驗證中。
Authorized drawings of equipment should be current, accurate and available. Equipment surface area calculations should be documented and justified. The source data for these calculations should be available. The calculated values should be used in the calculations in cleaning validation.
設備的已批準圖紙應是最新、準確且可用的。對于設備表面積的計算，應形成文件并證明其合理性。這些計算的源數據應該可用。計算值應用于清潔驗證的計算中。
All equipment and components, including those that are difficult to clean (for example, sieves, screens, filters and bags (such as centrifuge bags) should be considered in cleaning validation and calculations. Where the need is identified, dedicated equipment and or components should be used.
所有設備和組件，包括那些難以清潔的設備和組件（例如，篩子、篩網、過濾器和袋子（例如離心袋）都應在清潔驗證和計算中予以考慮。需要時，應使用專用設備和/或組件。
5.3 Cleaning agents 清潔劑
Cleaning agents (including solvents and detergents used in cleaning processes) should be selected with care. They should be appropriate for their intended use. The selection of the relevant cleaning agent should be scientifically justified.
應當謹慎選擇清潔劑（包括清潔工藝中使用的溶劑和清潔劑）。它們應適合其預期用途。有關清潔劑的選擇應有科學依據。
There should be proof of effectiveness and appropriateness of the selected cleaning agent.
應當有所選清潔劑的有效性和適當性的證明。
Other points to consider include the concentration in which these are used, their composition and removal of their residues to an acceptable level.
其他要考慮的因素包括這些物質的使用濃度，其組成以及將殘留物清除至可接受水平。
When cleaning agents are used in cleaning processes, these should be included in cleaning process development studies and cleaning validation.
在清潔工藝中使用清潔劑時，應將其納入清潔工藝開發研究和清潔驗證中。
5.4 Sampling 取樣
Historically, cleaning validation included different methods being applied to determine whether or not there was any residue remaining on surface areas after cleaning. The focus was mainly on product contact surface areas.
從傳統上看，清潔驗證包括：采用不同的方法來確定清潔后表面上是否殘留任何殘留物。重點主要放在產品接觸表面積上。
A combination of at least two or three methods should normally be used. These include, for example, swab samples, rinse samples and visual inspection. Visual inspection should always be performed. Swab sampling is the preferred other method to be used. Rinse samples should be taken for areas which are inaccessible for swab sampling.
通常應至少結合使用兩種或三種方法。這些包括例如棉簽樣品、沖洗樣品和目檢。目檢應始終進行。相當于其他使用方法，棉簽取樣是首選的。應在無法進行棉簽取樣的區域，進行沖洗樣品的取樣。
Appropriate sampling procedures, swab material and sampling techniques should be selected and used to collect swab and rinse samples. The detail should be clearly described in procedures and protocols. The number of swabs, location of swabbing, swab area, rinse sample volume and the manner in which the samples are collected should be scientifically justified.
應選擇適當的取樣程序，棉簽材料和取樣技術，并將其用于收集棉簽和沖洗樣品。應在程序和草案中清楚地描述細節。對于棉簽的數量、棉簽的位置、棉簽的面積、沖洗樣品的量以及收集樣品的方式，應在科學上合理。
Swab and rinse sample methods should be validated. Recovery studies for swab and rinse sampling should be performed.
棉簽和沖洗樣品方法應經過驗證。應進行棉簽和沖洗樣品的回收率研究。
Where microbiological sampling is carried out, the microbiological method should also be validated.
在進行微生物取樣的地方，微生物方法也應得到驗證。
The manner in which collected samples are stored (if required) and prepared for analysis should be appropriate, described in detail and included in the cleaning validation.
已收集樣品的存儲方式（如果需要）和分析準備方式應該適當，詳細描述并包括在清潔驗證中。
5.5 Cleanability studies 清潔能力研究
Before a new cleaning procedure is validated and adopted for routine use, a cleanability study should be performed in order to determine the appropriateness of the procedure for removing for example product residue, cleaning agents and microorganisms. For cleaning procedures that have already been validated where the data show that the cleaning procedure is effective and consistent, or where risk assessment indicated that cleanability studies may not be required, this may be considered acceptable.
在確認新的清潔程序并將其用于日常使用之前，應進行清潔能力研究，以確定清除產品殘留物、清潔劑和微生物等程序的適當性。對于已驗證的清潔程序，如果數據表明清潔程序有效且一致，或者風險評估表明可能不需要清潔能力研究，則可以認為這是可以接受的。
5.6 Risk management 風險管理
Risk management should be implemented with a focus on the identification, evaluation, assessment and control of risks to mitigate the risk of contamination and cross-contamination.
實施風險管理時應側重于風險的識別、評價、評估和控制，以減輕污染和交叉污染的風險。
These controls should include technical and organization controls in order to deliver a validated cleaning process.
這些控制措施應包括技術和管理控制措施，以提供經過驗證的清潔工藝。
5.7 Guidance for Health-Based Exposure Limits (HBELs) setting HBEL的設置HBEL的設置
HBEL的設置
Manufacturers should establish, document and implement a company-wide policy on HBELs setting for shared facilities.
生產商應建立、記錄并實施公司范圍內有關共享設施HBEL設置的政策。
The appropriateness of the production and control of various APIs or various products in shared facilities should be evaluated on the basis of scientific data and information.
應當在科學數據和信息的基礎上，評估共享設施中各種API或產品生產和控制措施的適當性。
This is applicable to legacy products as well as when new products are planned to be introduced into a facility, for example, through a change control procedure.
這適用于老產品、以及計劃將新產品引入設施的情況（如通過變更控制程序）。
Procedures should be established and implemented describing how the scientific and toxicological data and information are obtained and considered and how HBELs are established.
應建立并執行程序，描述如何獲取和考慮科學和毒理學數據與信息，以及如何建立HBEL。
Data and information should be gathered by a person with appropriate qualifications and experience in the field of toxicology and/or pharmacology. The data and information should be presented in a report. The data and information presented should be free from bias.
數據和信息應由在毒理學和/或藥理學領域具有適當資質和經驗的人員收集。數據和信息應在報告中提供。所提供的數據和信息應沒有偏見。
Where this service is outsourced by the manufacturer, appropriate measures should be put in place in order to ensure that the data obtained are reliable. GMP requirements, such as vendor qualification, agreements and other related aspects, should be considered.
如果該服務由生產商外包，則應采取適當措施以確保獲得的數據是可靠的。應該考慮GMP要求，例如供應商資質、協議和其他相關方面。
Note: The HBEL value for the same substance sometimes differs when it is determined by different individuals. The reason for the difference between the values should be clarified and investigated.
注意：有時，同一物質的HBEL值由不同的人確定時會有所不同。值之間的差異的原因應予以澄清和調查。
The report for each substance should include scientific detail and information, as applicable, such as:
每種物質的報告應包括科學細節和信息（如適用），例如：
• substance identification
物質識別
• chemical structure
化學結構
• clinical indication
臨床適應癥
• mode of action
作用方式
• route of administration (Note: Where more than one route of administration is available, it may be necessary to calculate separate HBELs)
給藥途徑（注意：如果有多個給藥途徑，則可能有必要計算單獨的HBEL）
• preclinical/nonclinical data, for example, of acute and repetitive dose studies
o genotoxicity data
o reproductive toxicity data
o carcinogenicity data
o data relating to highly sensitizing potential
臨床前/非臨床數據，例如急性和重復劑量研究
o遺傳毒性數據
o生殖毒性數據
o致癌性數據
o與高敏感潛力有關的數據
• clinical data
臨床資料
• pharmacodynamics and pharmacokinetics
藥效學和藥代動力學
• identification of the critical effect(s)
確定關鍵影響
• point of departure for the HBEL calculation(s)
HBEL計算的出發點
• adjustment factors
調整因子
• justification of the selected lead rationale (if calculations with different points of departure were made).
證明所選擇的主要論證依據（如果進行了不同出發點的計算）。
The report should be reviewed for its completeness and appropriateness by the manufacturer’s designated internal personnel or by an appointed external persons. The person should have in-depth knowledge, appropriate qualifications and experience in the field of toxicology. A summary document may be prepared for each relevant substance and should contain information on the PDE value, and toxicity.
生產商指定的內部人員或指定的外部人員應檢查報告的完整性和適當性。該人員應在毒理學領域具有深入的知識、適當的資質和經驗。可能會為每種相關物質準備一份摘要文件，其中應包含有關PDE值和毒性的信息。
The scientific report and calculated PDE value should be used when defining the cleaning validation control measures.
定義清潔驗證控制措施時，應使用科學報告和計算出的PDE值。
Note: If no NOAEL is obtained, the lowest-observed-adverse-effect level (LOAEL) may be used. Alternative approaches to the NOAEL, such as the benchmark dose, may also be used. The use of other approaches to determine HBELs could be considered acceptable if adequately and scientifically justified.
注意：如果未獲得NOAEL，則可以使用觀察到的最低不良反應水平（LOAEL）。也可以使用NOAEL的替代方法，例如基準劑量。如果有充分和科學的理由，使用其他方法確定HBEL是可以接受的。
Manufacturers should periodically consider new data and information on HBELs. Appropriate action, such as the updating of PDE reports, should be taken where required.
生產商應定期考慮有關HBEL的新數據和信息。在需要時，應采取適當的措施，例如更新PDE報告。
5.8 Acceptance criteria 可接受標準
The limits established in cleaning validation should be justified.
清潔驗證中建立的限度應該是合理的。
Some manufacturers have specified acceptance criteria based on carryover limits or limits reflected in some GMP guidelines. These limits may no longer be acceptable as HBELs and related toxicity data were not included in the determination of such acceptance criteria.
一些生產商根據殘留限度或某些GMP指南中反映的限度，規定了可接受標準。這些限度可能不再可接受，因為確定此類可接受標準時，未包含HBEL和相關毒性數據。
Criteria such as Maximum Safe Carryover (MSC)/Maximum Allowable Carryover (MACO) and Maximum Safe Surface Residue (MSSR) values should be calculated. Calculations and data should be available and comply with data integrity principles. The calculation should include values of PDE, maximum daily dose, batch size and total shared equipment surface areas.
應計算諸如最大安全殘留（MSC）/最大允許殘留（MACO）和最大安全表面殘留（MSSR）值之類的標準。相關計算和數據應可查，并符合數據完整性原則。計算應包括PDE值、最大日劑量、批量和共用設備總表面積。
MSSR should be calculated and presented, for example, in table form listing preceding and following product values. The cleanability value obtained should be considered in determining the acceptability of the procedure(s) and whether other controls including separate, dedicated facilities are required. (See Annex 1 as an example.)
MSSR應該以表格形式進行計算和顯示，例如列出前后產品的值。在確定程序的可接受性、以及是否需要其他控制措施（包括單獨的專用設施）時，應考慮獲得的清潔能力值。（請參見附件1。）
The margin of safety (the distance between the analytical data and the HBEL base limit) should be identified.
應確定安全邊際（分析數據與HBEL限度之間的距離）。
5.9 Analytical procedures 分析程序
Samples obtained in cleaning validation should be analyzed by using procedures that are validated for their intended use. The procedures should be developed in accordance with the principles of Analytical Quality by Design.
在清潔驗證中獲得的樣品應使用經驗證可用于其預期用途的程序進行分析。應根據“質量源于分析設計”的原則制定程序。
Specific methods, such as High-performance Liquid Chromatography (HPLC), should be used where appropriate. Non-specific methods including UV spectrophotometry should only be used where specific methods cannot be employed and their use can be justified, for example, based on the outcome of risk assessment.
適當時應使用特定方法，例如高效液相色譜（HPLC）。僅在無法采用特定方法且可以合理使用它們的情況下，才應使用包括UV分光光度法在內的非特定方法，例如，基于風險評估的結果。
Testing for total organic carbon (TOC) may be used where indicated and where justified.
有說明和有論證時，可使用總有機碳（TOC）檢驗。
Where analytical procedures were developed and validated off-site, the scope and extent of validation when these are transferred to the site, should be defined and justified. This includes procedures that are transferred from research and development laboratories to site laboratories. Analytical procedures should be able to quantify or detect residue levels at the maximum safe surface residue level. (For analytical procedure validation, see reference 6.)
在制定分析程序并在場外進行驗證時，應定義并證明將其轉移到現場時的驗證范圍和程度。這包括從研發實驗室轉移到現場實驗室的程序。分析程序應能夠在最大安全表面殘留水平下量化或檢測殘留水平。（有關分析程序的驗證，請參見參考文獻6。）
Manufacturers should ensure that the procedures remain in a validated state.
生產商應確保程序保持已驗證的狀態。
5.10 Data integrity 數據完整性
Data, information and results pertaining to, for example, HBELs, PDE reports, results obtained from cleaning validation and calculations, should be scientific and should be in compliance with the principles as contained in data integrity guidelines.
有關數據、信息和結果，例如HBEL、PDE報告、從清潔驗證和計算中獲得的結果，應是科學的，并且應符合數據完整性指南中包含的原則。
5.11 Cleaning validation and cleaning verification 清潔驗證和清潔確認
Cleaning validation 清潔驗證
The cleaning procedure should be validated.
清潔程序應已驗證。
Cleaning validation should include proof of, for example, the applicability of the procedure to clean equipment that:
清潔驗證應包括證明該程序是否適用于清潔設備的證明：
• had been kept in an unclean state for a period of time (dirty equipment hold time);
保持不清潔狀態一段時間（設備清潔前放置時間）；
• are used after a product is planned (e.g. change from one product to another product);
在計劃產品之后使用（例如，從一種產品更改為另一種產品）；
• are used in a campaign, where multiple batches of a product are produced one after the other; and/or
用于一個周期生產中，一個接一個地生產多批產品；和/或
• are stored in a clean state for defined periods of time (clean equipment hold time).
以清潔狀態存儲規定的時間（設備清潔后放置時間）。
HBEL should be considered when establishing carryover limits in cleaning validation.
在清潔驗證中建立殘留限度時，應考慮使用HBEL。
Cleaning verification 清潔確認
The company should describe the policy and approach to cleaning verification. Cleaning verification is where the effectiveness of the validated cleaning procedure is routinely verified. The approach may include swab or rinse samples. The results obtained from testing on a routine basis should be reviewed and subjected to statistical trending.
公司應說明清潔確認的政策和方法。清潔確認，是對已驗證清潔程序的有效性進行例行的確認。該方法可能包括棉簽或沖洗樣品。常規檢驗獲得的結果應進行審查，并進行統計趨勢分析。
5.12 Visually clean 目檢干凈
Visually clean is an important criterion in cleaning validation. It should be one of the acceptance criteria used on a routine basis. Personnel responsible for visual inspection should be appropriately trained. Training records should be kept.
目檢干凈是清潔驗證的重要標準。它應該是常規使用的驗收標準之一。負責目檢的人員應接受適當的培訓。應保留培訓記錄。
Where visual inspection is used as a quantitative method, then Visible Residue Limits (VRLs) should be determined. The process to determine the limit should be appropriately described in procedures and protocols covering, for example, concentrations, method of spiking, surface areas, material of construction and other conditions such as light (LUX level) and angles.
如果使用目檢作為定量方法，則應確定可見殘留限量（VRL）。確定限度的過程應在程序和草案中適當描述，包括濃度、加標方法、表面積、結構材料和其他條件，例如，光（LUX水平）和角度。
5.13 Cleaning process capability 清潔工藝能力
The cleaning procedure should remain in a validated state. It is recommended that cleaning verification results and calculated process capability data be used to support this. For example, the results from cleaning verification sample analysis could be statistically trended. The capability of the cleaning process is then calculated by using an appropriate statistical process.
清潔程序應保持在已驗證的狀態。建議使用清潔驗證結果和計算出的過程能力數據，來支持這一點。例如，清潔驗證樣品分析的結果可以統計趨勢。然后通過使用適當的統計過程，來計算清潔工藝能力。
Data should be presented, for example, in graph form, and the capability of the process in relation to control limits and the margin of safety should be presented and discussed as part of continuous improvement over the life cycle.
數據應該以圖表的形式呈現，并且過程控制能力和安全邊際能力應作為生命周期內持續改進的一部分，進行呈現和討論。
5.14 Personnel 人員
Personnel should be trained on the procedures and principles of cleaning and cleaning validation, including contamination and cross-contamination control, HBELs setting, equipment disassembly, visual inspection, sampling, testing and statistical calculations, as appropriate and based on their responsibilities.
應根據人員的職責，對人員進行清潔和清潔驗證的程序和原則方面的培訓，包括污染和交叉污染控制、HBEL設置、設備拆卸、目檢、取樣、檢驗和統計計算。
5.15 Quality metrics and performance indicators 質量指標和績效指標
Aspects of cleaning validation and cleaning verification should be considered in quality metrics, with performance indicators identified and monitored.
應在質量指標中，考慮清潔驗證和清潔確認的各個方面，并確定和監控性能指標。
5.16 Life cycle 生命周期
Cleaning procedures, cleaning validation and cleaning verification should be included in the life cycle approach described by the company.
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