Points to consider when including Health-Based Exposure Limits(HBELs) in cleaning validation

清潔驗證使用基于健康的暴露限（HBEL）的考量

1. Introduction andbackground

介紹和背景

2. Scope

范圍

3. Glossary

術語

4. Historical approach

傳統(tǒng)方法

5. New approaches

新的方法

5.1Documentation

文件

5.2 Equipment

設備

5.3 Cleaningagents

清潔劑

5.4 Sampling

取樣

5.5Cleanability studies

清潔能力研究

5.6 Riskmanagement

風險評估

5.7 Guidancefor Health-BasedExposure Limits (HBELs) setting

基于健康的暴露限設定的指南

5.8Acceptance criteria

接受標準

5.9Analytical procedures

分析方法

5.10 Dataintegrity

數(shù)據(jù)完整性

5.11 Cleaningvalidation andcleaning verification

清潔驗證和清潔確認

5.12 Visuallyclean

目視干凈

5.13 Cleaningprocess capability

清潔工藝能力

5.14Personnel

人員

5.15 Qualitymetrics andperformance indicators

質(zhì)量量度和性能指標

5.16 Lifecycle

生命周期

References

參考文獻

Furtherreading

擴展閱讀

Annex 1

附錄1

1.      Introductionand background

介紹及背景

The World HealthOrganization (WHO) has published the guideline entitled Good manufacturing practicesfor pharmaceutical products: main principles in the WHO Technical ReportSeries, No. 986, Annex 2, 2014 (1).

WHO 于 2014 年 TRS 986 附錄2 發(fā)布了題為“藥品 GMP：主則”的指南。

The WHOSupplementary guidelines on good manufacturing practice: validation werepublished in 2006andwere supported by seven appendices. The main text (2) and its appendixes (3, 4, 6, 7, 8, 9) were revised between 2006and 2019. Appendix 3, relating to cleaning validation(5), was not updated at that time. Its revision, however, was discussed duringan informal consultation held in Geneva, Switzerland, in July 2019. The outcomeof the discussion was presented to the WHO Expert Committee on Specificationsfor Pharmaceutical Products (ECSPP) meeting in October 2019. The ECSPPacknowledged the importance of harmonization in regulatory expectations withregards to cleaning validation approaches. The Expert Committee recommended a“Points to consider” document be prepared in order to describe the currentapproaches used in cleaning validation and highlighting the complexitiesinvolved in order to establish a common understanding. A revision of therelevant appendix would then be considered by the Expert Committee thereafter.

WHO 于 2014 年 TRS 986 附錄 2 發(fā)布了題為“藥品 GMP：主則”的指南。WHO 的“GMP 補充指南：驗證”于 2006 年發(fā)布，有 7 個附錄作為支持文件。該主文件及其附錄于2006到2019年之間進行了修訂。與清潔驗證有關的附錄 3 當時未更新。但在 2019 年 7 月瑞士日內(nèi)瓦的非正式溝通期間對其修訂進行了討論，討論結果于2019 年 10 月提交給了ECSPP 會議。ECSPP 了解清潔驗證方法的監(jiān)管要求保持一致的重要性，因此專家委員會建立起草一份“考量要點”文件，以闡述當前清潔驗證中所用方法，強調(diào)其所涉及的復雜性，以求對此達成共識。鑒于此，專家委員會隨后考慮要對相關附錄進行修訂。

Many manufacturersproduce products in multi-product facilities where there is a risk ofcontamination and cross-contamination. Some of the main principles of goodmanufacturing practices (GMP) include the prevention of mix-ups and theprevention of contamination and cross-contamination. It is therefore importantthat manufacturers identify all risks for contamination and cross-contamination and identify and implement the appropriate controls to mitigate theserisks.

許多生產(chǎn)商會在多產(chǎn)品設施中生產(chǎn)多個產(chǎn)品， 這時就會存在污染和交叉污染的風險。優(yōu)良生產(chǎn)規(guī)范（GMP）的一些重要原則包括有防止混淆和防止污染與交叉污染，因此生產(chǎn)商識別所有污染與交叉污染，識別實施適當控制措施以降低這些風險就非常重要。

These controls mayinclude, for example, technical and organizational measures, dedicatedfacilities, closed systems, cleaning and cleaning validation.

這些控制措施可以包括例如技術和組織措施、使用專用設施、封閉系統(tǒng)、清潔和清潔驗證

It is stronglyrecommended that manufacturers review their existing technical andorganizational measures, suitability of cleaning procedures and appropriatenessof existing cleaning validation studies.

強烈建議制造商審查其現(xiàn)有的技術和組織措施、清潔程序的適用性以及現(xiàn)有清潔驗證試驗的適當性。

Technical controls,such as the design of the premises and utilities (e.g. heating, ventilation and air-conditioning {heating, ventilation and airconditioning (HVAC)}, water and gas), should be appropriatefor the range of products manufactured (e.g.pharmacological classification, activities and properties). Effective controls should be implemented to prevent cross-contaminationwhen air is re-circulated through the HVAC system.

技術控制，如廠房和公用設施的設計（如暖通空調(diào)[HVAC）系統(tǒng)，應適用于所制造的產(chǎn)品范圍（如藥理類別、活性和特性）。當空氣通過 HVAC 系統(tǒng)重新循環(huán)時，應實施有效的控制以防止交叉污染。

Organizational controls, such as dedicated areas and utilities,dedicated equipment, procedural control, and campaign production, should beconsidered where appropriate as a means to reduce the risk ofcross-contamination.

組織控制，如專用區(qū)域和公用設施、專用設備、程序性控制和錯峰生產(chǎn)，應酌情考慮作為減少交叉污染風險的一種手段。

It should be noted that the above examples are described in more detailin other documents. The focus of this document is on Health-Based ExposureLimits (HBELs) setting in cleaning validation

應當指出，上述事例已在其他文件進行了更為詳細的描述。本文的重點是在清潔驗證中基于健康的暴露限（HBEL）的設置

2.      Scope

范圍

Thisdocument provides points to consider for a risk and science-based approach when considering HBELs, based on pharmacological andtoxicological data,in cleaning validation.

本文件提供了在清潔驗證中考慮基于藥理學和毒理學數(shù)據(jù)的 HBEL 時需要考慮的風險和科學方法。

This documentfurther provides points to consider when reviewing the current status andapproaches to cleaning validation in multiproduct facilities.

本文件進一步提供了在審查多產(chǎn)品設施清潔驗證的現(xiàn)行狀態(tài)和方法時要考慮的點。

Theprinciples describedin this document may be applied in facilities where activepharmaceutical ingredients (APIs), investigational medical products (IMP), vaccines, human and veterinary medicalproducts are manufactured. The principles may also be considered, whereappropriate, in facilities where medical devices are manufactured.

本文件所描述的原則適用于活性藥物成分（API）、臨床試驗用藥物產(chǎn)品（IMP）、疫苗、人用和獸用藥品的生產(chǎn)設施。醫(yī)療器械的生產(chǎn)設施，也可酌情考慮這些原則。

This documentshould be read in conjunction with the main GMP text and supplementary texts onvalidation (1-9).

本文件應與GMP主文本和驗證補充指南(1-9)一起閱讀。

3.      Glossary

術語

adjustment factor (safety factors). A series of modifying or safetyfactors are applied to take into account the fact that data from toxicological studiesof differing types and durations in differing species have been used.

調(diào)整系數(shù)（安全系數(shù)）。一系列調(diào)整或安全系數(shù)，用以考慮來自其他物種不同類型和持續(xù)時間的毒理學研究數(shù)據(jù)。

cleanability. The ability of a cleaning procedure to effectively removematerial, cleaning agent residue and microbial contamination

清潔能力。清潔程序有效去除物料、清潔劑殘留物和微生物污染的能力。

cleaningvalidation. Documented evidence to establish that cleaning procedures areremoving residues to predetermined levels of acceptability, taking intoconsideration factors such as batch size, dosing, toxicology and equipmentsize.

清潔驗證：證明清潔方法可將殘留清除至預定的可接受水平的文件化證據(jù)，同時考慮的因素有如批量、給藥劑量、毒性和設備尺寸。

contamination. Theundesired introduction of impurities of a chemical or microbiological nature,or of foreign matter, into or on to a starting material or an intermediate orpharmaceutical product during handling, production, sampling, packaging,repackaging, storage or transport.

污染：起始物料或中間體或藥品在處理、生產(chǎn)、取樣、包裝、重新包裝、存貯或運輸期間引入的不希望存在的化學或微生物雜質(zhì)，或異物。

cross-contamination.Contamination of a starting material, intermediate product or finished productwith another starting material or product during production.

交叉污染：起始物料、中間體或成品與另一起始物料或產(chǎn)品在生產(chǎn)期間相互污染。

Health Based Exposure Limits (HBELs)

基于健康的暴露限（HBEL）

See definition of Permitted Daily Exposure (PDE)

見日允許接觸量（PDE）的定義。

margin of safety.The margin of safety is the difference between the cleaning acceptance limit based on HBEL andthe process residue data.

安全空間。安全空間是基于 HBEL 的清潔接受限值與工藝殘留數(shù)據(jù)之間的差值。

maximum safe carryover(MSC). The maximum amount of carryover of a residual process residue (API, cleaningagent, degradant, and so forth) into the next product manufacturedwithout presenting an appreciable health risk to patients..

最大安全殘留（MSC）。殘留下一個產(chǎn)品但不會給患者帶來明顯的健康風險的（API、清潔劑、降解物等）的工藝殘留的最大量。

maximum safesurface residue (MSSR). The MSSR is the maximum amount of process residue that can remain on equipment surfaces and still besafe to patients. The MSSR is mathematically calculateddividing the Maximum Safe Carryover (MSC) bythe total area of contact (MSC/Total).

最大安全表面殘留（MSSR）。MSSR 是殘留在設備表面但對患者仍是安全的工藝殘留的最大量， MSSR以最大安全殘留（MSC）除以總接觸面積（MSC/Total）算得。

permitted daily exposure (PDE). PDE represents a substance-specific dosethat is unlikely to cause an adverse effect if an individual is exposed at orbelow this dose every day for a lifetime.

日允許接觸量（PDE）。PDE 代表一種物質(zhì)的特定劑量，即如一個人在一生中每天以或低于該劑量接觸該物質(zhì)，不太可能造成不良影響。

point of departure. The dose at which a significant adverse effect isfirst observed, or the lowest-observed-adverse-effect level (LOAEL).

參考點。首次觀察到嚴重不良反應的劑量，或最低可見不良反應水平（LOAEL）。

verification. Theapplication of procedures to provide evidence through chemicalanalysis (e.g. after a batch or campaign) to show that the residues of theprevious product and cleaning agents, where applicable, have been reduced belowthe scientifically set maximum allowable or maximum safe carryover level.

確認。應用程序通過化學分析（例如在批次或運動之后）提供證據(jù)，以表明以前產(chǎn)品和清潔劑的殘留物（如適用）已降低到科學設定的最大允許或最大安全結轉(zhuǎn)水平以下。

4.    Historical approach

舊的方法

For details on the historical approaches incleaning validation, see the WHO Technical Report Series, No. 1019, Annexure 3,Appendix 3, 2019 (5).

有關清潔驗證的傳統(tǒng)方法的詳細信息，請參閱 WHO 技術報告，第 1019 號，附錄 3，附錄 3,2019(5)。

The acceptance criteria for cleaning validationrecommended in historical GMP texts did not account for HBELs.

傳統(tǒng)GMP 正文中建議的清潔驗證的接受標準不包括HBEL。

A limit based on HBELs should still beestablished. Historically established limits may be used as alert limits whenthese are more stringent than HBELs .

應建立基于HBEL 的限度。當使用傳統(tǒng)方法確立的限度比HBEL更嚴時，可用作警戒限。

Where the historical approach cannot besatisfactorily justified, and in view of the risks of contamination andcross-contamination, the new approaches, as described below, should beprioritized and implemented.

如傳統(tǒng)方法不能令人滿意地證明合理，并且鑒于污染和交叉污染的風險，應毫不拖延地實施下文所述的新方法。

5.       New approaches

新的方法

Historical cleaning validation approaches often merely showed that usinga defined cleaning procedure achieved an objective of meeting historicallimits. In many instances, no development work or cleanability studies weredone nor was consideration given to toxicological data for establishing limitsfor cleaning residues.

傳統(tǒng)清潔驗證方法通常只是表明，使用既定的清潔程序?qū)崿F(xiàn)了滿足傳統(tǒng)限度的目標。在許多情況下，沒有進行開發(fā)工作或清潔能力研究，也沒有考慮毒理學數(shù)據(jù)以確定清潔殘留的限度。

Manufacturers should ensure that their cleaningprocedures are appropriately developed and that their cleaning validationprovides scientific evidence that residues of identified products that can bemanufactured in shared facilities are removed to safe levels, providinga high margin of safety to patients. Control measures should be implemented tomitigate the risks of contamination and cross-contamination.

制造商應確保其清潔程序得到適當開發(fā)，并確保其清潔驗證提供科學證據(jù)，證明在共用設施中生產(chǎn)的相關產(chǎn)品的殘留可以被清除到安全水平，為患者提供高度安全空間。應實施控制措施，以減輕污染和交叉污染的風險。

This approach should include at least thefollowing points (which are further described in the text below):

這種方法至少應包括以下幾點（下文將進一步說明）：

risk assessmentto identify hazards, analyse risks, and to identify risk controls;

風險評估，以識別風險、分析風險并制定風險控制措施;

cleaningprocedure development studies including cleanability studies, where applicable(e.g. new products or cleaning procedures);

清潔程序開發(fā)研究，包括清潔能力研究（如適用）（例如新的產(chǎn)品或新的清潔程序）;

determinationof technical and organizational controls;

確定技術性和組織性控制措施;

HBELs setting;

HBEL設置

selection ofappropriate analytical procedures; and

選擇適當?shù)姆治龇椒ǎ灰约?/p>

cleaningprocess control strategy.

清潔工藝控制策略

Manufacturers should describe and implement theirpolicy and approaches, including the points mentioned above, in a document suchas a master plan.

制造商應在總計劃等文件中描述和實施其政策和方法，包括上述要點。

Genotoxic and carcinogenic substances,degradants and other contaminants should be identified and their risksevaluated. Appropriate action should be taken where required (11).

應識別基因毒性和致癌物質(zhì)、降解物和其他污染物，并評估其風險。必要時應采取適當措施（11）。

5.1       Documentation

文件

Risk management principles, as described by WHOand other guidelines on quality risk management (10), should be applied toassist in identifying and assessing risks. The appropriate controls should beidentified and implemented to mitigate contamination and cross-contamination.

應使用風險管理原則，如WHO和其他質(zhì)量風險管理指南（10）所述，以幫助確定和評估風險。應確定并實施適當?shù)目刂拼胧?，以減輕污染和交叉污染。

The policy and approaches in cleaning andcleaning validation require that good scientific practices should be applied(including the use of appropriate equipment and methods). This should bedescribed in a cleaning validation master plan. Development studies, cleaningand cleaning validation should be performed in accordance with predefined,authorized standard operating procedures, protocols and reports, asappropriate. Records should be kept.

清潔和清潔驗證的政策和方法要求使用良好的科學實踐（包括使用適當?shù)脑O備和方法）。應在清潔驗證總計劃中對此進行說明。開發(fā)研究、清潔和清潔驗證應按照既定的、經(jīng)批準的標準操作程序、方案和報告進行。記錄應保存。

The design and layout of documents, and thereporting of data and information, should be in compliance with the principlesof good documentation practices (12) and should also meet data integrityrequirements (12).

文件的設計和布局以及數(shù)據(jù)和信息的報告應符合良好的文件規(guī)范原則（12），還應符合數(shù)據(jù)完整性要求（12）。

5.2       Equipment

設備

Cleaning validation should cover direct productcontact surfaces. Non-contact surfaces should be included in cleaning validationwhere these have been identified as areas of risk.

清潔驗證應覆蓋產(chǎn)品直接接觸的表面。非接觸表面如被確定為風險區(qū)域也應包含在清潔驗證中。

Authorized drawings of equipment should becurrent, accurate and available. Equipment surface area calculations should bedocumented and justified. The source data for these calculations should beavailable. The calculated values should be used in the calculations in cleaningvalidation.

已批準的設備圖紙應是最新的、準確的和可用的。應記錄并論證設備表面積的計算。應有這些計算的源數(shù)據(jù)。算出的值應在清潔驗證的計算中使用。

All equipment and components, including thosethat are difficult to clean (for example, sieves, screens, filters and bags(such as centrifuge bags) should be considered in cleaning validation andcalculations. Where the need is identified, dedicated equipment and orcomponents should be used.

在清潔驗證和計算時，應考慮所有設備和部件，包括難以清潔的設備（例如篩子、篩網(wǎng)、過濾器、過濾器和袋子（如離心袋）。必要時，應使用專用設備和/或部件。

5.3       Cleaning agents

清潔劑

Cleaning agents (including solvents anddetergents used in cleaning processes) should be selected with care. Theyshould be appropriate for their intended use. The selection of the relevantcleaning agent should be scientifically justified.

清潔劑（包括清洗過程中使用的溶劑和洗滌劑）應謹慎選擇。它們應適合其預期用途。有關清潔劑的選擇應具有科學依據(jù)。

There should beproof of effectiveness and appropriateness of the selected cleaning agent.

應證明所選清潔劑的有效性和適當性。

Other points to consider include theconcentration in which these are used, their composition and removal of theirresidues to an acceptable level.

需要考慮的其他事項包括使用這些物質(zhì)的濃度、組成及其殘留的清除。

When cleaning agents are used in cleaningprocesses, these should be included in cleaning process development studies andcleaning validation.

當清潔過程使用清潔劑時，應包含在清潔工藝開發(fā)研究和清潔驗證中。

5.4       Sampling

取樣

Historically, cleaning validation includeddifferent methods being applied to determine whether or not there was anyresidue remaining on surface areas after cleaning. The focus was mainly onproduct contact surface areas.

傳統(tǒng)上，清潔驗證包括采用不同的方法來確定清潔后表面是否有殘留。重點主要在產(chǎn)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 preferredother method to be used. Rinse samples should be taken for areas which areinaccessible for swab sampling.

通常應使用至少兩種或三種方法的組合。包括，例如，擦拭樣品，沖洗樣品和目視檢查。應始終執(zhí)行目視檢查。其他方法首選擦拭取樣。對于無法進行擦拭取樣的區(qū)域，應采集沖洗樣品。

Appropriate sampling procedures, swab materialand sampling techniques should be selected and used to collect swab and rinsesamples. The detail should be clearly described in procedures and protocols.The number of swabs, location of swabbing, swab area, rinse sample volume andthe manner in which the samples are collected should be scientificallyjustified.

應選擇適當?shù)娜映绦?、棉簽材料和取樣技術，并用于收集擦拭和沖洗樣品。應在程序和方案中明確詳細描述。擦拭的數(shù)量、位置、面積、沖洗取樣的體積以及采集樣品的方式應科學論證。

Swab and rinse sample methods should be validated.Recovery studies for swab and rinse sampling should be performed.

擦拭和沖洗取樣的方法應驗證。應執(zhí)行擦拭和沖洗取樣的回收率研究。

Wheremicrobiological sampling is carried out, the microbiological method should alsobe validated.

如進行微生物取樣，應驗證微生物方法。

The manner in which collected samples are stored (if required) andprepared for analysis should be appropriate, described in detail and includedin the cleaning validation.

樣品的存儲（如需要）和分析前的處理方式應適當，詳細描述并包含在清潔驗證中。

5.5       Cleanability studies

清潔能力研究

Before a new cleaning procedure is validated andadopted for routine use, a cleanability study should be performed in order todetermine the appropriateness of the procedure for removing for example productresidue, cleaning agents and microorganisms. For cleaning procedures that havealready been validated where the data show that the cleaning procedure iseffective and consistent, or where risk assessment indicated that cleanabilitystudies may not be required, this may be considered acceptable.

在新的清潔程序經(jīng)驗證和并供日常使用之前，應進行清潔能力研究，以確定去除產(chǎn)品殘留物、清潔劑和微生物等程序是否適當。對于已驗證的清潔程序，如果數(shù)據(jù)表明清潔程序有效且一致，或者風險評估表明可能不需要進行清潔能力研究，可能被認為可以接受。

5.6       Risk management

風險管理

Risk management should be implemented with afocus on the identification, evaluation, assessment and control of risks tomitigate the risk of contamination and cross-contamination.

風險管理應注重風險的識別、評價、評估和控制，以減少污染和交叉污染的風險。

These controls should include technical andorganization controls in order to deliver a validated cleaning process (10).

這些控制應包括技術性和組織性控制，以便提供有效的清潔工藝（10）。

5.7       Guidance for Health-Based Exposure Limits (HBELs) setting

基于健康的暴露限（HBEL）設置指南

Manufacturers should establish, document andimplement a company-wide policy on HBELs setting for shared facilities.

制造商應建立、記錄和實施關于共用設施的HBEL 設置的公司層面的策略。

The appropriateness of the production and control of various APIs orvarious products in shared facilities should be evaluated on the basis ofscientific data and information.

應根據(jù)科學數(shù)據(jù)和信息評估共用設施中不同 API 或不同產(chǎn)品的生產(chǎn)和控制是否適當。

This is applicable to legacy products as well aswhen new products are planned to be introduced into a facility, for example,through a change control procedure.

這適用于現(xiàn)有產(chǎn)品以及計劃將新產(chǎn)品引入設施時，例如通過變更控制程序。

Procedures should be established and implementeddescribing how the scientific and toxicological data and information areobtained and considered and how HBELs are established.

應建立和實施用以說明如何獲取和考慮科學和毒理學數(shù)據(jù)和信息，以及如何建立HBEL的程序。

Data and information should be gathered by aperson with appropriate qualifications and experience in the field oftoxicology and/or pharmacology. The data and information should be presented ina report. The data and information presented should be free from bias.

數(shù)據(jù)和信息應由在毒理學和/或藥理學領域具有適當資質(zhì)和經(jīng)驗的人收集。數(shù)據(jù)和信息應在一份報告中呈現(xiàn)。提供的數(shù)據(jù)和信息應無偏頗。

Where this service is outsourced by themanufacturer, appropriate measures should be put in place in order to ensurethat the data obtained are reliable. GMP requirements, such as vendorqualification, agreements and other related aspects, should be considered.

如果此服務由制造商外包，應采取適當措施，以確保獲得的數(shù)據(jù)是可靠的。應考慮GMP 要求，如供應商確認、協(xié)議和其他相關方面。

Note: The HBEL value for the same substancesometimes differs when it is determined by different individuals. The reasonfor the difference between the values should be clarified and investigated.

注：同一物質(zhì)的HBEL值有時因不同個體而不同。這種差異的原因予以說明和調(diào)查。

The report foreach substance should include scientific detail and information, as applicable,such as:

每種物質(zhì)的報告應包括科學細節(jié)和信息（如適用），例如：

substanceidentification

物質(zhì)名稱

chemicalstructure

化學結構

clinicalindication

臨床指征

mode of action

作用方式

route ofadministration (Note: Where more than one route of administration is available,it may be necessary to calculate separate HBELs)

給藥途徑（注：當有超過一種給藥途徑時，應分別計算HBEL）

preclinical/nonclinicaldata, for example, of acute and repetitive dose studies

臨床前/非臨床數(shù)據(jù)，例如急性和重復給藥研究

genotoxicitydata

遺傳毒性數(shù)據(jù)

reproductivetoxicity data

生殖毒性數(shù)據(jù)

carcinogenicitydata

致癌性數(shù)據(jù)

data relatingto highly sensitizing potential

與高致敏性相關的數(shù)據(jù)

clinical data

臨床數(shù)據(jù)

pharmacodynamicsand pharmacokinetics

藥理學和藥代動力學

identificationof the critical effect(s)

確定關鍵反應

point of departurefor the HBEL calculation(s)

用于HBEL計算的開始點

adjustmentfactors

調(diào)整因子

justificationof the selected lead rationale (if calculations with different points ofdeparture were made).

所選引線理由的理由（如果進行了不同出發(fā)點的計算）。

The report should be reviewed for its completeness and appropriatenessby the manufacturer’s designated internal personnel or by an appointed externalpersons. The person should have in-depth knowledge, appropriate qualificationsand experience in the field of toxicology. A summary document may be preparedfor each relevant substance and should contain information on the PDE value,and toxicity (13).

該報告應由制造商指定的內(nèi)部人員或外部人員審查其完整性和適當性。該審查人員應具有深入的知識、適當?shù)馁Y質(zhì)和毒理學領域的經(jīng)驗?？蔀槊糠N相關物質(zhì)編寫一份總結文件，并應包括關于PDE值和毒性的信息（13）。

The scientific report and calculated PDE valueshould be used when defining the cleaning validation control measures.

在制定清潔驗證控制措施時，應使用科學的報告和所計算的PDE值。

Note: If no NOAEL is obtained, thelowest-observed-adverse-effect level (LOAEL) may be used. Alternativeapproaches to the NOAEL, such as the benchmark dose, may also be used. The useof other approaches to determine HBELs could be considered acceptable if adequatelyand scientifically justified (13).

注意：如果未獲得NOAEL，則可以使用最低可見不良反應水平（LOAEL）。也可以使用NOAEL的替代方法，如基準劑量。如充分并經(jīng)科學論證，使用其他方法確定HBEL可被視為可以接受（13）。

Manufacturers should periodically consider newdata and information on HBELs. Appropriate action, such as the updating of PDEreports, should be taken where required.

制造商應定期考慮有關HBEL 的新數(shù)據(jù)和信息。必要時，應采取適當行動，例如更新PDE報告。

5.8       Acceptance criteria

接受標準

The limitsestablished in cleaning validation should be justified.

制定的清潔驗證限度應進行論證。

Some manufacturers have specified acceptancecriteria based on carryover limits or limits reflected in some GMP guidelines.These limits may no longer be acceptable as HBELs and related toxicity datawere not included in the determination of such acceptance criteria.

一些制造商根據(jù)某些GMP 指南中反映的殘留限度來制定接受標準。這些限度可能不再被接受，因為此接受標準的制定未包含HBEL和相關毒理數(shù)據(jù)。

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 availableand comply with data integrity principles. The calculation should includevalues of PDE, maximum daily dose, batch size and total shared equipmentsurface areas.

應計算最大安全殘留（MSC）/最大允許殘留（MACO）和最大安全表面殘留（MSSR）值等標準。計算和數(shù)據(jù)應可用，并符合數(shù)據(jù)完整性原則。計算應包括PDE 值、最大日劑量、批量大小和總設備共用表面積。

MSSR should be calculated and presented, for example, in table formlisting preceding and following product values. The cleanability value obtainedshould be considered in determining the acceptability of the procedure(s) andwhether other controls including separate, dedicated facilities are required.(See Annex 1 as an example.)

應計算和呈現(xiàn)MSSR，例如，在表格中列出清潔前后產(chǎn)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（包括獨立的專用設施）時，應考慮所獲得的清潔能力的值。（見附件1）。

The margin of safety (the distance between theanalytical data and the HBEL base limit) should be identified.

應確定安全空間（分析數(shù)據(jù)與HBEL 基準限度之間的距離）。

5.9       Analytical procedures

分析程序

Samples obtained in cleaning validation shouldbe analyzed by using procedures that are validated for their intended use. Theprocedures should be developed in accordance with the principles of AnalyticalQuality by Design.

清潔驗證中獲得的樣品應使用經(jīng)過驗證適合其預期用途程序進行分析。應基于分析質(zhì)量源于設計的原則來開發(fā)程序。

Specific methods, such as High-performance Liquid Chromatography (HPLC),should be used where appropriate. Non-specific methods including UVspectrophotometry should only be used where specific methods cannot be employedand their use can be justified, for example, based on the outcome of riskassessment.

應酌情使用專屬性方法，如高效液相色譜（HPLC）法。非專屬性方法（包括紫外分光度法）應僅在無法使用專屬性方法，并經(jīng)論證的情況下方使用，例如，根據(jù)風險評估結果。

Testing for total organic carbon (TOC) may be used where indicated andwhere justified.

如經(jīng)說明并論證的情況下，可以使用總有機碳（TOC）測試。

Where analytical procedures were developed andvalidated off-site, the scope and extent of validation when these aretransferred to the site, should be defined and justified. This includesprocedures that are transferred from research and development laboratories tosite laboratories. Analytical procedures should be able to quantify or detectresidue levels at the maximum safe surface residue level. (For analyticalprocedure validation, see reference 6.)

如果分析程序不是在工廠開發(fā)和驗證的，則應界定和說明其轉(zhuǎn)移至工廠時需要驗證的范圍和程度。這包括從研發(fā)實驗室轉(zhuǎn)移到工廠實驗室的程序。分析程序應能夠定量或檢測最大安全表面殘留水平的殘留水平。（有關分析方法驗證，見參考文獻6）

Manufacturersshould ensure that the procedures remain in a validated state.

生產(chǎn)商應確保該保持已驗證狀態(tài)。

5.10 Dataintegrity

數(shù)據(jù)完整性

Data, information and results pertaining to, forexample, HBELs, PDE reports, results obtained from cleaning validation and calculations,should be scientific and should be in compliance with the principles ascontained in data integrity guidelines (12).

與HBEL、PDE報告、清潔驗證和計算所得結果相關的數(shù)據(jù)、信息和結果應科學，并應當符合數(shù)據(jù)完整性指南（12）所載的原則。

5.11 Cleaningvalidation and cleaning verification

清潔驗證和清潔確認

Cleaningvalidation

清潔驗證

The cleaningprocedure should be validated (5).

清潔程序應被驗證。

Cleaning validation should include proof of, forexample, the applicability of the procedure to clean equipment that:

清潔驗證應包括證明清潔方法對以下設備狀態(tài)的適用性：

had been keptin an unclean state for a period of time (dirty equipment hold time);

待清潔狀態(tài)的保持時間（臟的保持時間） ;

are used after a product is planned (e.g. change from one product toanother product);

一個產(chǎn)品生產(chǎn)后，例如，從一個產(chǎn)品更換為另一個產(chǎn)品;

are used in acampaign, where multiple batches of a product are produced one after the other;and/or

連續(xù)生產(chǎn)的設備，一個產(chǎn)品的多個批次連續(xù)生產(chǎn);及/或

are stored in aclean state for defined periods of time (clean equipment hold time).

潔凈狀態(tài)下存放一定時長（干凈的保持時間）

HBEL should be considered when establishing carryover limits in cleaningvalidation.

確定清潔驗證中殘留限度時，應考慮 HBEL。

Cleaningverification

清潔確認

The companyshould describe the policy and approach to cleaning verification. Cleaningverification is where the effectiveness of the validated cleaning procedure isroutinely verified. The approach mayinclude swab orrinse samples. The results obtained from testing on a routine basis should bereviewed and subjected to statistical trending.

公司應說明清潔確認的政策和方法。清潔確認用于定期確認已驗證清潔程序的有效性。該方法可能包括擦拭或淋洗取樣。應審查日常測試的結果，并進行趨勢分析。

5.12 Visuallyclean

目視潔凈

Visually clean is an important criterion incleaning validation. It should be one of the acceptance criteria used on aroutine basis. Personnel responsible for visual inspection should beappropriately trained. Training records should be kept.

目視干凈是清潔驗證的一個重要標準。它應該是日常使用的接受標準之一。負責目視檢查的人員應接受適當培訓。應保存培訓記錄。

Where visual inspection is used as aquantitative method, then Visible Residue Limits (VRLs) should be determined.The process to determine the limit should be appropriately described inprocedures and protocols covering, for example, concentrations, method ofspiking, surface areas, material of construction and other conditions such aslight (LUX level) and angles.

目視檢查用作定量方法時，應確定可見殘留的限度（VLL）。確定限度的過程應在程序和方案中適當描述，包括濃度、涂布方法、表面積、載體材料和其他條件，如光線（LUX水平）和角度。

5.13 Cleaningprocess capability

清潔工藝能力

The cleaning procedure should remain in avalidated state. It is recommended that cleaning verification results andcalculated process capability data be used to support this. For example, theresults from cleaning verification sample analysis could be statisticallytrended. The capability of the cleaning process is then calculated by using anappropriate statistical process.

清潔程序應保持已驗證狀態(tài)。建議使用清潔確認結果和所計算的工藝能力數(shù)據(jù)來支持此要求。例如，清潔確認樣品分析的結果可以統(tǒng)計趨勢。然后使用適當?shù)慕y(tǒng)計過程計算清潔工藝的能力。

Data should be presented, for example, in graphform, and the capability of the process in relation to control limits and themargin of safety should be presented and discussed as part of continuousimprovement over the life cycle.

例如，數(shù)據(jù)應以圖表形式呈現(xiàn)，并給出過程與控制限度和安全邊際的能力，并討論作為生命周期持續(xù)改進的一部分。

5.14 Personnel

人員

Personnel should be trained on the proceduresand principles of cleaning and cleaning validation, including contamination andcross-contamination control, HBELs setting, equipment disassembly, visualinspection, sampling, testing and statistical calculations, as appropriate andbased on their responsibilities.

應酌情根據(jù)職責，對人員進行清潔和清潔驗證的程序和原則的培訓，包括污染和交叉污染控制、HBEL設置、設備拆解、目視檢查、取樣、檢驗和統(tǒng)計計算。

5.15 Qualitymetrics and performance indicators

質(zhì)量量度和性能指標

Aspects ofcleaning validation and cleaning verification should be considered in qualitymetrics, with performance indicators identified and monitored.

應在質(zhì)量量度中考慮清潔驗證和清潔確認的各個方面，并確定和監(jiān)測性能指標。

5.16 Life cycle

生命周期

Cleaningprocedures, cleaning validation and cleaning verification should be included inthe life cycle approach described by the company.

清潔程序、清潔驗證和清潔確認應包含在公司描述的生命周期方法中。

Annex 1. Using Health-Based Exposure Limit(HBEL) to assess risk in cleaning validation*

附錄1 在清潔驗證中使用基于健康的暴露限（HBEL）評估風險

Permitted DailyExposure (PDE)

日允許暴露限（PDE）

The Permitted Daily Exposure (PDE) can becalculated based on the data and information obtained. For example:

日允許暴露量（PDE）可以根據(jù)獲得的數(shù)據(jù)和信息進行計算。例如：

Where NOAEL isno-observed adverse effect level, and

NOAEL為無可見不良反應水平

F representsvarious adjustment factors. The value selected for each factor should bejustified.

F為不同調(diào)整因子。每個因子選擇的值應論證。

The PDE is derived by dividing the NOAEL for thecritical effect by various adjustment factors (also referred to as safety-,uncertainty-, assessment- or modifying factors) to account for variousuncertainties and to allow extrapolation to a reliable and robust no-effectlevel in the human or target animal population. F1 to F5 are addressing thefollowing sources of uncertainty:

PDE通過將關鍵反應的NOAEL除以各種調(diào)整因子(也稱為安全性、不確定性、評估或修改因子)得出，以考慮各種不確定性，并允許外推到一個可靠的、穩(wěn)健的人類或目標動物種群的無反應水平。F1到F5用以解決以下不確定性來源：

F1: A factor(values between 2 and 12) to account for extrapolation between species;

F1：一個因子（值介于 2 和 12 之間），用于考慮物種之間的推斷;

F2: A factor of10 to account for variability between individuals;

F2：取10，用于解釋個體差異;

F3: A factor 10to account for repeat-dose toxicity studies of short duration, i.e., less than 4-weeks;

F3：重復給藥毒性研究為短期，取10，即少于4周;

F4: A factor(1-10) that may be applied in cases of severe toxicity, e.g. non-genotoxiccarcinogenicity, neurotoxicity or teratogenicity;

F4：用于嚴重毒性情況的因子（1-10），例如非基因毒性致癌性、神經(jīng)毒性或致畸性;

F5: A variable factor that may be applied if theno-effect level was not established. When only an LOEL is available, a factorof up to 10 could be used depending on the severity of the toxicity.

F5：如未建立無反應水平，可應用該因子。當只有LOEL 可用時，根據(jù)毒性的嚴重程度，可以使用高達10 的因子。

The use of additional modifying factors to address residualuncertainties not covered by the above factors may be accepted provided theyare well supported with literature data and an adequate discussion is providedto support their use (Ref: EMA document).

如有充分的文獻數(shù)據(jù)支持并充分討論了其使用支持，也可以使用其它調(diào)整因子來解決上述未涵蓋的其他不確定性（參考：EMA文件）。

If no NOAEL is obtained, the lowest-observed-adverse-effect level(LOAEL) may be used.

如未獲得NOAEL，可以使用最低可見不良反應水平（LOAEL）。

Calculating MSCand MSSR

計算MSC（最大安全殘留）和MSSR（最大表面安全殘留）

MSC and MSSRcan be calculated by using HBELs, to determine the risks associated withcleaning validation.

MSC和MSSR可通過使用HBEL算得，以確定與清潔驗證相關的風險。

It can alsogive an indication of the acceptability, or not, of manufacturing specifiedproducts in shared facilities. For example:

它還可以提供在共用設施中制造特定產(chǎn)品的可接受性或不可接受性的指標。例如:

Step 1.Calculate MSC

步驟1：計算MSC（最大安全殘留）

相關知識

英語作文：健康減肥方法（中英文對照）
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