WHO清潔驗(yàn)證新指南

1、WHO 在上個(gè)月發(fā)布新指南 WHO TRS 1019-53，英文全文303頁(yè)，本文節(jié)選其中 清潔驗(yàn)證部分，進(jìn)行了翻譯，供參考。Appendix3Cleaningvalidation 清潔驗(yàn)證Thetext of this appendix was previously published as:本附錄的文本以前以下列形式發(fā)表: Appendix 3: Cleaning validation. In: WHO Expert Committee onSpecificationsfor Pharmaceutical Preparations fortieth report. Geneva: Worl

2、d HealthOrganization; 2006: Annex 4 (WHO Technical ReportSeriesNo. 937; 附錄3:清潔驗(yàn)證。在:世界衛(wèi)生組織藥物制劑規(guī)范專家委員會(huì)第四十次報(bào)告。日內(nèi)瓦世界衛(wèi)生組織;2006:附件4(世衛(wèi)組織技術(shù)報(bào)告系列，第937號(hào);/medicines/areas/quality_safety/quality_assurance/SupplementaryGMPValidationTRS937Annex4.pdf?ua=1).1.Principle 原則1382.Scope 范圍1383.General

3、概述1394.Cleaning validation protocols and reports 清潔驗(yàn)證方案和報(bào)告1395.Personnel 人員1426.Equipment 設(shè)備1427.Detergents 清洗劑1428.Microbiology 微生物1439.Sampling 取樣14310.Analytical methods 分析方法14511.Establishing acceptable limits 確定可接受標(biāo)準(zhǔn)1461.Principle原則1.1The obxxxxjectives of good manufacturing practices (GMP) inc

4、lude the prevention of possiblecontamination and cross-contamination of pharmaceutical starting materials andproducts.藥品生產(chǎn)質(zhì)量管理規(guī)范(GMP)的目標(biāo)包括防止可能的污染和藥物原料和產(chǎn)品的交叉污染。1.2Pharmaceutical products can be contaminated by a variety of substances such ascontaminants associated with microbes previous products (bot

5、h activepharmaceutical ingredients APIs and excipient residues) residues of cleaningagents airborne materials such as dust and particulate matterlubricants andancillary material such as disinfectants and decomposition residues from:藥品可以被各種物質(zhì)污染如污染物與微生物有關(guān)以前的產(chǎn)品(包括原料藥(api)和賦形劑殘留)殘留的清潔劑空氣傳播的物料如灰塵和顆粒物。潤(rùn)滑劑

6、和輔助材料如消毒劑、和殘留降解產(chǎn)物: product residue breakdown occasioned by for example the use of strongacids and alkalis during the cleaning process;例如，在清洗過程中使用強(qiáng)酸和強(qiáng)堿會(huì)導(dǎo)致產(chǎn)品殘?jiān)纸?breakdown products of the detergents acids and alkalis that may beused as part of the cleaning process.洗滌劑、酸和堿的分解產(chǎn)物，可作為清洗工藝的一部分。1.3Adequate

7、cleaning procedures play an important role in preventing contaminationand cross-contamination. Validation of cleaning methods provides documentedevidence that an approved cleaning procedure will provide clean equipmentsuitable for its intended use.適當(dāng)?shù)那逑闯绦驅(qū)Ψ乐刮廴竞徒徊嫖廴揪哂兄匾饔?。清洗方法的?yàn)證提供文件證明，經(jīng)批準(zhǔn)的清洗程序?qū)⑻峁┡c其預(yù)

8、期用途相適應(yīng)的清潔設(shè)備。1.4The obxxxxjective of cleaning validation is to prove that the equipment is consistentlycleaned of product detergent and microbial residues to an acceptable level toprevent possible contamination and cross-contamination.清潔驗(yàn)證的目的是證明設(shè)備對(duì)產(chǎn)品、洗滌劑和微生物殘留物的清洗一致并達(dá)到可接受的水平，以防止可能的污染和交叉污染。1.5Cleaning

9、 validation is not necessarily required for non-critical cleaning suchas that which takes place between batches of the same product (or differentlots of the same intermediate in a bulk process) or of floors walls theoutside of vessels and following some intermediate steps.清潔驗(yàn)證對(duì)于非關(guān)鍵性的清洗并不一定是必需的，例如批次相

10、同的產(chǎn)品(或散裝過程中相同中間體的不同批次)、地板、墻壁、容器外部以及以下一些中間步驟之間的清洗。1.6Cleaning validation should be considered important in multiproduct facilitiesand should be performed among others for equipment sanitization proceduresand garment laundering.清潔驗(yàn)證應(yīng)被認(rèn)為在多產(chǎn)品設(shè)施中很重要，并應(yīng)在設(shè)備、消毒程序和服裝洗滌等方面進(jìn)行驗(yàn)證。2.Scope 范圍2.1These guidelines de

11、scribe the general aspects of cleaning validation excludingspecialized cleaning or inactivation that may be required for example forremoval of viral or mycoplasmal contaminants in the biological manufacturingindustry.這些指南描述了清潔驗(yàn)證的一般方面，不包括可能需要的特殊清洗或滅活，例如，在生物制造業(yè)中去除病毒或支原體污染物。2.2Normally cleaning validat

12、ion would be applicable for critical cleaning such ascleaning between manufacturing of one product and another of surfaces thatcome into contact with products drug products and APIs.一般情況下，清潔驗(yàn)證適用于關(guān)鍵的清洗，例如在生產(chǎn)一種產(chǎn)品與另一種產(chǎn)品，與產(chǎn)品、藥品和原料藥接觸的表面之間的清洗。3.General 概述3.1There should be written standard operating proc

13、edures (SOPs) detailing thecleaning process for equipment and apparatus. The cleaning procedures should bevalidated.應(yīng)該有書面的標(biāo)準(zhǔn)操作規(guī)程(sop)，詳細(xì)說明設(shè)備和儀器的清洗過程。清洗程序應(yīng)經(jīng)過驗(yàn)證。3.2The manufacturer should have a cleaning policy and an appropriate procedure forcleaning validation covering:制造商應(yīng)制定清洗策略和適當(dāng)?shù)那鍧嶒?yàn)證程序，包括: surfa

14、ces that come into contact with the product;與產(chǎn)品接觸的表面; cleaning after product changeover (when one pharmaceutical formulationis being changed for another completely different formulation);產(chǎn)品轉(zhuǎn)換后的清洗(當(dāng)一種藥物配方被另一種完全不同的配方替換時(shí)); between batches in campaigns (when the same formula is being manufacturedover a

15、period of time and on different days);在批次之間的活動(dòng)(當(dāng)同一配方是在一段時(shí)間內(nèi)，在不同的日期生產(chǎn)); bracketing products for cleaning validation. (This often arises whereproducts contain substances with similar properties such as solubility or thesame substance in different strengths. An acceptable strategy is to firstmanufactur

16、e the more dilute form not necessarily the lowest dose and then themost concentrated form.用于清潔驗(yàn)證的產(chǎn)品組。(這種情況經(jīng)常發(fā)生在產(chǎn)品中含有具有類似性質(zhì)(如溶解度)或具有不同強(qiáng)度的相同物質(zhì)的地方。一種可接受的策略是首先制造含量較低的劑型(不一定是最低劑量)，然后是含量較高的形式。Thereare sometimes “families” of products which differ slightlyas to actives or excipients.);有時(shí)產(chǎn)品的“組”在活性物質(zhì)或賦形劑方面略有

17、不同。 periodic evaluation and revalidation of the number of batches manufacturedbetween cleaning validations.定期評(píng)估和清潔再驗(yàn)證之間生產(chǎn)的批次數(shù)量。3.3.At least three consecutive applications of the cleaning procedure should be performedand shown to be successful to prove that the method is validated.至少連續(xù)三次應(yīng)用清洗程序，并證明是成功

18、的，以證明該方法是有效的。4.Cleaning validation protocols and reports Cleaning validation protocols清潔驗(yàn)證方案和清潔驗(yàn)證報(bào)告。4.1Cleaning validation should be described in cleaning validation protocols whichshould be formally approved for example by the quality control or qualityassurance unit.清潔驗(yàn)證應(yīng)在清潔驗(yàn)證方案中進(jìn)行描述，該方案應(yīng)得到正式批準(zhǔn)，例如

19、由質(zhì)量控制或質(zhì)量保證部門批準(zhǔn)。4.2In preparing the cleaning validation protocol the following should be considered:在制定清潔驗(yàn)證方案時(shí)，應(yīng)考慮以下事項(xiàng): disassembly of the system;系統(tǒng)拆卸 precleaning; 預(yù)清洗 the cleaning agent concentration solution volume water quality; 清洗劑、濃度、溶液體積、水的質(zhì)量; the time and temperature;時(shí)間和溫度 the flow rate pressu

20、re and rinsing; 流速、壓力和沖洗 the complexity and design of the equipment;設(shè)備復(fù)雜性及設(shè)備設(shè)計(jì) training of operators; 操作員培訓(xùn) the size of the system. 系統(tǒng)尺寸4.3The cleaning validation protocol should include: 清潔驗(yàn)證方案應(yīng)該包括： the obxxxxjectives of the validation process; 驗(yàn)證過程的目標(biāo)； the people responsible for performing and app

21、roving the validation study;負(fù)責(zé)實(shí)施和批準(zhǔn)驗(yàn)證研究的人員; the descxxxxription of the equipment to be used including a list ofthe equipment make model serial number or other unique code;所使用設(shè)備的說明，包括設(shè)備清單、制造、型號(hào)、序列號(hào)或其他唯一代碼； the interval between the end of production and the commencement ofthe cleaning procedure (the i

22、nterval may be part of the validation challengestudy itself) the maximum period that equipment may beleft dirty before being cleaned as well as the establishment of the time thatshould elapse after cleaning and before use;之間的時(shí)間間隔的生產(chǎn)和清潔過程的開始(間隔可能驗(yàn)證挑戰(zhàn)研究本身的一部分)設(shè)備的最大時(shí)期可能離開臟在清洗之前以及之后建立的時(shí)間應(yīng)該消逝的清潔和使用前; the

23、 levels of microorganisms (bioburden);微生物（生物負(fù)載）的水平 the cleaning procedures (documented in an existing SOP including definitionof any automated process) to be used for each product each manufacturingsystem or each piece of equipment;為每一產(chǎn)品、每一制造系統(tǒng)或每一設(shè)備所采用的清洗程序(已編制在現(xiàn)行SOP中，包括任何自動(dòng)化過程的定義); all the equipmen

24、t used for routine monitoring for example conductivitymeters pH meters and total organic carbon analysers;用于日常監(jiān)測(cè)的電導(dǎo)率儀、pH儀、總有機(jī)碳分析儀等設(shè)備; the number of cleaning cycles to be performed consecutively;連續(xù)進(jìn)行清洗的次數(shù); the sampling procedures to be used (direct sampling rinse samplingin-process monitoring and sam

25、pling locations) and the rationale for their use;所采用的取樣程序(直接取樣、沖洗取樣、過程中監(jiān)測(cè)和取樣位置)及其使用理由; the data on recovery studies (efficiency of the recovery of the samplingtechnique should be established);回收率研究的數(shù)據(jù)(應(yīng)確定取樣技術(shù)的回收效率); the analytical methods (specificity and sensitivity). including thelimit of detectio

26、n and the limit of quantification;分析方法(特異性和敏感性)。包括檢測(cè)限和定量限; the acceptance criteria (with rationale for setting the specificlimits) including a margin for error and for sampling efficiency;可接受標(biāo)準(zhǔn)(包括設(shè)定具體限制的理由)，包括誤差范圍和取樣效率; Documentation of the choice of cleaning agent and approval by the qualityunit wh

27、ich should be scientifically justified on the basis of for example:選擇清洗劑的文件和質(zhì)量部門的批準(zhǔn)，這些文件應(yīng)科學(xué)地證明是合理的，例如: the solubility of the materials to be removed; 被除去的材料的溶解度 the design and construction of the equipment and surface materialsto be cleaned;設(shè)備的設(shè)計(jì)和施工及表面材料的清洗 the safety of the cleaning agent;清洗劑的安全性；

28、the ease of removal and detection; 清除的簡(jiǎn)便性和檢測(cè)； the product attributes;產(chǎn)品屬性 the minimum temperature and volume of cleaning agent and rinsesolution; 清洗劑和洗滌液的最低溫度和體積; the manufacturers recommendations; 制造商的建議 revalidation requirements. 再驗(yàn)證需求4.4Cleaning procedures for products and processes that are very

29、 similar do not needto be individually validated. A validation study of the “worst case” may be considered acceptable. There should be a justifiedvalidation programme for this approach referred to as “bracketing” addressing critical issues relatingto the selected product equipment or process. 非常相似的產(chǎn)

30、品和工藝的清洗程序不需要單獨(dú)驗(yàn)證。對(duì)“最壞情況”的驗(yàn)證研究可能被認(rèn)為是可以接受的。這種方法應(yīng)該有一個(gè)合理的驗(yàn)證方案，稱為“括號(hào)法”，處理與所選產(chǎn)品、設(shè)備或工藝有關(guān)的關(guān)鍵問題。4.5Where “bracketing” of products is done consideration should be given to the type ofproducts and equipment. 產(chǎn)品的“包裝”應(yīng)考慮產(chǎn)品和設(shè)備的類型。4.6Bracketing by product should be done only when the products concerned aresimilar

31、in nature or property and will be processed using the same equipment.Identical cleaning procedures should then be used for these products. 只有當(dāng)有關(guān)產(chǎn)品性質(zhì)或性質(zhì)相似，并將使用相同的設(shè)備加工時(shí)，才應(yīng)按產(chǎn)品進(jìn)行分組。然后應(yīng)該對(duì)這些產(chǎn)品使用相同的清洗程序。4.7When a representative product is chosen this should be the one that is most difficultto clean.當(dāng)選擇有代表性

32、的產(chǎn)品時(shí)，這個(gè)應(yīng)該是最難清洗的。4.8Bracketing by equipment should be done only when it is similar equipment orthe same equipment in different sizes (e.g. 300 L 500 L and 1000 L tanks).只有當(dāng)設(shè)備是類似的設(shè)備，或者相同的設(shè)備有不同尺寸時(shí)(例如300l、500l和1000l的儲(chǔ)罐)，才可以用設(shè)備組。Analternative approach may be to validate the smallest and the largest sizes

33、separately.另一種方法可能是分別驗(yàn)證最小和最大的尺寸。Cleaningvalidation reports 清潔驗(yàn)證報(bào)告4.9The relevant cleaning records (signed by the operator checked by productionand reviewed by quality assurance) and source data (original results) should bekept. The results of the cleaning validation should be presented in cleaningva

34、lidation reports stating the outcome and conclusion.應(yīng)保存相關(guān)的清洗記錄(由操作員簽字，由生產(chǎn)部門檢查，由質(zhì)量保證部門評(píng)審)和原始數(shù)據(jù)(原始結(jié)果)。清潔驗(yàn)證的結(jié)果應(yīng)在清潔驗(yàn)證報(bào)告中說明結(jié)果和結(jié)論。5.Personnel 人員5.1Personnel or operators who perform cleaning routinely should be trained andeffectively supervised.對(duì)日常清潔人員或操作人員應(yīng)進(jìn)行培訓(xùn)并進(jìn)行有效監(jiān)督。6.Equipment 設(shè)備6.1Normally only proce

35、dures for the cleaning of surfaces of the equipment thatcome into contact with the product need to be validated. Consideration shouldbe given to “non-contact” parts of the equipment intowhich product or any process material may migrate. Critical areas should beidentified (independently from the meth

36、od of cleaning) particularly in largesystems employing semi-automatic or fully automatic clean-in-place systems.通常，只需要驗(yàn)證與產(chǎn)品接觸的設(shè)備表面清洗程序。應(yīng)該考慮設(shè)備的“非接觸”部件，產(chǎn)品或任何工藝材料可能會(huì)遷移到這些部件中。關(guān)鍵區(qū)域應(yīng)該被識(shí)別(獨(dú)立于清洗方法)，特別是在使用半自動(dòng)或全自動(dòng)就地清洗系統(tǒng)的大型系統(tǒng)中。6.2Dedicated equipment should be used for products that are difficult to clean equip

37、mentthat is difficult to clean or products with a high safety risk where it is notpossible to achieve the required cleaning acceptance limits using a validatedcleaning procedure.專用設(shè)備應(yīng)用于難以清洗的產(chǎn)品、難以清洗的設(shè)備或具有較高安全風(fēng)險(xiǎn)的產(chǎn)品，這些產(chǎn)品使用經(jīng)過驗(yàn)證的清洗程序不可能達(dá)到所需的清洗接受限度。6.3Ideally there should be one process for cleaning a pie

38、ce of equipment or system.This will depend on the products being manufactured whether the cleaningoccurs between batches of the same product (as in a large campaign) or whetherthe cleaning occurs between batches of different products.理想情況下，應(yīng)該有一個(gè)清洗設(shè)備或系統(tǒng)的過程。這將取決于所生產(chǎn)的產(chǎn)品，清洗是否發(fā)生在同一產(chǎn)品的批次之間(如在大型活動(dòng)中)，或者清洗是否

39、發(fā)生在不同產(chǎn)品的批次之間。6.4The design of equipment may influence the effectiveness of the cleaning process.Consideration should therefore be given to the design of the equipment whenpreparing the cleaning validation protocol for example V-blenders transferpumps or filling lines.設(shè)備的設(shè)計(jì)可能會(huì)影響清洗過程的效率。因此，在編制清潔驗(yàn)證規(guī)程時(shí)，

40、應(yīng)考慮設(shè)備的設(shè)計(jì)，例如v型攪拌機(jī)、輸送泵或灌裝管路。7.Detergents 清潔劑7.1Detergents should facilitate the cleaning process and be easily removable. Detergentsthat have persistent residues such as cationic detergents which adhere verystrongly to glass and are difficult to remove should be avoided wherepossible.洗滌劑應(yīng)便于清洗過程，并易于拆卸。

41、應(yīng)盡可能避免使用具有持久性殘留物的洗滌劑，例如陽(yáng)離子洗滌劑，它們對(duì)玻璃的附著力非常強(qiáng)，難以去除。7.2The composition of the detergent should be known to the manufacturer and itsremoval during rinsing demonstrated.清潔劑的成分應(yīng)告知生產(chǎn)商，并在清洗過程中演示其去除方法。7.3Acceptable limits for detergent residues after cleaning should be defined. Thepossibility of detergent breakdown should also be considered when validatingcleaning procedures.清洗后洗滌劑殘留的可接受限度應(yīng)加以規(guī)定。在驗(yàn)證