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1、WHO 清洁验证新指南-WHO-1KS-1019-53WHO在上个月发布新指南WHOTRS 1019-53，英文全文303页，本文节选其中清洁验证部分，进行了翻译，供参考 .Appendix3Cleaningali daiion清洁验证Thctcxt of this appendix w 能 previously piublishcd as ：本附录的文本以前以下列形式发表：A Append3ix： Cleaning vslidation. In ： WHO Expert Committee onSpecificationsfor Pharrcaceuticzl Pieparaziongfor
2、iieth r 印 ort Geneva: World Healthorganization ； 2006: Annex 4 (WHO echnical ReportSeriesNo. 937 ；附录&清沽验证。在：世界卫生组织药物制剂规范专家委员会第四十次报告。日内瓦世界卫主组织; 2006： 附件4(世卫组织技术报告系列，第93丁号；https: Z/wwwA whzi ? int/ medic ines/aieas/ qualify_s afe ty/AAqual i ty_ as surance,/ S up p 1 eine nt a rrGMPV 81idationTRS93 7A
3、nnex4.pdf ?ua=1) ?A1. Principle 原则 1382. Scope 范围 1383. General 概述 13 94o Cleaning validation protocols and reports 洁沽骑证方案和报告1395. Posonnel 人员 1426. Equipmcnt 设备 1427-Detergents 清洗剂 1 吃&Microbiology 澈生物 1439. Sampling 取样 M31 0。 Analytical methods 分析方法 145IL Establishing acceptable limits 确定可按吴尿隹146A
4、1。 Pri nciple 原则1 o IThe obxxxxjectives of good manufacturing practices (GMP/ include the prevention of possiblez ： ont inination and cross - contamination of pliannaceutical starting matmial s andproductSc药品生产质量管理规范GMP)的目标包括防止可能的污染和药物原料和产品日勺交叉污染。1? 2Pbermaccutical products can be contarn inated by
5、a variety of substances such asexAntaminant s associated with microbes previous predicts (both activepharmAeutical mgredietits APIs and excipient residues) re si dies of cleaning 略 errts airborne materials such as dust and particulate mAterlubricants andancillary material such as disinfectants end d
6、ecomposition residues from ：药品可以被各种物质污染如污杂物与毅生物有关以前日勺产品（包括原料药（api）和赋形剂残留）残留的清洁剂空气传播的物料如灰尘和颗粒物.润滑剂和辅助材料如消尊剂、和残留降解产物： product re si due breakdown occasioned by fc： r example the use of strongacids and alkalis during the cleaning process;例如，在清洗过程中使用强骏和强碱会导致产品残渣分解 breakdown products of the detergentsaci
7、ds and alkalis that may beused as part of the cleanirg process.洗涤剂、酸和碱的分解产物.可作为清洗工艺的一部分。1。 3Adequate cleaning proceduresplay an important role in preventing contarninationand cicss- contaminaticn ? Validation of cleaning methods provides documcnt edcvi dencc that an approved cleaning procedure will
8、provide clean equipmentsui table for its intended use.适当的清洗程序对防止污臬和交叉污染具有重要作甩清洗方法的验证提供文件证明？经此隹 的清洗程序将提供与其预期用途相适应的清洁设各。1? 4The obxxxxjective oF cleaiiirig validation is to prove that the equipment is consistentlycleaned of product detergent and microbial residues to an acceptable level toprevent poss
9、ible caita mi nation and cross-contaminati eti?清洁验证的目的是证明设备对产品、洗涤剂和微生物残留物的清洗一致并达到可接爻的水平， 以防止可肓因勺污染和交叉污架。h 5Cleaning validation is not necessarilj T required for non crtticsl cleaning such as that which tgkes place between batches of the same product （cr different ots of the same intermediate in abul
10、k processA or of floors walls theoutside of vessels and following some intsme diate steps ?清沽验证对于非关键性的待洗并不一定是必需的.例如批次相同的产品（或散装过程中相同中 间体的不同批次） 、地板、堵矍容器外郃以及以下一些中间步骤之间的清洗.1 .GCkarung validetion should be consi dered important in multiproduct facilitiesar d -should be performed among others for equipmen
11、t sanitization proceduresard garment launderingo 清沽验证应被 认为在多产品设施中很重要，并应在设备 消李程序和服装洗涤等方面进行验证. A2? Scope范围2.1Tliese Audelines describetlie general aspects oF cleaiiiiA validation excludingspecialized cleaning or inactivation that may be required for example forremovaf of viral or mycoplasmal contamina
12、nts in the biological manufachn ingindustry这空指南描述了清沽验证的一般方面，不包括可育孺要的恃殊清洗或灭活，例如，在生物制造 业中去除病毒或支原体污染物 .2o 2Normally clcani ng validation would be appiicable for critical cleaning such asdecning between msnufacturing of one product and another of suidaces thatcome into ccntacl with products drug product
13、s and APIs, 一般情况下 , 清洁验证适用于关髓的清洗，例如在生产一种产品与另一种产品，与产 品、药品和 原料药接高隹的表面之间的待洗. .Genera概述3? ITherE should be written st 已 adsrd openatit 粤 ptocedures （SOPs） detailingHiecleaim ng process for equipment and apparatus. The cleaning procedures should bevalidated? 应该有书面的标准操作规程 （ sop） ,详细说明设备和仪器的清洗过程。清冼程序应经过验证。
14、3 2The manufacturer should have a cl eaning policy and an appropriate procedure fbrcleaning validation coven ng :制造商应制定清洗策略和适当的清洁验证程序，包括： surfaces that come irto contact with the product ； 与产品接触的表面； cleaning after product changeovei（ when one pharmaceutical fomiulationis being changed for another cc
15、mpldc !y dificrent formu ation ） ;产品转换后日勺清洗（当一种药物配方被另一种完全不同的配方替换时； between batches in carripaigns（ when the same formula is being manufacturccbvcr a period of time and on different days ）；在批次之间的活动（当同一配方是在一段时间内 . 在不同的日期生产）； brackdzing products for cleaning validation。 （ibis ofien arises A/h er eprodu
16、cts contain substances with similarpnzperties such as solubility or thesaine substance in difFerent strengths & An acceptable strategy is tofirstmanufacture the more dilute form not necessar-ily the lowest close and then themost concentiated form用干清洁验证的产品组。（这种情况经常发生在产品中含有具有类似性质（如溶解度）或具有不同强度日勺相同物质的地方
17、。一种可接受的策略是首先制造含量较低的剂型（不一定是最低；剂量 ），然后是含量较高的形式。Thereat sometimes :femilieg of prcducts which diffe* slightiyas to actives or excipients ? ）； 有时 产品 B 护组“在活性物质或赋形剂方面略有不同。 periodic evaluation and reval idation of the number of batches meu-ufacturcdlDetwcen oleani r （ g val idations.定期评估和清沽再验证之间生产的批次数量。3.
18、3。 At least three consecutive applicAions of the cleaning procedure should beperformedand skawii to be successful to prove that the method is validated 。至少连续三次应用清洗程序，并证明是成功的 , 以证明该方法是有效的。4。Cleaning validdbion protocols and reports Cleaning validation protocols 清洁验证方案和清洁骑证 报告 .4。 lClesning validation
19、 should be described in cleanitig validation protocols whichshould be formally approved for example by the qualitj r control or quality assurance unit, 清洁验证应在清洁验证方案中 进行描述，该方案应得到正式批准，例如由质量控制或质量保证部门批准。4。2Iri preparing the cleaning validation protocol the following should be considered : 在制定清沽验 证方案时，应考
20、虑以下宰项：A disassembly of the syste情统寸斤隹 P precleaning； 预 ; 青 ;: 先 the cleaning agent concentration solution volume wets 口 uality;清洗剂、浓度、溶液体积、水的质量； the time and temperature；时间和温度 theflow rate pressure and rinsing ； 流速、压力和冲洗 the complexity and design of the equipment;设各复杂性及设备设计 training of operators 操作员
21、培训 the size of the system?系统尺寸A4-3The cleaning validation protocol should include ： 清洁验证方案应该包括: the obxxjKjectives of the validation process； 验证过程 0 勺目 标； the people respons ble for perlormirig and approving the validation study ； 负责实施和批准验证研究的人员； thedescxxxxription of tlie equipment to be used inclu
22、ding a list ofttie equipment mdke model serial number or other unique code ：所使用设备的说明，包括设备清单、制造、型号.?序列号或其他唯一代码； the interval between the end of product oti and the commencement ofthe cleaning procedure (the interval may be part of the validation chsllengestudy itself) 一 ths maximum period that cqiipm
23、ent mAbelcft dirty before being cleaned as well as the establishment of the time thatshould elapse after cleaning and before use;之间的时间间隔的生产和清洁过程的开始 ( 间隔可能验址挑战研究本身的一部分) 设备的最大时期可能离开脏在清洗之前以及之后建立的时间应该消逝的清洁和使用前； the levels of microorganisms (bioburden);微生物生物负载；)日勺水平 the cleaning procedures (documented in
24、 an existing SOP includng definiticnof any automated process) to be used for each product each maniifacturingsystem or each piece of cquiprnert;为每一产品、每一制造系统或每一设备所采用的清洗程序(已编制在现行SOP中，包括任何自动化过程的定义) ： al1 the equipment used for routine monitoring fee example conductivitymeters pH meters and total organi
25、c carbon aialvscrs ；用于日常监测的电导率汶、pH仪、总有机磴分析仪等设备； the number of cleaning cycles to be performed consecutively;连续进行清洗的次数； the .sampling procedures to be used (dinset sampling rinsesainplingin process monitoring and sampling locations) aid the rationale for their use;所采用的取样程序 ( 直接取样、冲洗取样、过程中监测和取样位置及其使用理
26、由； the data on recovery studies (efficiency of the recovery of the samplingtechnique should be estatilished)；回收率研究的数据(应确定取样技术的回U又效率)； the analytical methods (specificity and sensitivity) ? including theliniit of detection snd the lirn itof quanti fioation:分析方法 ( 特异性和敏感性 ) 。包括检测限和定量限； the acceptance
27、critena (with rationale for setting the spccificlimits) including a margin For error an d for sampling efficiency;可接受标左包括设定具体限制的理由愈包括误差范国和取样效率； Documentation of the choice of cleaning 笔 cut and approval by the qiialityimit which should be scientifically justified on the basis of for example ：选择清洗剂的文
28、件和月重量部门的批准，这些文件应科学地证明是合理妁，例如：一 thesolubility 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 meter i el sto be cleaned; 设备的设计和施工及表面才羽谢清洗 the safety of the cleaning agent ；清洗剂的安全性； the ease of removal and detection;清味的简便性和检测； the product attributes
29、 ；产品属性 the minimum tcmpcreturc and volume of d eanirjg agent and rinscsolution; 清洗剂和洗涤液的最低温度和体积； the manufacturers reccmmendetions； 制造商的建议 revalidation requiremeniSo 再验证需求A4 4Cleaning procedu es for products and processes that arc very simil 曰 do not needto be individually validated. A validation st
30、udy of the worst case may be considered acceptable ? I here should be a jlistifiedval idation programme for tliis approach referred to as c;bracketing M addressing critical issues relatingto the selected product equipment or process 。非常相似妁产品和工艺的清洗程序不需要单独验证。对 最坏情况 的验证研究可能被认为足可以接爱的。这种方法应该有一个合理的验证方案，称为
31、 括号法 ，处理与所选产品、设备或 工艺 有关的关犍问题.4。5 Where bracketingA of products is done consideration should be given to the type ofproducts and equipment.产品的?包装”应考虑产品和设备的类型.4.6Bi*acketingby product should be done only when the products concerned aresimilar i n natu 已 or property and will be processed using the same
32、 equipment. Identical cleaning procedures should then be used for thege products只有当有关产品性质或性质相似，井将使用相同妁设各加工时，才按 产品进行分组。然后应该对这些产品使用相同的清洗程序。1 .7When a representative product i s chosen this should be the one that is most diflicultto clean.当选择有代表性的产品时，这个应该定最难 ; 青洗的?4 8Bracketing by equipment should be d
33、one only when it is sim ilar equipment orthe seme equipment in different sizes (e. g. 300 L 500 L and 1000 L tanks) ?只有当设各是类姒的设备，或者相同的设备有不同尺寸时(例如kOL MO1和HJ0O1的储碓)，才 可以用设备组.Analtc native approach may be to validate the smelliest and the largest sizcsseparatcly。 另一种方法可能是分别验证最小和最大的尺寸。CIeaningvalidaiion
34、 reports 清沽验证报告4? 97he relevant cleaning records (signed by the operator checked by pro?duciionand reviewed byquality assuraiice） and source data （original results） should bekept 。 The results of the cleaning validaton should be presented in clcaningAlidation reports stating the outcome and conclusi
35、oa 应保存相 关的清洗记录（由操作员签字，由生产部门检杳，由质量保证部门评审）和原窗 1（ 原始结 果）。清洁验证的结果应在清洁验证报告中说明结果和结论。A5 .Personnel人员5 lPersonnel or operator who perform cleaning routinely should be trained and effectively supervised?对日常清沽人员或操作人员应进行培训并进行有效曲督6 。 Equipment 设各6.1 Nomiallv only pnAcedurcsfo rt he cleaning of surfaces of the e
36、quipment thatc om e into contact with the product need to be validated. Consideration shouldbe gi ven to 4knon ontacf parts of the equipment intowhich product or any process m Serial may migrate ? Critical areas shou d beidentified（ independently from the method of cleaning ） particularly in large s
37、ystems employing antomatic or ftil ly automatic clean in place systems.通常，只需要验证与产品接触的设备表面清洗程序。应该考虑设备的“非接触部件，产品或任何工艺材料可能会迁移到这些部件中?关谨区域应该被识别（独立于清洗方法），特别是在使用半自动或全自动就地清洗系统的大型系统中。A6. 2Dedicated equip?nent shouIdbe used for products tfiat are difficult to dean equipmentthat is difficult to clean or produc
38、ts with a high safety risk where it is notpossible to achieve the required cleaning acceptance limits using a validateckleailing procedure ? 专用设备应用于难以洁洗的产品、难以清洗 的设备或具有较高安全风险的产品 , 这些产品使用 经过验证眄清洗程序不可能达到所需的清洗接受限民G.SIdeally there sb- ： juld be one process fbr cleaning apiece of equipment cr system. This
39、 will depend on the products being manufactured whether the cleaningoccurs between batches of the ssmeptrxluct（ as in alaige campaign） or whNherthe cleaning occurs between batches of different products ? 理想情况下，应该有一个清洗设备或系统的过程。这将取决于所主产的产品，清洗是否发生在 同一 产品的批次之间（如在大型活动中），或者清洗是否发生在不同产品的批次之间。7. 4The design
40、of equipmert msy influence th 亡 effectiveness of the cleaning process ?Consideration should therefore be given to the design of the equipment whenpreparirig the cleaning validaticAn protocol for example V-blenders transferpumps or filling lineso设备的设计可能会影响清洗过程的效率。因此在编制清洁验证规程时 , 应考虑设备的设计，例 如 V 型搅拌机、输送
41、泵或灌装管路.8. Detergents 清洁齐1Jrabl Detergentsthat have pssistent residues such as cationic detergents which adhere veAshongl y to glass and difficult to remove should be avoided wfierepzssibleA 洗瘵剂应便于清洗过程，并易于拆应尽可能避免使用具有持久性残留物的洗涤剂，例如阳 离子洗涤剂，它们对玻璃的附着力非常强，难以去除。8.2 The composition oF the detergent should be
42、 known to the manufacturer and itsremoval during rinsing demonstrsted0清洁剂的成分应告知生产商，并在清洗过程中演示其去除方密8.3 Acceptable limits for detergent residues aft 日 cleaning should be de 五 ned. ThepossibiliA of detergent breakdown should also be cejnsidered when validatingcl eariing procedures.清洗后洗涤剂残留的可接爻限度应加以规定。在验
43、证清洗程序时，还应考虑洗涤剂损坏的可能性8.4 Detcrgt3nts should be released by quality control and where possible should mectlccal food standards or regulations.洗涤剂应通过质量腔制放行，并在可能的情况下 . 应符合当地食品标准或法规。8。 Microbiology 微生物9. 1 The need to include measures to prevent microbial growth and remove cnation where it has occurred s
44、hould be consi da-edc应考虑采取措施防止微生物生长和清除已发生的污染S6 2There should be documented evidence to indi cate that routine cleaning andstorage of equipment does not allow microbial proliferation.应该有书面证据表明，设备的常规清洗和储存不允许微生物增殖。8Q 3The period and conditions for storage of unclean equipment before cleaning aiidthe ti
45、me betvzeoi cleaning and equipment reuse should ferrn port of thevalidation of cleaning procedur 已 g。清洗前不沽净设备的睹存期限和条件，以及清洗和设备重宜使用之间的时间.应构成清洗方法脸证的一部分.8.4Equipment should be stored in a ciy condition after clcani ng ? Stagnant watcrshoulcl not be allowed to remain in equipment after cleaning ?设备清洗后应存放
46、在干燥的坏境中。清洗后，不应让积水留在设备内。8。 5Control of the bioburden through adequate cleaning and 印 propriate storAe ofequipment is i mportant to ensure that subsequent sterilization or sail it izationprocedures achieve the necessary assurance of sterility and the control ofpyrogens in sterile processing. Equipment stail ization processes may not beadequate to achieve sign ificatit inactivation or removal of pyrogois ?通过适当妁清洁和适当的设备储存来控制生物群落，对于硝保后续的灭菌或消毒程序实现必 要 的无菌保证，以及在无菌处理过程中对热源的控制非常重要 . 设备灭菌过程可能不足以实现显著B 勺失活或去除热源.A8/7