設(shè)定設(shè)備清潔殘留限度時需要考慮的20個問題

1、設(shè)定設(shè)備清潔殘留限度時需要考慮的20個問題！OtherConsiderations其他需考慮因素Theitemsdiscussedbelowareissuesthatmaybeconsideredaspartofanyevaluationinestablishinglimit.以下是設(shè)定限度時，可能需要考慮的問題MultipleNextProducts后續(xù)生產(chǎn)產(chǎn)品的多樣性Inmanypharmaceuticalmanufacturingsituations,thereisnotjustoneproductthatcouldpossiblybemanufacturedafteragivenpro

2、ductforwhichlimitsarebeingestablished.Ifflexibilityisdesiredtomanufactureproductsinanyorder,calculationsshouldbeconsideredforall“subsequentlymanufacturedproducts”,andtheresultinglowestlimit（typicallythelowestlimitpersurfacearea）shouldbeestablishedforthecleanedproduct.Asdiscussedpreviously,relevantfa

3、ctorstoconsiderforthenextproductaredosing,batchsizeandsharedsurfacearea.Inthismanner,anyoftheproductsconsideredmaybesafelymanufacturedaftercleaningofthefirstproduct.Insuchevaluations,thecombinationofthespecificrelevantfactorsforeachnextproductshouldbeconsidered.However,itisalsoacceptableasaworst-cas

4、etoconsideronlythemoststringentofeachofthethreerelevantfactors.在制藥行業(yè)中，很多時候在一個指定產(chǎn)品（其殘留限度已確定）生產(chǎn)結(jié)束后，后續(xù)生產(chǎn)的可能不只是一個產(chǎn)品。如果希望可以靈活生產(chǎn)任何產(chǎn)品，計算已清潔產(chǎn)品殘留最低限度（通常是每單位表面積的最低限度）時應(yīng)考慮所有后續(xù)生產(chǎn)產(chǎn)品”。如之前討論，需要考慮的后續(xù)生產(chǎn)產(chǎn)品的相關(guān)因素包括劑量、批量以及共用表面積。這樣，第一個產(chǎn)品清潔之后，可以安全地生產(chǎn)任何其他產(chǎn)品。評估時應(yīng)該綜合考慮每一種后續(xù)生產(chǎn)產(chǎn)品的相關(guān)因素組合。當然，釆用最嚴格的三個相關(guān)因素組合作為最差條件也是可以接受的。Anotherop

5、tionistorestricttheorderofmanufacturingbased,forexample,onaspecificsubsequentlymanufacturedproductcausingalimittobeverylow.Insuchcases,proceduresshouldbeinplacetoassurethattherestrictedorderofmanufactureisconsistentlyfollowed.另一種方式是限定生產(chǎn)順序，例如，基于后續(xù)生產(chǎn)產(chǎn)品建立的殘留限度非常低。這種情況下，要有相應(yīng)的規(guī)程以確保嚴格執(zhí)行限定的生產(chǎn)順序。Athirdoptio

6、nistooperateincleaningverificationmodewheretheacceptabilityofeachspecificcleaningeventisdeterminingbasedonalimitfortheimmediatelyfollowingnextproduct.Inthisway,thelimitforcleaningagivenproductmayvarydependingonsubsequentlymanufacturedproduct.Inthisverificationmode,residuesaremeasuredaftereachcleanin

7、geventandcomparedtotheacceptancelimitcalculatedbasedontheproductimmediatelyfollowing.第三種方式是按照清潔效果確認的模式來執(zhí)行，基于后續(xù)生產(chǎn)的第一個產(chǎn)品建立的殘留限度，確定每一清潔活動是否符合要求。這樣的話，指定產(chǎn)品的清潔限度可能會根據(jù)后續(xù)生產(chǎn)產(chǎn)品的不同而不同。在這種清潔效果確認模式中，每次清潔后都要測量殘留，并同基于后續(xù)生產(chǎn)產(chǎn)品計算出的殘留可接受限度進行比較。NextProductinVerificationApproach清潔效果確認方法中的后續(xù)產(chǎn)品Inacleaningverificationprotoc

8、ol,onlytheactualimmediatelyfollowingproductisrequiredforestablishinglimits.Particularlyindevelopmentorclinicalmanufacturing,whereaverificationapproachiscommonlyused,thenextproductmaynotbeknownatthetimeofthecleaningverificationevaluation.Insuchcases,oneapproachistomeasureresiduesfollowingcleaning,and

9、thennottoreleasetheequipmentuntilthenextproductisdetermined.Atthattime,acarryoverevaluationisperformedtodeterminewhethertheresiduesmeasuredareacceptable.Ifthemeasuredresiduesarenotacceptable,theequipmentmayberecleanedandcleaningverificationperformedagain.Asecondapproachistoestablish,basedonthetypeso

10、fproductsmanufactured,someworst-casevaluesfortherelevantfactorsforthenextproduct.Theseworst-casevaluesareusedforestablishinglimits,andtheequipmentiscleanedtomeetthosevalues.Whenthenextproductisdetermined,itisappropriatetoverifythattherelevantparametersofthenextproductarewithintheworst-casevalues.清潔效

11、果確認方案中，只需要根據(jù)緊接著生產(chǎn)的產(chǎn)品確定殘留限度。尤其是在研發(fā)批或臨床批的生產(chǎn)中，經(jīng)常使用清潔清潔效果確認方案中，只需要根據(jù)緊接著生產(chǎn)的產(chǎn)品確定殘留限度。尤其是在研發(fā)批或臨床批的生產(chǎn)中，經(jīng)常使用清潔效果確認的方法，在清潔效果確認的評估時可能不知道后續(xù)產(chǎn)品會是什么。這種情況下，一種方式是清潔后檢測殘留，直到確定了后續(xù)生產(chǎn)產(chǎn)品后才允許設(shè)備的使用。進行殘留評估，決定檢測出來的殘留是否可接受。如果檢測出來的殘留無法接受，應(yīng)重新清潔設(shè)備并再次進行清潔效果確認。第二種方式是基于生產(chǎn)的產(chǎn)品類型，為后續(xù)產(chǎn)品建立一些最差條件。這些”最差條件”數(shù)值被用于設(shè)定限度，同時設(shè)備清潔后需要符合這些數(shù)值。當確定了后續(xù)生

12、產(chǎn)產(chǎn)品時，合適的做法是確認該后續(xù)產(chǎn)品的相關(guān)參數(shù)沒有超出最條件數(shù)值范圍。DefaultLimits默認限度Asusedinthisdocument,defaultlimitsareoneoftwotypes.Onetypeisadefaultlimitwhichisutilizedifthedefaultvalueismorestringentthanwhatisestablishedbythemedicallysafecalculation(asgiveninSections5.3through5.8).Asecondtypeisadefaultlimitwhereamedicallysafe

13、limitcannotbeestablished,suchasforintermediatesinAPImanufacture.Inthelattercase,thedefaultlimitmaybeestablishedoncriteriathatarespecifictotheindividualsituation,basedonprocessunderstandingandariskassessment.本文件有兩種類型默認限度，。第一種默認限度是默認值比通過醫(yī)學安全計算(如5.3至5.8中所描述)建立的限度更嚴格。第二種默認限度是醫(yī)學安全限度無法建立時，女API生產(chǎn)過程中的中間體。在后

14、一種情況中，默認限度可根據(jù)對工藝的理解以及風險評估，建立針對特定情況的限度標準。OneexampleofthefirsttypeofdefaultlimitisadefaultlimitusedfortheARL.Fordrugproducts,themostcommondefaultlimitfortheARL(thelimitinthenextproduct)is10ppm;however,othervaluesmaybeused.IftheARLcalculation(Equation5A,5Dor5F)resultsinavalueabove10ppm,then10ppmisuseda

15、stheARL.IftheARLcalculationresultsinavaluebelow10ppm,thenthatlowercalculatedvalueisusedastheARL.ForAPImanufacture,morecommondefaultlimitsfortheARLare50ppmor100ppm(18),althoughothervaluesmaybeselectedandusediftheyaremorestringentthanwhatisestablishedbythemedicallysafecalculation.第一種情況可以ARL使用的默認限度為例。對

16、于制劑來說，ARL(下一產(chǎn)品中殘留可接受標準限度)最常用的默認限度為10ppm。當然，也可以釆用其他數(shù)值。如果ARL計算結(jié)果(公式5A,5D或5F)大于1Oppm,則選用1Oppm作為ARL。如果ARL的計算結(jié)果小于1Oppm,則選擇計算得來的較小的數(shù)值作為ARL。在API生產(chǎn)中，ARL更常用的默認限度是50ppm或1OOppm(18),當然如果其他數(shù)值比醫(yī)學安全計算得來的數(shù)值更嚴格，則也可能被選用。AsecondexampleofthistypeofdefaultlimitisadefaultlimitfortheSAL.ForeitherdrugproductorAPImanufactur

17、e,themosttypicaldefaultvaluefortheSALusedis4yg/cm2.Thisleveliscommonlycitedastheupperlimitforwhatisconsideredvisuallyclean.IftheSALcalculation(Equation5l)resultsinavalueabove4yg/cm2,then4yg/cm2isusedastheSAL.IftheSALcalculationresultsinavaluebelow4yg/cm2,thenthatlowercalculatedvalueisusedastheSAL.這一

18、情況的第二個例子是SAL的默認限度。無論是對于制劑還是API生產(chǎn)，最廣泛使用的SAL默認限度是4|jg/cm2。這水平常被作為上限，也就是目檢潔凈。如果SAL計算結(jié)果(Equation5l)大于4yg/cm2,則選用4yg/cm2作為SAL。如果SAL計算結(jié)果(Equation5I)小于4yg/cm2,則選擇計算得來的較小數(shù)值作為SAL。Itshouldbeunderstoodthatinthesetwoexamples,thelogicisthatanyvaluebelowthemedicallysafevaluemaybeusedasitrepresentsamorestringentcr

19、iterion.需要理解的是，這兩個示例的邏輯是可釆用任何低于醫(yī)學安全數(shù)值的值作為限度，因為它代表了一個更嚴格的標準。UseofDifferentSafetyFactors不同安全系數(shù)的使用ThesafetyfactorappliedtoaminimumdailydoseistypicallyO.OO1(oneone-thousandth),regardlessoftherouteofadministration.Basedonariskassessment,amorestringentorlessstringentsafetyfactormaybeappliedasappropriatefo

20、raspecificsituation.Forexample,forclinicaltrialmaterialswherethedoseisnotfullyestablished,amorestringentsafetyfactormaybeconsidered.SincethesafetyfactorofO.OO1wasoriginallyestablishedfordrugproductadministeredchronically,itmaybeacceptable(againbasedonariskassessment)tousealessstringentfactorfordrugp

21、roductsadministeredforashorttime(suchascoldtablets,whichmaybeadministeredforonly1Odays).無論什么類型的給藥途徑，每日最小有效劑量的安全系數(shù)通常是O.OO1?；陲L險評估，在特定的情況，可以適當使用一個更嚴格或不那么嚴格的安全系數(shù)。例如，對于用于臨床試驗的藥品，其劑量尚未完全確定，則可以考慮使用一個更嚴格的安全系數(shù)。因為安全系數(shù)O.OO1本是為長期給藥的制劑而設(shè)定的，那么基于風險評估，對于短期給藥的制劑(如治療感冒的片劑，服藥時間可能只有1O天)，則可以使用一個不那么嚴格的安全系數(shù)。治療感冒的片劑，服藥時間可

22、能只有10天），則可以使用一個不那么嚴格的安全系數(shù)。DifferentRoutesofAdministration不同的給藥途徑Ifthecleanedproductandthenextproductareadministeredbydifferentroutes(suchasthefirstproductbeinganoraldoseandthesecondproductbeinganinjectable),ariskassessmentshouldbeconsidered.Thisriskassessmentmightincludeanevaluationofhazardsoftheora

23、ldrugifadministeredasaninjectable,oritmightincludeareviewofdatafortheextentofsystemicavailabilityoftheoraldrugifgivenorally.如果已清潔產(chǎn)品和接下來要生產(chǎn)的產(chǎn)品使用不同的給藥途徑(比如第一的產(chǎn)品是口服給藥，第二個產(chǎn)品用于注射)，則需進行風險評估。風險評估可能包括對口服給藥的產(chǎn)品如果被用于注射的危害評估，或者可能包括口服制劑口服給藥后的生物利用度的數(shù)據(jù)回顧。DifferentDosesforAdultsandChildren成人和兒童劑量差異Fortwoproductswhe

24、rebothproductshavedifferentdosesforadultsandforchildren,itisappropriatetodeterminetheARLbasedonbothproductswiththeadultdose,andthenforbothproductsusingthechildsdose.ThelowerARLofthetwovaluesshouldbeusedforsubsequentlimitcalculations.Incaseswhereoneproductmaybedosedonlyforadultsandthenextproductonlyd

25、osedforchildren,thenariskassessmentshouldbeconsidered.如果兩個產(chǎn)品對于成人和兒童都分別有不同的劑量，比較合適的做法是先基于兩個產(chǎn)品的成人劑量計算ARL,再基于兩個產(chǎn)品的兒童劑量計算ARL。較小的ARL將被釆納用于后續(xù)限度計算。如果一個產(chǎn)品只有成人劑量，后續(xù)產(chǎn)品只有兒童劑量，則需要進行風險評估。HumanandVeterinaryProductsManufacturedontheSameEquipment同一設(shè)備用于生產(chǎn)人用產(chǎn)品和獸用產(chǎn)品Forthissituation,ariskassessmentshouldbeconsideredtos

26、etlimitsappropriately.Inadditiontothespeciesdifference,thebodyweightdifferencemayalsobeasignificantfactor.在這種情況下，應(yīng)進行風險評估以設(shè)定適當?shù)南薅?。除了物種不同，個體重量差異也可能是個重要因素。ResiduesofGenotoxicandOtherHighlyHazardousActiveIngredients基因毒性殘留以及其他高?；钚猿煞諳neapproachtogenotoxicresiduesiscoveredinSection5.3.3,whichistoutilizethe

27、ThresholdofToxicologicalConcern(TTC)valueof1.5yg/dayasthesafedailyintake(16),andutilizeconventionalcalculationstosetanacceptablelimitinananalyticalsample.Anotherapproachforgenotoxicresidues(providedthegenotoxicresidueistheactiveingredientandnotadegradant),aswellasotherresiduesofspecialmedicalconcern

28、,istodedicateequipmenttothatoneproductandthusavoidtheissueofthegenotoxicresiduebeingcarriedovertoadifferentproduct.Athirdapproachistoperformcleaningvalidation,withlimitsbasedonatoxicologicalevaluationrelatedtothegenotoxiceffect(orotherspecialtoxicityconcern)usingtheprinciplesinSection.Afourth

29、approachistosetthelimitforthegenotoxicresidueasbelowthelimitofdetectionofthebestavailableanalyticaltechnique.Inthelattercase,amedicalriskassessmentshouldbeperformedtodeterminewhetherresiduesatthatdetectionlimitareacceptable.Inthislattercase,itmayalsobepossibletoincludeinthecleaningprocessastepwhichd

30、eactivatesordegradesthegenotoxicmaterialsuchthatgenotoxicpropertiesarenolongerpresent.Suchadeterminationofdeactivationordegradationispreferablyperformedasalaboratorystudy.Theseapproachesmayalsobeapplicabletootheractiveingredientswithspecialconcerns,suchasreproductivetoxicityhazards,allergenicity,cyt

31、otoxicity,andmutagenicity.5.3.3節(jié)涵蓋了基因毒性殘留限度的一個設(shè)定方法，也就是利用毒理學閾值TTC)1.5g/day作為每日安全攝入量(16),并利用傳統(tǒng)的計算方法設(shè)定分析樣品中殘留的允許限度。對于基因毒性殘留(假如該基因毒殘留是活性成分而不是降解產(chǎn)物)以及其他需特殊醫(yī)學關(guān)注的殘留，另一個方法，是釆用專用設(shè)備生產(chǎn)該產(chǎn)品以防止基因毒性殘留轉(zhuǎn)移到另一個產(chǎn)品中。第三種方法是進行清潔驗證，使用節(jié)的理論，根據(jù)基因毒性(或其他需要關(guān)注的特殊毒性)作用進行毒理學評估并設(shè)定限度。第四種方法是將基因毒性殘留的限度設(shè)置為低于目前最好的分析技術(shù)的檢測限。在最后一個方法中，

32、需要進行醫(yī)學風險評估以決定是否是可以接受位于檢測限的殘留水平，同時可能需要在清潔程序中增加一步，使基因毒性的物料因失活或降解而不再表現(xiàn)出基因毒性?；蚨疚锪系氖Щ罨蚪到夥椒ㄗ詈米鳛閷嶒炇已芯窟M行。步，使基因毒性的物料因失活或降解而不再表現(xiàn)出基因毒性?；蚨疚锪系氖Щ罨蚪到夥椒ㄗ詈米鳛閷嶒炇已芯窟M行。以上方法可能也適用于其他需特殊醫(yī)學關(guān)注的活性成分，如生殖毒性、致敏性、細胞毒性和致突變性。LimitsBasedonAnalyticalDetectionLimits基于分析方法檢測限的限度Limitsmaybeestablishedbasedontheanalyticaldetectionlimi

33、tsprovidingresiduesatthoseanalyticaldetectionlimitsaredeterminedtobesafe.Itshouldberecognizedthatthismethodisnotnormallyrecommendedbecausewitheverimprovinganalyticalmethods,thelimitswillbedrivenexceedinglylowsoasnotbepracticallyachievable.Theissueisnotwhethertheresiduecanbemeasured,butratherwhethert

34、heresidueismedicallysafeanddoesnotaffectsubsequentproductquality.如果確定殘留水平位于檢測限是安全，則可以基于分析方法檢測限確定殘留允許限度。需注意的是，通常并不推薦釆用該方法，因為檢測方法的不斷改進，檢測限度趨于非常低，以至于實際操作中無法達到該水平。問題不在于殘留是否是可以被測量的，而是從醫(yī)學的角度來說殘留是否是安全的，且不會對后續(xù)產(chǎn)品的質(zhì)量產(chǎn)生影響。DegradationoftheActiveIngredient活性成分的降解Iftheactiveingredientdegradesduringthecleaningproc

35、ess(orafterthecleaningprocessduringthetimebeforesampling),itmaynotbeappropriatetomeasureresiduesofthatactiveingredientusingaspecificanalyticalprocedureinacleaningvalidationprotocol.Thereasonisthattherelevantresiduetomeasureisthedegradant.Thereareatleasttwoapproachestodealingwiththissituation.Oneappr

36、oachistosetlimitsforthedegradant,andthenmeasurethedegradantintheprotocolusinganappropriateanalyticalmethod.Thisassumesthatthereisaspecificdegradantforwhichlimitscanbeestablished(e.g.,basedonatoxicitycalculation).Anotherapproachistosetlimitsfortheundegradedactivebasedonitsdose.Residuesarethenmeasured

37、withanonspecificanalyticalmethod(suchasTOC).Theresidueasmeasuredbythatnonspecificmethodisconvertedtoanequivalentamountofundegradedactiveingredientandcomparedtothecalculatedlimit.Thisapproachmaybeacceptableifthesafetyconcernsfromresiduesofthedegradant(s)arenomoreseriousthanthesafetyconcernsoftheactiv

38、eingredient.Theremaybeotheracceptableapproachesbasedonthespecificofthesituationandariskassessment.如果活性成分在清潔過程中降解，或清潔后取樣前這一時間降解，則清潔驗證方案中使用指定分析方法測量該活性成分的殘留是不合適的，因為應(yīng)該測量的是降解產(chǎn)物的殘留。至少有兩個方案可解決這個問題。一個是為降解產(chǎn)物設(shè)定限度，然后在方案中用合適的分析方法測量降解產(chǎn)物。前提是可以設(shè)定一個特定降解產(chǎn)物的殘留限度(如，基于毒性計算)。另一個方案是基于活性成分的劑量，為未降解的活性成分設(shè)置限度，再釆用非專屬的檢測方法測量殘留

39、量，如TOC。使用非專屬檢測方法測量出的殘留被轉(zhuǎn)換成相應(yīng)的未降解的活性成分的含量，并同計算得來的限度進行對比。如果降解產(chǎn)物殘留的安全危害沒有活性成分的安全危害嚴重，則可以釆用這個方法。根據(jù)特定的情況和風險評估，也可釆用其他方法。LimitsNotMeasureable無法測量的限度Ifcalculationsforthelimitoftheactiveingredientintheanalyticalsampleresultinvaluesthatarenotmeasurablebyavailableanalyticalmethods,thereareseveraloptions.Oneopt

40、ionistodedicatetheequipmenttothatoneproduct,therebyreducingtheneedtomeasuretheactiveingredientexceptbyavisuallycleancriterion.Asecondoptionistomodifytheparametersofthenextmanufacturedproductsuchthatthelimitishigher.Forexample,raisingtheminimumbatchsizeofthenextproductwillincreasethelimit.Itmayalsobe

41、possibletorestricttheorderofmanufacturesuchthatcertainproducts,whichdrivethelimitlower,arenotmanufacturedafterthecleanedproductwiththelowlimit.Insuchcases,appropriatemeasuresshouldbeputinplacetoinsurethatonlythoseapprovedproductsaremanufacturedasthenextproduct.Athirdoptionistomodifythesamplingparame

42、ters.Forexample,forswabsampling,samplingalargerarea(100cm2ratherthan25cm2)orextractingtheswabwithasmalleramountofsolventwillresultinanincreasedlimitintheanalyticalsample.Afourthoptionislowertherinsevolumeforrinsesampling.Afifthoptionistoconcentratetherinsesamplebyatechniquesuchasvacuumevaporation.如果

43、計算得來的被檢測樣品中活性成分限度無法釆用現(xiàn)有的檢測方法進行測量，可有多種選擇。一種是該設(shè)備專用于一個產(chǎn)品，因此減少了測量該有效成分的需要，僅需符合目檢清潔標準。第二個選擇是調(diào)整后續(xù)生產(chǎn)產(chǎn)品的相關(guān)參數(shù)以提高殘留限度。例如，增大后續(xù)產(chǎn)品的最小批量會提高限度。也可能限制生產(chǎn)順序，如果已清潔的產(chǎn)品殘留限度較低，則下一生產(chǎn)產(chǎn)品不能為限度更低的部分產(chǎn)品。這樣的話，需要用適當措施來保證只有被批準的產(chǎn)品才能作為下一生產(chǎn)產(chǎn)品。第三個選擇是更改取樣參數(shù)。例如，擦拭取樣中，通過增大取樣面積(從25cm2增加到100cm2)或者減少拭子萃取的溶劑量來提高被檢測樣品的殘留限度。第四個選擇是沖洗取樣過程中減少沖洗量。第

44、五是通過技術(shù)，如真空蒸發(fā)，對沖洗樣品進行濃縮。對沖洗樣品進行濃縮。LimitsforOrganicSolvents有機溶劑限度FororganicsolventsthataretypicallyusedforcleaninginsmallmoleculeAPIsynthesis,limitsmaybeestablishedbasedontoxicitycalculations.AnotherapproachistousethevaluesinICHQ3C(R5),whichestablishesacceptablelevelsforsolventsinAPIsandindrugproducts

45、(19).ItshouldberecognizedthatQ3CtechnicallyappliestosolventsusedinthemanufactureofAPIs.Whilecleaningprocessesaresometimesconsideredmanufacturingsteps,theyareoftenconsideredpartofthesupporting“equipmentandfacilities”.Thereforethisapproachshouldbecarefullyevaluatedbeforeuse.Anotherapproachisnottosetli

46、mitsforvolatileorganicsolvents.Onesituationwherethismayapplyisifthereisanadequatedetermination(basedonprocessunderstandingandappropriatestudies)thatthereareadequateconditionsforthevolatilesolventtoevaporate.Notethatthislatterconsiderationalsoappliestouseofisopropanolorethanolusedasfinalrinseorwipefo

47、rdrugproductmanufacture.對小分子原料藥合成的清潔時使用的有機溶劑，可根據(jù)毒性計算來設(shè)定殘留限度。另一種方式是使用CHQ3C(R5)中的數(shù)值，建立原料藥和制劑中的溶劑的可接受標準。需要注意的是，從技術(shù)角度來說，Q3C適用于生產(chǎn)API過程中使用的溶劑。雖然有時候清潔過程也會被認為是生產(chǎn)步驟，更多的是將其作為對設(shè)備、設(shè)施的支持程序。因此這個方法在使用前需要仔細評估。另一種方法是不對揮發(fā)性有機溶劑設(shè)定限度，當有充分理由(基于對工藝的理解以及適當?shù)难芯?確定可有充分的條件允許該揮發(fā)性有機溶劑揮發(fā)時，可以釆用該方法。注意這一要求同樣適用于制劑生產(chǎn)中使用異丙醇或乙醇進行最終的沖洗或擦

48、拭。Anothersituationwherelimitsmaynotberequirediswherethesamesolventisusedforthefinalrinseasformanufactureofthenextproduct.另一種不需要設(shè)定限度的情況是下一產(chǎn)品生產(chǎn)中使用相同的溶劑進行最終沖洗。DedicatedEquipment專用設(shè)備Forequipmenttrainsdedicatedtomanufactureofonlyoneproduct,theconcernaboutcarryoveroftheactiveingredientfromonebatchtothenex

49、tisminimized.AsstatedintheU.S.FDAguidancedocument,visuallycleanmaybeappropriatetoaddresssuchaconcern(20).However,cleaningvalidationmaystillberequiredbecauseofconcernsaboutotherresidues,suchasdegradants,cleaningagentandbioburden,carryingovertothenextbatchofthesameproduct.對于只用于生產(chǎn)一個產(chǎn)品的專用設(shè)備組，則較少擔心將活性成分轉(zhuǎn)

50、移至下一批產(chǎn)品中。如美哥DA指南文件所述，目視潔凈即可。但是，考慮到其他殘留可能仍需進行清潔驗證，如降解產(chǎn)物，清潔劑和生物負載，這些殘留可能轉(zhuǎn)移到相同產(chǎn)品的下一批次中。Ifonlypartsofanequipmenttrainarededicatedtooneproduct,thenthatdedicatedpartisnotconsideredaspartofthesharedsurfaceareaforcalculatinglimitsforanactiveingredient.However,thesurfaceareaofthatpartmayberelevantforcalculat

51、ingotherlimits,suchasthelimitforthecleaningagent.如果設(shè)備組中只有一部分是專用于一個產(chǎn)品，那么在計算活性成分殘留限度時，這一部分不視為共用表面積。但是，在計算其他限度時，這一部分表面積可能是相關(guān)的，比如清潔劑的限度。Anotherapproachistosetlimitsfortheactiveingredientandmeasureresiduesoftheactiveingredientinacleaningvalidationprotocolfordedicatedequipmentforotherreasons,suchasconcern

52、saboutbatchintegrityorcertainequipmentsurfacesmaynotbeeasilyevaluatedbyvisualexamination.考慮到批的完整性，或有些特定的設(shè)備表面可能不容易通過目檢來評估，另一種方法是設(shè)定活性成分的殘留限度，并在專用設(shè)定的清潔驗證方案中對活性成分殘留進行測量。DividingaLimitamongVariousPiecesofEquipment區(qū)分不同設(shè)備的限度Inordertoevaluateaprocessingoperationcomposedofseveralunitoperations,itisimportantt

53、oconsidertheaccumulatedresiduefromeachpieceofprocessequipment.TheMACisthesumofalltargetresiduesthatcouldbepresentonthevariouspiecesofrelevantsharedequipmentsurfaces.AcommonpracticeistorequirethesameSALforeachandeverysurfaceinanequipmenttrain.Analternativeistoapportionthetotalamount(theMAC)differentl

54、yamongthedifferentequipmentitems,suchthatthetotalamountpresentstillreflectstheMACamount.Forexample,foramongthedifferentequipmentitems,suchthatthetotalamountpresentstillreflectstheMACamount.Forexample,foranequipmenttraincomprisingthreeseparatevesselseachofthesamesurfacearea,theSALlimitmightbel.Oyg/cm

55、2iftheMACisdistributedevenlyoverallsurfaceareas.Incontrast,theMACmightbeapportionedsuchthattheSALwas0.5yg/cm2forEquipmentA,1.0yg/cm2forEquipmentB,and1.5yg/cm2forEquipmentC,providedthetotalcarryoverlimitwasstillatthecalculatedMACvalue.為了評估一個由多個操作單元組成的操作步驟，重要的是計算每一操作設(shè)備中的累積殘留。MAC是可能存在于不同設(shè)備的共用面積上所有目標殘留的

56、總和。通常一個設(shè)備組中每一共用表面都釆用相同的SAL。另一種選擇是將MAC的總量不平均地分配給不同的設(shè)備，其總量依然可以有效反應(yīng)出MAC。例如，如果一個設(shè)備組包含三個獨立容器，三個容器具有相同的表面積，如果將MAC按照總表面積平均分配，則SAL限度可能為1.0口g/cm2，相反，可以不平均地分配MAC,使設(shè)備A的SAL為0.5yg/cm2,設(shè)備B是1.0yg/cm2,設(shè)備C是1.5yg/cm2,殘留限度總和仍然等同計算出的MAC值。LimitsforPreferentialTransfertoaFirstPortionoftheNextProduct向下一個產(chǎn)品前一部分優(yōu)先轉(zhuǎn)移的殘留限度Ane

57、quipmenttrainshouldbedelineatedtoseparatethoseportionsinwhichtheresiduewouldbeevenly(homogeneously)distributedinthenextproduct(e.g.,blender,granulator)fromthoseinwhichtheresiduecouldbetransferredtoanindividualdosageunitofthenextproduct(e.g.,tabletpress,vialfiller).Toaddressthesituationofpreferential

58、(non-homogeneous)transfer,thecarryovercalculationscanbeadjustedbasedonthesurfaceareasubjecttopreferentialtransferandtheportionofthenextbatchsubjecttobeingpotentiallycontaminatedwiththetransferredresidue.Thiswillresultinusingadifferent,morestringentlimittotheequipmentsurfaceswhichcanpreferentiallytra

59、nsfertothenextproduct,thusrestrictingpotentialcarryovertoaninitiallymanufacturedsingleproductdoseofthenextproduct.Inaddition,thispreferentialtransfercanbeaddressedbasedonproductiontechniquesifanadequatefirstportionofthenextmanufacturedproduct(e.g.,filledvials,tablets)isdiscarded.Anotheroptionistouti

60、lizeequipmentpartsdedicatedtooneproductwherethispreferentialtransfermayoccur.設(shè)備組中有些設(shè)備上的殘留會平均的(均勻的)分布在下一產(chǎn)品(如，混合機，制粒機)中，有些設(shè)備的殘留會轉(zhuǎn)移至下一產(chǎn)品單個劑量單元(如壓片、裝瓶)中，應(yīng)將這兩類設(shè)備區(qū)分開來。對優(yōu)先轉(zhuǎn)移(不均勻)的情況，可以根據(jù)優(yōu)先轉(zhuǎn)移的設(shè)備表面積以及下一批次中可能受到殘留污染的產(chǎn)品的多少對殘留計算結(jié)果進行調(diào)整。這將導致對存在優(yōu)先轉(zhuǎn)移設(shè)備表面釆用不同的、更嚴格的殘留限度，以控制下一產(chǎn)品中最初生產(chǎn)單個劑量單元中殘留量。另外，如果下一產(chǎn)品最初生產(chǎn)的部分(如已灌裝的瓶子、