FDA工业指引非青霉素β内酰胺类药品防止交叉污染的指导原则2014

1、工业指南非青霉素&内酰胺类药品防止交叉污染的指导原则目录I. 简介II. 背景III. 建议Youcanuseanalternativeapproachiftheapproachsatisfiestherequirementsoftheapplicablestatutesandregulations.Ifyouwanttodiscussanalternativeapproach,contacttheFDAstaffresponsibleforimplementingthisguidance.IfyoucannotidentifytheappropriateFDAstaff,calltheapp

2、ropriatenumberlistedonthetitlepageofthisguidance.本指南代表当前FDA对本议题的看法。本指南并不授予任何人任何特权，也不对FDA或公众起任何约束作用。如果有替代的方法能满足法律法规的要求，则可以使用该替代方法。如果想要讨论替代方法，请与FDA负责实施该指南的工作人员联系。如果不能与指定的合适FDA工作人员联系，请拨打该指南标题页列出的电话号码。I. INTRODUCTIONI.简介Thisguidancedescribestheimportanceofimplementingmanufacturingcontrolstopreventcross-

3、contaminationoffinishedpharmaceuticalsandactivepharmaceuticalingredients(APIs)withnon-penicillinbeta-lactamdrugs.Thisguidancealsoprovidesinformationregardingtherelativehealthriskof,andthepotentialfor,cross-reactivityintheclassesofsensitizingbeta-lactams(includingbothpenicillinsandnon-penicillinbeta-

4、lactams).Finally,thisguidanceclarifiesthatmanufacturersgenerallyshouldutilizeseparatefacilitiesforthemanufactureofnon-penicillinbeta-lactamsbecausethosecompoundsposehealthrisksassociatedwithcross-reactivity.本指南描述了对非青霉素b内酰胺类成品和原料药的生产过程进行控制，以防止交叉污染的重要性。本指南也提供了有关不同类别致敏性伊内酰胺类药品(包括青霉素类和非青霉素类)发生交叉反应的可能性及其

5、相对健康风险信息。最后，本指南阐明生产商通常应利用单独的生产设备来生产非青霉素S内酰胺类药品，因为此类化合物会对健康造成交叉反应的风险。Drugcross-contaminationisthecontaminationofonedrugwithoneormoredifferentdrugs.Penicillincanbeasensitizingagentthattriggersahypersensitiveexaggeratedallergicimmuneresponseinsomepeople.Accordingly,implementingmethodsforpreventingcross

6、-contaminationofotherdrugswithpenicillinisakeyelementofmanufacturingpenicillinandcurrentgoodmanufacturingpractice(CGMP)regulationsrequiretheuseofsuchmethods.See,e.g.,21CFR211.42(d),211.46(d),and211.176.Non-penicillinbeta-lactamdrugsalsomaybesensitizingagentsandcross-contaminationwithnon-penicillinbe

7、ta-lactamdrugscaninitiatethesametypesofdrug-inducedhypersensitivityreactionsthatpenicillinscantrigger,includinglife-threateningallergicreactions.Therefore,manufacturersofnon-penicillinbeta-lactamdrugsshouldemploysimilarcontrolstrategiestopreventcross-contamination,therebyreducingthepotentialfordrug-

8、induced,life-threateningallergicreactions.药品交叉污染指一种药品对另一种或其他多种药品造成的污染。青霉素是一种会引起一些人发生过激过敏免疫反应的敏化剂。因此，生产青霉素类药物时采取措施以防止其他药品与青霉素间的交叉污染是一个关键因素，现行药品生产管理规范也要求实施此类措施，见21CFR211.42(d),211.46(d),以及211.176。非青霉素&内酰胺类药品也可能是敏化剂，被其污染可能会引起造成与青霉素类药物相同的超敏反应，包括可能危及生命的过敏反应。因此，非青霉素伊内酰胺类药品的生产商应采取类似的控制措施以防止交叉污染，减少药品引起的危及生命

9、的过敏反应的可能性。TheinformationinthisguidanceisintendedformanufacturersoffinishedpharmaceuticalsandAPIs,includingrepackagers.Otherestablishmentsthathandledrugs,suchaspharmacycompounders,mayfindthisinformationuseful.本指南的信息主要用于成品和原料药的生产商，包括再包装商。对其他药物处理机构，如药物配制商等也有用处。FDAsguidancedocuments,includingthisguidanc

10、e,donotestablishlegallyenforceableresponsibilities.Instead,guidancedocumentsdescribetheAgencyscurrentthinkingonatopicandshouldbeviewedonlyasrecommendations,unlessspecificregulatoryorstatutoryrequirementsarecited.TheuseofthewordshouldinFDAguidancemeansthatsomethingissuggestedorrecommended,butnotrequi

11、red.FDA的指南文件，包括本指南，无法律责任约束力。指南文件描述的是FDA现在对某一问题的看法，应被视为对这些问题的建议，除非指南文件参考了特定法律法规的要求。FDA指南中should一词表示要求，只是建议或意见，并非强制要求。II. BACKGROUNDII.目兄A. RegulatoryFrameworkA.法规框架Section501(a)(2)(B)oftheFederalFood,Drug,andCosmeticAct(21U.S.C.351(a)(2)(B)requiresthat,withfewexceptions,alldrugsbemanufacturedincompli

12、ancewithcurrentgoodmanufacturingpractices(CGMPs).DrugsthatarenotincompliancewithCGMPsareconsideredtobeadulterated.Furthermore,finishedpharmaceuticalsarerequiredtocomplywiththeCGMPregulationsat21CFRparts210and211.联邦食品药品和化妆品法案(21U.S.C.351(a)(2)(B)中501(a)(2)(B)部分要求：除少数例外情况外，所有药品生产都应符合现行药品生产质量管理规范(CGMPs

13、)。不符合该要求的将被视为假药。止匕外，成品药应符合联邦法规第21章中第210和211部分对CGMP方面的要求。SeveralCGMPregulationsdirectlyaddressfacilityandequipmentcontrolsandcleaning.Forexample,211.42(c)requiresbuildingandfacilitycontrolsingeneraltopreventcross-contaminationofdrugproducts.Specifically,theregulationstates,thereshallbeseparateordefin

14、edareasorsuchothercontrolsystemsforthefirmoperationsasarenecessarytopreventcontaminationormix-upsduringmanufacturing,processing,packaging,storage,andholding.一些CGMP法规对设施和设备的控制和清洁有直接规定。比如211.42(c戌求对建筑物和设施应进行控制，以防止药品的交叉污染。该法规尤其指出，在生产、加工、包装、储存和处理过程中，应有独立或特定的区域或其他类似控制系统来防止污染或混淆”Withrespecttopenicillin,21

15、1.42(d)requiresthatoperationsrelatingtothemanufacture,processing,andpackingofpenicillinshallbeperformedinfacilitiesseparatefromthoseusedforotherdrugproductsforhumanuse.However,FDAha;clarifiedthatseparatebuildingsmaynotbenecessary,providedthatthesectionofthemanufacturingfacilitydedicatedtomanufacturi

16、ngpenicillinisisolated(i.e.,completelyandcomprehensivelyseparated)fromtheareasofthefacilityinwhichnon-penicillinproductsaremanufactured.2Under211.46(d),manufacturersmustcompletelyseparateairhandlingsystemsforpenicillinfromthoseusedforotherdrugsforhumanuse.Additionally,211.176requiresmanufacturerstot

17、estnon-penicillindrugproductsforpenicillinwherethepossibilityofexposuretocross-contaminationexists,andprohibitsmanufacturersfrommarketingsuchproductsifdetectablelevelsofpenicillinarefound.对于青霉素，211.42(d)要求与青霉素生产、加工和包装有关的操作必须与其他生产人用药品的场所分开。”但是，FDA也指出，如果用于生产青霉素的生产设施能与生产非青霉素产品的区域相隔离(完全和全面隔开)，那么就不一定非要采用

18、独立的建筑。211.46(d)规定，生产商必须将青霉素空调系统与其他人用药品的完全分开。止匕外，211.176还规定生产商应对可能与青霉素存在交叉污染的非青产品进行青霉素检测，并禁止销售检测出青霉素的其他药品。AlthoughFDAhasnotissuedCGMPregulationsspecifictoAPIs,theAgencyhasprovidedguidancetoAPImanufacturersintheguidanceforindustry,ICHQ7,GoodManufacturingPracticeGuidanceforActivePharmaceuticalIngredien

19、ts(ICHQ7guidance).BecausesomeAPIsaresensitizingcompoundsthatmaycauseanaphylacticshock,preventingcross-contaminationinAPIsisasimportantaspreventingcross-contaminationinfinishedproducts.TheICHQ7guidancerecommendsusingdedicatedproductionareas,whichcanincludefacilities,airhandlingequipmentandprocessinge

20、quipment,intheproductionofhighlysensitizingmaterials,suchaspenicillinsandcephalosporins.尽管FDA还未颁布过针对原料药的CGMP法规，但对原料药生产商提供过行业指南ICHQ7原料药GMP指南（ICHQ7指南）。由于一些原料药是可能引起过敏性休克的敏化剂，防止原料药的交叉污染和防止成品的交叉污染同样重要。ICHQ7指南建议使用特定的生产区来生产青霉素和头抱菌素等高致敏性材料，包括使用单独的生产场所、空气处理设备和加工设备。B. Beta-LactamAntibioticsB.伊内酰胺类抗生素Beta-lact

21、amantibiotics,includingpenicillinsandthenon-penicillinclasses,shareabasicchemicalstructurethatincludesathree-carbon,one-nitrogencyclicaminestructureknownasthebeta-lactamring.Thesidechainassociatedwiththebeta-lactamringisavariablegroupattachedtothecorestructurebyapeptidebond;thesidechainvariabilityco

22、ntributestoantibacterialactivity.Asofthedateofthispublication,FDAhasapprovedover34beta-lactamcompoundsasactiveingredientsindrugsforhumanuse.7Beta-lactamantibioticsincludethefollowingfiveclasses8:3内酰胺类抗生素，包括青霉素和非青霉素类，共有一个含3个C和一个N的环状氨基伊内酰胺环。与3内酰胺相关的侧链为可变基团，通过肽链和主体结构相连。侧链的变化可影响抗生素的抗菌活性。截至本指南文件发布之日，FDA已

23、批准了超过34种伊内酰胺类成分作为人用药物的活性成分。伊内酰胺类抗生素包括以下五类：penicillins（e.g.,ampicillin,oxacillin）青霉素类（如青霉素、苯唾西林）cephalosporins（e.g.,cephalexin,cefaclor法抱菌素类（如头抱氨苇、头抱克洛）penems（e.g.,imipenem,meropenem盾霉烯类，即碳青霉烯类（如亚胺培南、美罗培南）carbacephems（e.g.,loracarbe嬲头抱烯类（如氯碳头抱）monobactams（e.g.,aztreonam用环菌素类，即单环0内酰胺类（如氨曲南）Allergicrea

24、ctionsassociatedwithpenicillinsandnon-penicillinbeta-lactamsrangefromrashestolife-threateninganaphylaxis.ImmunoglobulinE（IgE）antibodiesmediatetheimmediatehypersensitivityreactionsthatareresponsibleforthesymptomsofhayfever,asthma,hives,andanaphylacticshock.IgE-mediatedhypersensitivityreactionsareofpr

25、imaryconcernbecausetheymaybeassociatedwithsignificantmorbidityandmortality.ThereisevidencethatpatientswithahistoryofhypersensitivitytopenicillinmayalsoexperienceIgE-mediatedreactionstootherbeta-lactams,suchascephalosporinsandpenems.青霉素类和非青霉素类&内酰胺类抗生素可能引发包括从皮疹到危及生命的过敏症等不用程度的过敏反应。其中由免疫球蛋白E(IgE)介导的超敏反应

26、相关症状主要包括枯草热、哮喘、尊麻疹以及过敏性休克，这类超敏反应由于发病率和死亡率高，是使用&内酰胺抗生素最应关注的问题。有证据证明，有青霉素过敏史的患者在使用头抱菌素类和青霉烯抗生素时也可能发生这类IgE介导的超敏反应。Allnon-penicillinbeta-lactamsalsohavethepotentialtosensitizeindividuals,andsubsequentexposuretopenicillinmayresultinsevereallergicreactionsinsomepatients.Althoughthefrequencyofhypersensitiv

27、ityreactionsduetocross-reactivitybetweenbeta-lactamclassescanbelowerthantheriskwithinaclass,thehazardposedispresentandpotentiallylife-threatening.Thepotentialhealthhazardofnon-penicillinbeta-lactamsthereforeissimilartothatofpenicillins.Furthersimilaritiesbetweennon-penicillinbeta-lactamsandpenicilli

28、nsareasfollows:所有非青霉素&内酰胺类抗生素都可能导致部分个体敏化，当再使用青霉素时部分患者可能会出现严重的过敏反应。尽管不同类的伊内酰胺类抗生素间发生交叉反应导致过敏反应的发生频率要比同类&内酰胺类抗生素间的风险低，但是产生的危害仍然存在并且可能危及生命。因此，这种菲青霉素伊内酰胺类抗生素的潜在风险是和青霉素类抗生素相似，两类抗生素的的相似之处还包括：Itisdifficulttodefinetheminimaldosebelowwhichallergicresponsesareunlikelytooccurinhumans.Thereisalackofsuitableanim

29、alorreceptortestingmodelsthatarepredictiveofhumansensitivity.Thethresholddoseatwhichallergenicresponsecouldoccurisextremelylowanddifficulttodetectwithcurrentanalyticalmethods.难以确定人不发生过敏反应的最大剂量。缺乏能预测人体过敏反应的动物或受体试验模型。发生过敏反应的阈剂量很低，按现有分析方法难以进行检测。Whilebeta-lactamantibioticsaresimilartooneanotherinmanyway

30、s,theymaydifferinpharmacokinetics,antibacterialactivity,andpotentialtocauseseriousallergicreactions.Becauseallergytestingmethodshavenotbeenwell-validated,itisclinicallydifficulttodeterminetheoccurrenceandrateofcross-reactivitybetweenbeta-lactamantibioticsinhumans.Therefore,undiagnosedorunderreported

31、casesofcross-reactivitylikelyexist.Somebeta-lactamantibioticshavenegligiblepotentialforcross-reactivitywithbeta-lactamsofotherclasses,whereasotherbeta-lactamcompoundsmayexhibitsensitizingactivityasderivativesbeforetheincorporationofsidechainsthatconferantibacterialactivity.尽管&内酰胺类抗生素在很多方面彼此都很相似，但在药代

32、动力学、抗菌行为和导致严重过敏反应的可能性上可能有所分别。由于目前过敏检测的方法都缺乏充分的验证，在临床上很难对伊内酰胺类抗生素间是否会发生人体交叉反应及其发生的概率进行检测。因此可能会存在临床上未诊断处或未汇报的交叉反应情形。一些&内酰胺类抗生素和其他类别的伊内酰胺类抗生素的交叉反应风险可以忽略不计，但是别的伊内酰胺类抗生素和引入抗菌活性的侧链前的衍生物一样可能表现出致敏性能。Regardlessoftherateofcross-reactivitybetweenbeta-lactamdrugsorthemechanismofactionbywhichsuchcross-reactivity

33、mayoccur,thepotentialhealthrisktopatientsindicatesthatdrugmanufacturersshouldtakestepstocontrolfortheriskofcross-contaminationforallbeta-lactamproducts.不管B内酰胺类药物之间发生交叉反应的频率或可能导致交叉反应的机理活动如何，潜在的患者健康风险要求生产商对所有的B内酰胺类产品都应采取措施以控制交叉污染的风险。C. Beta-LactamaseInhibitorsC.的酰胺类抑制剂Beta-lactamcompoundssuchasclavula

34、nicacid,tazobactam,andsulbactamhaveweakantibacterialactivitybutareirreversibleinhibitorsofmanybeta-lactamases.Thesecompounds,whicharepotentialsensitizingagents,aretypicallyusedincombinationwithspecificbeta-lactamagentstopreserveantibacterialactivity(e.g.,amoxicillin-clavulanate,piperacillin-tazobact

35、am).Becausethesecompoundsarealmostalwaysusedincombinationwithspecificbeta-lactamagents,anyclinicalobservationsofhypersensitivityreactionslikelywouldbeattributedtothebeta-lactamantibioticcomponentratherthantheinhibitor.Althoughtherehavebeennocasereportsconfirminganaphylacticreactionstoabeta-lactamase

36、inhibitorthatisalsoabeta-lactam,thesecompoundsarepotentiallysensitizingagents,andmanufacturersshouldimplementcontrolstoreducetheriskofcross-contaminationwithbeta-lactamaseinhibitorsaswithallotherbeta-lactamproducts.克拉维酸、三咏巴坦和舒巴坦等3内酰胺组分的抗菌活性较弱，但是对许多3内酰胺酶有不可逆的抑制作用。这些潜在的致敏原组分，典型地与特定的3内酰胺药物结合使用以保护其抗菌活性(

37、例如：阿莫西林-克拉维酸、哌拉西林-三咏巴坦)。由于这些组分经常和一些3内酰胺类抗生素仪器使用，过敏反应临床观察更愿意将这些组分归至3内酰胺类抗生素，而不是归至抑制剂。尽管没有过敏反应病例报告证明3内酰胺酶抑制剂也是3内酰胺类抗生素，这些组分依然存在潜在的致敏性可能。生产商应该采取同其他3内酰胺产品同样的控制措施，以降低3内酰胺酶抑制剂的交叉污染风险。D. Beta-LactamIntermediatesandDerivativesD.B内酰胺类中间体和衍生物Somebeta-lactamintermediatecompoundsandderivativesalsopossesssimilar

38、sensitizationandcross-reactivityproperties.Beta-lactamintermediatecompoundsusuallyareAPIprecursormaterialsthatundergomolecularchangeorpurificationbeforeuseinthemanufactureofbeta-lactamantibioticAPIs.Asaresultofthesechanges,theintermediatecompoundsmaydevelopantigeniccharacteristicsthatcanproducealler

39、gicreactions.Forexample,6-aminopenicillanicacid(6-APA)servesastheintermediatefortheformationofallsyntheticpenicillinsthatareformedbyattachingvarioussidechains.Thestructureof6-APAincludesunbrokenbeta-lactamandthiazolidinerings.Thebeta-lactamringisrelativelyunstable,anditcommonlybreaksopen.Inthecaseof

40、6-APA,thisbreakageleadstotheformationofapenicilloylmoiety,whichisthemajorantigenicdeterminantofpenicillin.Thismoietyisthoughttobeacommoncauseofpenicillinurticarialreaction.17Degradationof6-APAcanalsoresultintheformationofminorantigenicdeterminants,includingpenicilloicacids,penaldicacid,andpenicillam

41、ine.AnaphylacticreactionstopenicillinsusuallyareduetothepresenceofIgEantibodiestominordeterminantsinthebody.Although6-APAisnotatrueantibiotic,itstillcarrieswithitapotentialtoinduceallergenicity.一些B内酰胺类抗生素中间体和衍生物也具有类似的致敏性和交叉反应性。B内酰胺类抗生素中间体一般是原料药的前体，这些成分经过分子结构改变或纯化后可用于B内酰胺类抗生素原料药的生产。这些改变的结果可能导致中间体组分具有

42、抗原性和致敏性。例如，6-氨基青霉烷酸（6-APA）是合成青霉素类药物的中间体，青霉素类药物就是由这种中间体和各类侧链结合在一起反应而成。6-APA的结构包括一个未被破坏的B内酰胺环和一个嚷吵烷环，其中B内酰胺环并不稳定,容易断裂。对于6-APA,B内酰胺环打开后可以形成青霉嚷吵基，这是青霉素过敏的重要抗原决定簇，被认为是青霉素引发尊麻疹反应的主要原因。6-APA的降解还可能形成一些次要抗原决定簇，包括青霉素裂解酸、青霉醛酸和青霉胺。青霉素类抗生素的过敏反应主要是针对次要抗原决定簇的IgE抗体介导的，因此，尽管6-APA并不是一种真正意义上的抗生素，但是仍然具有导致过敏反应的风险。Deriva

43、tivesareunintendedby-productsthatoccurduringthemanufacturingprocess（i.e.,animpurityordegradant）.Likeintermediates,beta-lactamderivativescouldhavesensitizingpropertiesandmaydevelopantigenicpropertiesthatcanproduceallergicreactions.Beta-lactamchemicalmanufacturingprocessesincluding,butnotlimitedto,fer

44、mentationandsynthesis,maycreatebeta-lactamintermediatesorderivativeswithunknownhealthconsequences.Althoughthehealthriskofsensitizationandcross-reactionisdifficulttopredetermineforbeta-lactamintermediatesandderivativesandisnotalwayswell-defined,manufacturingcontrolsintendedtoreducetheriskofcross-cont

45、aminationshouldbeconsideredforoperationsthatproducebeta-lactamintermediatesorderivatives.衍生物是在生产过程中产生的非预期性副产物（如：杂质或降解产物）。和中间体类似，B内酰胺类抗生素的衍生物也具有致敏性，并可能形成导致过敏反应的抗原性。B内酰胺化学生产过程包括但不限于：发酵和化学合成，这些过程可能会产生对健康有未知的不良后果的B内酰胺中间体或衍生物。尽管B内酰胺中间体和衍生物的致敏作用和交叉反应的健康风险难以预测，也不能充分定义，B内酰胺中间体或衍生的生产操作应该加以控制以降低交叉污染的风险。III.RE

46、COMMENDATIONSIII.建议Becauseofthepotentialhealthrisksassociatedwithcross-reactivity(cross-sensitivity)ofbeta-lactams,manufacturersshouldassessandestablishstringentcontrols(includingappropriatefacilitydesignprovisionsassuringseparation)topreventcross-contamination.JustasFDAconsiderstheseparationofprodu

47、ctionfacilitiesforpenicillinstobecurrentgoodmanufacturingpractice,FDAexpectsmanufacturerstotreatsensitizingnon-penicillinbeta-lactam-basedproductssimilarly.Specifically,FDArecommendsthatmanufacturersestablishappropriateseparationandcontrolsystemsdesignedtopreventtwotypesofcontamination:(1)thecontami

48、nationofanon-penicillinbeta-lactambyanyothernon-penicillinbeta-lactam,and(2)thecontaminationofanyothertypeofproductbyanon-penicillinbeta-lactam.Accordingly,FDArecommendsthattheareainwhichanyclassofsensitizingbeta-lactamismanufacturedbeseparatedfromareasinwhichanyotherproductsaremanufactured,andhavea

49、nindependentairhandlingsystem.由于B内酰胺类抗生素的这些由交叉反应(交叉过敏)引发的健康风险，生产商在生产非的酰胺类药物时必须评估和采用紧急控制预防这类交叉污染，(比如采用适当的场所设计确保B内酰胺类抗生素和其它药物的生产场所能够相互独立)。正如FDA在CGMP中要求对青霉素类抗生素采用单独的生产场所，FDA希望生产商操作含致敏性非的酰胺类成分的药物时能采取类似的处理方法。FDA还推荐生产商采取适当的隔离和控制系统设计预防以下类型的交叉污染：(1)非的酰胺类抗生素污染另外的非汕酰胺类抗生素；(2)非B内酰胺类抗生素污染其它类型的药物。因此，FDA建议任何致敏性汕酰胺类抗生素生产区域应与其它类型药品生产区域隔离开，并采用单独的空气处理系统。Aswithpenicillin,thesectionofafacilitydedicatedtomanufacturingasensitizingnon-penicillinbeta-lactamshouldbeisolated（i.e.,complete