HACCP风险评估报告样板

DocumentN/Ame文件名称RiskAssessmentReportforPediatricSulfamethoxazole,SulfdiazineandTrimethoprimGranulesProcess

小儿双磺甲氧苄啶颗粒工艺风险评估报告DocumentNo.文件号Page页码RA-001-00PagePAGE15ofNUMPAGES63RiskAssessmentReportforPediatricSulfamethoxazoleSulfdiazineandTrimethoprimGranulesProcess小儿双磺甲氧苄啶颗粒工艺风险评估报告ReportApproval报告批准Company/Title公司/职务Name姓名Signature签名Date日期Writtenby编写Austar/ValidationEngineer奥星/验证工程师智晓日Reviewedby审核Approvedby

批准RevisionHistory版本修订索引Rev.版本Date日期RevisionReasons修订原因00InitialIssue首次颁布

Index目录TOC\o"1-2"\h\z\u1 Purpose目的 42 Scope范围 43 Responsibility职责 44 RegulationandGuidance法规和指南 65 Abbreviations缩略语 76 SystemDescription系统描述 86.1PlantDescription车间概述 86.2ProductInformation产品信息 87 ReferenceDocuments参考文件 188 RiskAssessmentMethod风险评估方法 198.1ConductaHazardAnalysis进行危害分析 198.2DeterminetheCriticalControlpoints(CCPs)关键控制点的确认 228.3EstablishTargetLevelsandCriticalLimits建立目标水平和关键限值 238.4EstablishSystem(s)tomonitoringCCP建立CCP监测系统 248.5EstablishanappropriateCorrectiveActionPlan建立适当的纠正计划 248.6EstablishProcedures建立规程 258.7EstablishDocumentationandkeeprecords建立文件并保留记录 269 RiskAssessmentMatrix风险评估矩阵 2810 Conclusion结论&建议 66

Purpose目的Thepurposeofthisprocessriskassessmentistoevaluate,define,anddocumentallpotentialhazardandcriticalcontrolpointsforPediatricSulfamethoxazole,SulfdiazineandTrimethoprimGranulesProcessinOralDosagePlantofXXXbyapplyingtheprincipleofICHQ9(QualityRiskManagement)andriskmanagementtoolofHazardAnalysisandCriticalControlPoint(HACCP).Thisassessmentactivityistoensurethattheproductscanbemanufacturedunderappropriatecontrolandsafetymethod,andprovidessupporttodefineprocesscriticalcontrolpointsofPediatricSulfamethoxazole,SulfdiazineandTrimethoprimGranulesProcess.

本工艺风险评估的目的是应用ICHQ9（质量风险管理）的原则以及使用危害分析和关键控制点（HACCP）的风险管理工具评估确定出XXX公司口服制剂车间小儿双磺甲氧苄啶颗粒生产工艺中所有的潜在危险和关键控制点，并记录在文件中。以保证具有适宜的控制，并以安全的方式生产该产品。这种评估行为针对小儿双磺甲氧苄啶颗粒的生产工艺关键控制点的制定提供了支持。Scope范围TheriskassessmentscopeisthePediatricSulfamethoxazole,SulfdiazineandTrimethoprimGranulesProcessinOralDosagePlantofXXXX.TheProductCode:1594.

本工艺风险评估的范围为XXXX车间小儿双磺甲氧苄啶颗粒，产品代码为1594。Responsibility职责Austarresponsibility奥星的职责：Riskassessmentexecution

进行风险评估RiskAssessmentReportcompilation

风险评估报告的编写XXXresponsibilityXXX的职责：ToassurethatdetailedknowledgeandspecificskilloftheproductareavailableforeffectivelydevelopingtheHACCPplanfordisciplineteams.Teammembersshouldrepresentalltherelevantdisciplines,suchasresearchanddevelopment,production,qualitycontrol,qualityassurance,microbiology,engineeringandshipmentorothersasapplicablewiththeabilityto:确保具有产品的详细知识和专业技术，用以各专业组开发有效地危害分析和关键工艺控制点的计划。小组成员应代表研发，生产，质量控制，质量保证，微生物学，工程和发货以及其他相关领域能力。Conductahazardanalysis

实施危害分析Identifypotentialhazards

识别潜在的危害Identifyhazardswhichshouldbecontrolled

识别应该控制的危害Recommendcontrolsandcriticallimits

建议的控制和关键限度Designproceduresformonitoringandverification

监测和确认的设计程序Recommendappropriatecorrectiveactionforoccurreddeviation

对发生的偏差推荐合适的纠正措施verifytheHACCPplan

确认危害分析和关键控制点计划Otherresponsibilities:其它职责Informationcollection

信息的收集Supplyallprocedure,data,manuals,drawinganddocumentationnecessaryforthecompletionoffinalreport

提供为报告编写所需要的所有的规程、数据、手册、图纸和文件TakingpartintheRA

参与风险评估Reviewandapprovethereport

报告的审核和批准RegulationandGuidance法规和指南(CFDA)GMP(2010Revision)

(CFDA)GMP(2010年修订版)ICHHarmonizedTripartiteGuidelineQualityRiskManagementQ9

ICH质量风险管理三方协调指导原则Q9ISPEGuidelineVolume7,Risk-BasedManufactureofPharmaceuticalProducts,1stEdition,2010ISPE指南7“基于风险分析的制药产品生产”，2010年第一版WHOTechnicalReportseriesNo.908,2003,Annex7WHO技术报告系列No.908，2003，附录7

Abbreviations缩略语Abbreviations缩略语Definition定义RARiskAssessment

风险分析QRMQualityRiskManagement质量风险管理HACCPHazardAnalysisandCriticalControlPoints危害分析和关键控制点CCPCriticalControlPoints关键控制点SOPStandardOperatingProcedure标准操作规程PWPurifiedWater纯化水

SystemDescription系统描述6.1PlantDescription车间概述XXXX6.2ProductInformation产品信息6.2.1ProductName产品名称：GeneralName:PediatricSulfamethoxazole,SulfdiazineandTrimethoprimGranules通用名称：小儿双磺甲氧苄啶颗粒EnglishName:PediatricSulfamethoxazole,SulfdiazineandTrimethoprimGranules英文名称：小儿双磺甲氧苄啶颗粒Pinyin:Xiao’erShuanghuangjiayangbiandingKeli汉语拼音：Xiao’erShuanghuangjiayangbiandingKeliDosage:Granules剂型：颗粒剂6.2.2Description描述：ActivityingredientsofthisproductareSulfamethoxazole(SMZ),Sulfadiazine(SD),Trimethoprim(TMP).本品主要成份为磺胺甲噁唑(SMZ)，磺胺嘧啶(SD)，甲氧苄啶(TMP)。Chemicalstructuralformula化学结构式：(SMZ)(SD)(TMP)MolecularFormula:（SMZ）C10H11N3O3S(SD)C10H10N4O2S(TMP)C14H18N4O3分子式：（SMZ）C10H11N3O3S(SD)C10H10N4O2S(TMP)C14H18N4O3MolecularWeight分子量：(SMZ)253.28(SD)250.28(TMP)290.326.2.3Character:Whitegranules.

性状：本品为白色的颗粒。6.2.4Methodofcleaning.Donotusecleanagent,andusePWdriect.

不使用清洁剂，直接用纯化水冲洗。6.2.5GrindingandsievingThreerawmaterialsshouldbegrindingandsievingwith80meshsieve,andsucroseneedbegrindingseperatelyandsievingwith80meshsieve.AlltheotherexcipientsexceptSilicashouldbesievingwith80meshsieveseperately.

本品3种原料需经粉碎并80目筛，蔗糖需单独粉碎并过80目筛，除二氧化硅外其他辅料筛分过80目筛。6.2.6PVerifythattheper-blendingoperationsareconformingtotheGMPrequirementsand10-12minper-blendingcanensurethecontentuniformityofgranuleisconformingtotherequirements.确认预混过程符合GMP的要求，预先混合10-12min以保证最终颗粒的含量均匀性达到要求。6.2.7SolutionPreparationAddthesameamountsofPWandsugar，essenceusedforsolutionpreparationintojacketedpot,andheatingthemwithsteam.Thenletitcooldowntoroomtemperatureandpouritintostainlesssteelbucketforuse.

将浆用蔗糖、香精和等量纯化水倒入夹层锅，通蒸汽加热配浆，然后放冷至室温，倒入洁净不锈钢桶中待用。6.2.8DryingSuckthewetgranulesaftersortingintoboilinggranulatorandturnonheatwindtokeeptemperatureinsideofthefluidbedwithin38~60℃inordertodrythegranules,testwatercontentofthedehydratedgranuletocheckthedehydrationefficacy.

将整粒后的湿颗粒吸入沸腾制粒机，开启热风保持床内温度38~60℃烘干颗粒并对水分进行测定，以确定颗粒的干燥效果。6.2.9BlendingMixingrotationalspeedis8rpm，andmixingtimeisvalidatedduringprocessvalidationwhichtakeassaysampleat5min,10min,15mintovalidatebestmixingtime.

混合转速为8rpm，混合时间在工艺阶段进行验证，可在5min,10min,15min分别取样检测含量以确定最佳混合时间。6.2.10PIncludinginnerpackagingandexternalpackaging.InnerpackagingwillbeperformedunderclassDcleanarea.Fillblendinggranulesintocomplexfilmbagsbygranulesfillingmachine,andduringfillingprocessfilledquantityandapperancewillbechecked.Externalpackagingincludingcartonning,strapping,sealingandpacking,willbeperformedundergeneralarea.

包装分内包和外包。内包在D级洁净区完成，使用颗粒分装机把总混后的颗粒装入复合膜小袋中，分装期间对装量、外观进行检测。外包在一般区进行，完成装盒、捆扎、封箱、打包。6.2.11Semi-finishedproductstoredinstainlesssteelbucket,whichlabeledwithstatusidentification,andkeptunderclassDcleanarea.Sulfadiazineshallbeprotectedfromlightduringgrindingandweighingprocess.

中间产品在不锈钢桶中密封，挂好状态标示牌，D级洁净区保存。磺胺嘧啶在粉碎、称量过程中要避光。

6.2.12Items项目Specification规格Strength规格containing0.1gsulfamethoxazole(SMZ),0.1gsulfadiazineand40mgmethoxybenzylaminopyrimidine

磺胺甲噁唑0.1g，磺胺嘧啶0.1g,甲氧嘧啶40mgPackageMaterials包装材料Pharmaceuticalcomplexfilmsmallbagforsealing

药用复合膜小袋封装ExpiryDate有效期Temporary24months暂定24个月NationalMedicinePermitNo.:国药准字H13023581ProductCode产品代码1594Specification执行标准TheNationaldrugstandardsoftheSFDA：QS-10001-(HD-1065)-2002国家药品监督管理局国家药品标准WS-10001-(HD-1065)-20026.2.13IntendeduseTotreatUrinarytractinfection,enteralinfection,respiratorytractInfection,meningitis,tympanitis,furuncleandsepticemiacausedbysensitivebacteria.用于敏感菌所致的尿路感染、肠道感染、呼吸道感染以及脑膜炎、中耳炎、痈肿及败血症等。

6.2.14TestItems检验项目In-house内控标准Q/HYGJ03.05.1001-2001TheNationaldrugstandardsoftheSFDA：WS-10001-(HD-1065)-2002国家药品监督管理局国家药品标准WS-10001-(HD-1065)-2002Character

形状Whitegranules

本品为白色的颗粒Whitegranules

本品为白色的颗粒Identification1

鉴别1Formedorangeredprecipitation

应生产橙红色沉淀Formedorangeredprecipitation

应生产橙红色沉淀Identification2

鉴别2Appearedscarlet

应显深红色Appearedscarlet

应显深红色Identification2

鉴别3Theretentiontimeofmainpeaksofsulfamethoxazole(SMZ),sulfadiazineandmethoxybenzylaminopyrimidineinsampleshouldbecorrespondingtotheoneofreferencesubstance.

供试品中磺胺甲噁唑、磺胺嘧啶、甲氧苄啶主峰的保留时间应与对照品主峰的保留时间一致Theretentiontimeofmainpeaksofsulfamethoxazole(SMZ),sulfadiazineandmethoxybenzylaminopyrimidineinsampleshouldbecorrespondingtotheoneofreferencesubstance.

供试品中磺胺甲噁唑、磺胺嘧啶、甲氧苄啶主峰的保留时间应与对照品主峰的保留时间一致Sulfamethoxazole(SMZ)assay

磺胺甲噁唑含量93.0~107.0%90.0~110.0%Sulfadiazineassay

磺胺嘧啶含量93.0~107.0%90.0~110.0%Methoxybenzylaminopyrimidineassay

甲氧苄啶含量93.0~107.0%90.0~110.0%Lossondrying%

干燥失重%≤1.7≤2.0Contentuniformity%

装量差异%±6.5±7Particlesize

粒度%≤13≤15Bacterial

细菌数≤500cfu/g≤1000cfu/gFungiandmolds

霉菌和酵母菌数≤50cfu/g≤100cfu/gE.coli

大肠埃希菌Absent

不得检出Absent

不得检出Moldyandacarid

霉变、活螨Absent

不得检出Absent

不得检出6.2.15FlowChart

磺胺甲噁唑磺胺嘧啶甲氧苄啶枸橼酸钠粉碎称量80目磺胺甲噁唑磺胺嘧啶甲氧苄啶枸橼酸钠粉碎称量80目处理后物料二氧化硅筛分称量处理后物料40目混合机预混10-12min预混物料琼脂、甜菊素、筛分称量80目处理后物料蔗糖糖粉称量粉碎80目湿法制粒机混合5-8min混合物蔗糖、香精纯化水糖浆夹层锅配浆80目过筛湿法制粒机制粒3-10min湿颗粒湿法整粒机整粒8.0×8湿整后颗粒干颗粒沸腾制粒机38℃~6振荡筛筛分12:60目整粒后颗粒小袋小盒包装小盒、说明书捆扎机捆扎捆扎膜颗粒分装机分装、控制装量差异中包装成品装箱、称重、打包箱皮总混后颗粒混合机混合10min装盒机装盒复合膜称量粉碎、80目氯化钠sodiumchlorideSulfamethoxazole;sodiumchlorideSulfamethoxazole;Suafadiazin;trimethoprimSodiumcitratecrushdispensing80meshmaterialafterdealwithSilica;Siftingdispensingmaterialafterdealwith40meshMixerPre-mix10-12minMatrialafterpre-mixsiftingdispensing80meshmaterialafterdealwithsugarSugarcrushdispensing80meshWetgranulatorMixingfor5-8minMixedmaterialSugaressencepurifiedwatersyrupJacketedKettleMakesyrupsieving80meshWetguanulator3-10minWetgranuleWetsievingaperture8*8mmSievinggranuleDrygranuleFBD38~60sieving12:60meshQualifiedgranuleBagsCartonCarton,leafletStrappingmachineStrapfilmpackingInterproductFinishedproductBoxing,weightingBoxskinFinalgranulemixing10minCartonermachineComplexfilmAgarSteviosincrushdispensing80mesh6.3Equipments/SystemList设备/系统清单No.序号EquipmentName设备名称TypeMode规格型号Quantity数量1Sievingmachine

筛分机S2012Grindingmachine

粉碎机DWM10013Grindingandweighingintegrativemachine

粉碎称量一体机50B-1.5t14Jacketedpot

夹层锅150L-B15Wetgranulator

湿法制粒机HSZ600B16Boilinggranulator

沸腾制粒机FS300B17Vibrationsievingmachine

震荡筛分机ZS80018Pyramidblender

方锥混合机HF-300019Granulebagfillingmachine

颗粒条包分装机TM80-12110Cartonningmachine

装盒机C200111Boxcheckweigher

小盒检重秤Versaweigh112Strappingmachine

捆扎机PEWO-Pack250CK113Sealing,weighingandpackingmachine

封箱称重打包机N/A1

ReferenceDocuments参考文件DocumentName

文件名称DocumentNo.

文件号Pediatricsulfamethoxazolesulfadiazineandtrimethoprimgranulein-housestandard

小儿双磺甲氧苄啶颗粒企业标准Q/HYGJ03.05.1001-2011sFDAdrugstandard

国家药品监督管理局国家药品标准WS-10001-(HD-1065)-2002Pediatricsulfamethoxazolesulfadiazineandtrimethoprimgranuleprocessprocedure

小儿双磺甲氧苄啶颗粒工艺规程Q/HYGJ05.01.1001-2011Semi-finishedproductspecificationforpediatricsulfamethoxazolesulfadiazineandtrimethoprimgranule

小儿双磺甲氧苄啶颗粒中间产品质量标准Q/HYGJ06.02.1001-2011VMPoforaldosageplant

口服制剂车间验证主计划VMP-KF-2011-00

RiskAssessmentMethod风险评估方法8.1ConductaHazardAnalysis进行危害分析Riskevaluationcomparestheidentifiedandanalyzedriskagainstgivenriskcriteria.Itdeterminesthequalityoftheoutput.风险评估将所识别和分析的风险与给定的风险标准进行对比，确定生产产品的质量。8.1.1HazardIdentificationIdentifyallpotentialhazardsthatmaybereasonablyexpectedtooccurateachstepfromproduction,testinganddistributiontothepointofuse.对各个生产工序中所有可能发生的偏差进行识别。8.1.2HazardAnalysis危害分析Atwo-stagehazardanalysisistobecarriedout.Duringthefirststage,theteamwillreviewthematerials,activities,equipment,storage,distributionandintendeduseoftheproduct.Alistofthepotentialhazards(biological,chemicalandphysical)whichmaybeintroduced,increasedorcontrolledineachstepwillbedrawnup.开展两个阶段的危害分析，在第一阶段中，评估团队将审核产品的物料，活动，设备，储存，分发和预计用途。每一步骤将写出可能引入、增加或控制的潜在的危害（生物、化学和物料）的清单。Inthehazardanalysis,thefollowingshouldbeincludedwhereverpossible:在危害分析中，可能包括下述问题：theprobableoccurrenceofhazardsandtheseverityoftheiradversehealtheffects;可能发生的危害及其危害健康的严重性；thequalitativeand/orquantitativeevaluationofthepresenceofhazards;危害存在的定性和/或定量评估；thesurvivalormultiplicationofmicroorganismsofconcern;相关微生物的残存或繁殖；theproductionorpresentindrugsoftoxins,chemicalsorphysicalagents;毒性，物理或化学试剂的生产或在药品中的残留；theconditionsleadingtotheabove.上述内容的引导条件。Duringthesecondstage,ahazardevaluationwillbeconducted,i.e.theseverityofthepotentialhazardsandtheprobabilityoftheiroccurrencewillbeestimated.第二阶段，危害评估的执行，即，潜在危害的严重性和发生的可能性的评估。TheteamwillthendecidewhichpotentialhazardswillbeaddressedintheHACCPplan,andwhatcontrolmeasures,ifany,existthatcanbeappliedforeachhazard.Morethanonecontrolmeasuremayberequiredtocontrolaspecifichazard(s)andmorethanonehazardmaybecontrolledbyaspecifiedcontrolmeasure.评估团队将决定在关键工艺控制点计划中说明存在有哪些潜在的危害，采取什么控制措施，如果存在，可以应用于每个危害。控制一个具体的危害可能要求至少一个控制措施，一个具体的控制措施可能控制多个危害。Potentialhazardsinrelationtoatleastthefollowingistobeconsidered:潜在的危害至少要考虑以下因素：materialsandingredients;原辅料；physicalcharacteristicsandcompositionoftheproduct;物理特性和产品的组成；processingprocedures;加工过程；microbiallimits,whereapplicable;微生物限度，如果适用；premises;厂房设施；equipment;设备；packaging;包装；sanitationandhygiene;消毒和卫生；personnel;人员；riskofexplosions;暴露风险；mix-ups.混淆。8.1.2.1HazardEvaluation

危害评估Possibility可能性Possibilityofhazard,likedeviationordefect

发生偏差或缺陷等危害的可能性。High:operationrangeisclosetosettinglimit,orparameterrangeisnarrow,andparameterisdifficulttocontrol.Deviationfromtherangemayoccurevenundernormalcondition.高：操作范围接近于设定范围，或参数范围比较窄，参数本身较难控制。正常情况下也可能会偏离范围。Medium:operationrangeisclosetosettinglimit,orparameterrangeiswide,andparameteriseasytocontrol.Deviationfromtherangemayoccuronlyunderabnormalcondition.中：操作范围接近于设定范围，或参数范围比较宽，参数本身比较容易控制。异常情况下才会偏离范围。Low:operationrangeisfarnarrowtosettinglimit,orparameterrangeiswide.Deviationfromtherangemayoccuronlyunderemergencycondition.低：操作范围远比设定范围窄，或参数范围比较宽，紧急情况下才会偏离设计空间。SeverityRating严重性Impactofhazardonproductquality发生危害后对产品质量的影响程度。High:impacttoproductquality,whichmustbecontrolledstrictlytoensurethequality.Deviationfromparameterrangeiscriticaldeviation高：对产品质量有影响，必须严格控制才能保证质量，参数偏离范围为重大偏差。Medium:middleimpacttoproductquality,maindeviationmayoccurunlessstrictlycontrolistaken.中：对产品质量可能有影响。不严格控制会出现主要偏差。Low:minorimpacttoproductquality,deviationfromparameterrangeisminordeviation.低:对产品质量影响很小，参数偏离范围为次要偏差。Theseverityandprobabilityratingwillbecombinedtoevaluatecriticality.Thefollowingmethodwillbeusedtodefinethecriticality.将把严重性和可能性合在一起来评价关键性。将采用如下方法来确定关键性：HighSeverity严重性高Potential-Critical潜在关键Critical关键Critical关键MediumSeverity严重性中等Non-Critical非关键Potential-Critical潜在关键Critical关键LowSeverity严重性低Non-Critical非关键Non-Critical非关键Potential-Critical潜在关键LowPossibility可能性低MediumPossibility可能性中等HighPossibility可能性高Thepurposedofevaluationistodefinecritical,potential-criticalandnoncriticalforeachcriticalprocessandfacility.Areasonableproposalshouldbegivenforcriticalandpotential-criticalcontrolpoints,appropriatecontrolmethodmustbedecidedforcriticalcontrolpoint.评估的目的，是对每个关键工序和设施中确定关键、潜在关键和非关键。关键控制点和潜在关键控制点需要给出合理建议，关键控制点需确定适宜的控制方法。8.2DeterminetheCriticalControlpoints(CCPs)关键控制点的确认DeterminationofCCPwilldependontheoperationconcerned,e.g.production,packing,reprocessing,storage,distribution.Ifahazardhasbeenidentifiedatastepwherecontrolisnecessaryforsafety,andnocontrolmeasureexistsatthatstep,oranyother,theproductorprocessshouldbemodifiedatthatstep,oratanearlierorlaterstage,toincludesuchacontrolmeasure.关键控制点的确认将取决于相关的操作，例如，生产、包装、再加工、储存、发放。如果已经在一个步骤中识别出危害需要安全方面的控制措施，并且在这步骤中并不存在控制措施，或者在其他情况下，产品和工艺在那一步骤中需要修改，或在早期或晚期阶段，也应该包括这样的控制措施。8.3EstablishTargetLevelsandCriticalLimits建立目标水平和关键限值Criticallimitswillbespecifiedandverified,ifpossible,foreachcriticalcontrolpoint.Morethanonecriticallimitmaysometimesbeelaboratedataparticularstep.Thecriteriausedusuallyincludemeasurementsoftemperature,time,moisturelevel,pH,andsensoryparameters,suchasvisualappearanceandtexture.Criticallimitswillbebasedonscience.将对关键限度进行规定和确认，如果可能的话，对每一个关键控制点进行确认。在一个特殊的步骤有时可能超过一个关键限度，通常使用的标准包括温度、时间、水分、pH，和感官参数，例如外观和质感。关键限度必须基于科学的原理。TargetLevelsandCriticalLimitsmustbeestablishedforcriticalcontrolpoints.对判定为关键的控制点必须建立目标水平和关键限值。8.4EstablishSystem(s)tomonitoringCCP建立CCP监测系统ThemonitoringproceduresusedmustbeabletodetectthecontroldeficiencyofCCP,andthisinformationshouldbeavailableintimetomakeadjustmentstoensurecontroloftheprocessandpreventviolationsofthecriticallimits.However,processadjustmentsshouldbemadewhenmonitoringresultsindicateatrendtowardslossofcontrolataCCP.Theseadjustmentsshouldbemadebeforeadeviationoccurs.采用的检测程序必须能检测到关键控制点控制的缺失，并且应能及时了解这些信息进行调整，以确保工艺的控制和避免超出关键限度。然而，当监测到关键控制点缺失的趋势出现时，应该调整工艺，这些调整应该在偏差发生前进行。MonitoringDatamustbeevaluatedbyadesignatedpersonwiththeknowledgeandauthoritytocarryoutcorrectiveactionswhenindicated.监测的数据必须由指定的具有专业知识和授权的，执行纠正措施的人进行评估。Monitoringmeasureforcriticalcontrolpointmustbedefinedandperformed.AllrecordsanddocumentsassociatedwithmonitoringCCPsmustbesignedanddatedbytheperson(s)carryingoutthemonitoringandbyaresponsiblereviewingperson(s)ofthecompany.对关键控制点制定监控措施并执行。所有的监测关键控制点的相关记录和文件必须由执行监测的人员和审核人员签名和日期。8.5EstablishanappropriateCorrectiveActionPlan建立适当的纠正计划SpecificcorrectiveactionsshouldbedevelopedforeachCCPinordertodealwithdeviationswhentheyoccur.TheseactionsshouldensurethattheCCPisundercontrol.为了在偏差发生时能够及时进行处理，必须开发每一个关键控制点的具体的纠正措施，这些措施应该确保关键控制点在控制中。Correctiveactionsshouldincludeatleastthefollowing:纠正措施应该至少包括以下内容：(a)verificationandcorrectionofthecauseofnon-compliance;(a)不符合性原因的确认和纠正；(b)verificationofthedispositionoftherejectedproduct;(b)不合格产品处理的确认；(c)recordsofthecorrectiveactionsthathavebeentaken.(c)已经采取的纠正措施的记录。Appropriatecorrectiveactionforeachcriticalcontrolpointshouldbeestablishedtoensuredeviationoccurredincriticalcontrolpointcanbecorrectedintime.应当对建立的每一个关键控制点制定纠正措施，关键控制点出现偏差时能及时的被纠正。8.6EstablishProcedures建立规程ProcedureofmonitoringmeasureshallbedraftedtoensuretheeffectiveoperationofHACCPsystem.Verificationandauditingmethods,proceduresandtests,includingrandomsamplingandanalysis,canbeusedtodeterminewhetherthesystemisworkingcorrectly.Thefrequencyofverificationshouldbesufficienttoconfirmtheproperfunctioningofthesystem.应该起草危害分析分析和关键控制点系统监测措施程序，以确保其有效的运行。确认和审计方法，程序和测试，包括随机取样和分析，可以用于确认系统是否正常的工作。应该有充分的确认频率以确保系统功能的正确性。Examplesofverificationactivitiesmayinclude,butnotlimitedto:确认活动的例子可能包括，但不局限于：reviewoftheHACCPsystemanditsrecords;危害分析和关键控制点系统及其记录的审核；reviewofdeviationsandproductdispositions;产品处理和偏差的审核；confirmationthatCCPsarekeptundercontrol.关键控制点的确认必须在控制中进行。8.7EstablishDocumentationandkeeprecords建立文件并保留记录Efficientandaccuratedocumentationandrecordshouldbekept.Examplesofactivitiesforwhichdocumentationisrequiredmayinclude,butnotlimitedto:应该保留有效的和精确的文件和记录。文件要求的活动的例子可能包括，但不限于：hazardanalysis;危害分析；CCPdetermination;关键控制点的确认；HACCPplan;危害分析和关键控制点计划；criticallimitdetermination.关键限度的确认。Examplesofactivitiesforwhichrecordsarerequiredinclude:

要求记录的活动的例子包括：CCPmonitoringactivities;关键控制点监测活动；processsteps;工艺步骤；associatedhazards;相关的危害；criticallimits;关键的限度；verificationproceduresandschedule;程序和时间表的确认；deviations;偏差；associatedcorrectiveactions;相关的纠正措施；modificationstotheHACCPsystem.危害分析和关键控制点体系的修改。Relevantprocedureshallbefollowedforqualityriskmanagementactivities,andrelevantdocumentationandrecordshallbekeptastheevidenceofimplementation.应当按照规程进行质量风险管理工作并保留文件和记录来证明实施了风险控制措施。DocumentN/Ame文件名称RiskAssessmentReportforPediatricSulfamethoxazole,SulfdiazineandTrimethoprimGranulesProcess

小儿双磺甲氧苄啶颗粒工艺风险评估报告DocumentNo.文件号Page页码RA-001-00PagePAGE61ofNUMPAGES61RiskAssessmentMatrix风险评估矩阵No.序号ProcessStep(Area)工艺步骤（区域）Description描述PossibleDeviation可能发生的偏差SPCriticality关键性ControlMeasure控制措施ControlRange/Limit控制范围/限度MonitoringProcedure监测程序CorrectiveAction纠正措施Document&Record文件和记录备料1Grindingandsieving(ClassDarea)

粉碎、过筛（D级区）Therawmaterialandsugarshouldgrindwith80meshsieve.theothermaterialexceptSilicaonlysievedwith80mesh.

原料、蔗糖均粉碎过80目筛。其他辅料,除二氧化硅过40目，过80目筛Contaminatedduringexposureprocess

暴露过程污染产品MMPotentialcritical

潜在关键Controlpressuredifferentialandcleanness

控制房间压差及房间洁净度ClassDstandard

D级洁净区标准CompileSOP制定SOPMaterialsdispensingisnotapproved

禁止投料Batchrecordandsuperviserecord

批记录监控记录Sievebreakingaftergrindingandsieving

粉碎、过筛后筛网损坏MHCCPCheckingbeforeandaftergrindingandsieving

粉碎、过筛前后均检查。Integrityandnobreakage

完整、无破损CompileSOP制定SOPMaterialsdispensingisnotapproved禁止投料BatchRecord批记录Wrongsievingmeshspecification

筛网规格错误LHPotentialcritical

潜在关键Checkingsievingmesh

检查筛网目数80目CompileSOP制定SOPMaterialsdispensingisnotapproved禁止投料BatchRecord批记录Wrongmaterials

原辅料错误LHPotentialcritical

潜在关键Checkingbeforeusing

使用前检查NACompileSOP制定SOPMaterialsdispensingisnotapproved禁止投料BatchRecord

Inletandoutletoftransfermaterialsrecord批记录中转物料进出记录Noprotectionfromlightduringsulfapyridineproducingprocess

磺胺嘧啶没有采取避光操作MMPotentialcritical

潜在关键Reducelightbrightnessorreplacethelight

降低灯光亮度、或更换照具N/ACompileSOP制定SOPStopproductionandadoptlight-keepingmeasure

立即停止生产，采取避光措施Batchrecord

批记录Equipmentisoutofcleaningstatus

设备没有处于清洁状态LHPotentialcritical

潜在关键Checkingbeforeusing

使用前检查Cleaningandwithincleaningexpiration

应干净清洁、在清洁有效期内CompileSOP制定SOPRe-clean重新清洗BatchRecordandCleaningRecord批记录清洗记录2Weighing(ClassDarea)

称量（D级区）Weighingmaterialsafterprocessingseparatelyaccordingtodispensing

处理好的物料按每料投料量分别称量Contaminatedunderexposingprocess

暴露过程污染产品LLNon-critical

非关键N/AN/AN/AN/AN/A称量器具没有清洁Weighingutensilisoutofcleaningstatus

称量器具没有处于清洁状态LHPotentialcritical

潜在关键Checkingbeforeusing

使用前检查Cleaningandundercleaningexpiration

应干净清洁、在清洁有效期内CompileSOP制定SOPRe-clean重新清洗Cross-contamination

交叉污染LHPotentialcritical

潜在关键Weighinginstrictaccordancewithweighingprocedure

严格按照物料称量程序进行N/ACompileSOP制定SOPMaterialscannotbereleased.禁止放行Batchrecord

weighingrecord

批记录称量记录Noprotectionfromlightduringsulfapyridineproducingprocess

磺胺嘧啶没有采取避光操作MMPotentialcritical

潜在关键Reducelightbrightnessorreplacethelight

降低灯光亮度、或更换照具N/ACompileSOP制定SOPStopproductionandprotectedfromlight

立即停止生产，采取避光措施Batchrecord

批记录Inaccuracyweighing

称量不准确MHCCPDoublecheck采取双人复核Formulatedamount

处方量CompileSOP制定SOPMaterialscannotbereleased.禁止放行Batchrecord

批记录Weighingsystemdidnotcalibrate

称重系统没有校验LHPotentialcritical

潜在关键Timelycalibrated

应及时校验Routinecalibration:beforeandafterproduction

Periodicallycalibration:AccordingtoSOP

日常校验：生产前后周期性校验：按照SOPCompileSOP制定SOPSystemcannotbeused.禁止使用BatchRecord批记录BatchRecord校验记录Wrongmaterialsstatus

原辅料状态不正确MHCCPConfirmthename,batchno.,strength,quantityofmaterialwhichwaitingfordispensing确认待投料原辅料品名、批号、规格、数量N/ACompileSOP制定SOPMaterialsdispensingisnotapproved禁止投料BatchRecord批记录yieldandrecocilation物料收率及物料平衡率MHCCPPersonneltraining

人员培训物料收率：91.0～100.0%物料平衡率：98.0～100.0%Validateduringprocessvalidation

工艺验证中进行验证Increasetraining

加强培训Batchrecordandprocessvalidationprotocol

批记录工艺验证方案3Pre-mixing(ClassDarea)

预混（D级区）Pre-mixingrawmaterials,silicondioxideandsodiumcitratefor15mininthemixingmachine

湿法制粒前原料需和二氧化硅、枸橼酸钠在混合机预混10-12minWrongpre-mixingtimeandrotationalspeed

预混时间、转速不正确HLPotentialcritical

潜在关键Doublecheck采取双人复核Time:10min

Rotationalspeed:8rpm

时间：10min转速：8rpmCompileSOP制定SOPMaterialscannotbereleased.禁止放行BatchRecordAndProcessValidationProtocol批记录工艺方案Unevenmixing

混合不均匀HMCCPCheckaftermixing

混合完成后检查Uniformcolor

颜色均一Processvalidationprotocol

工艺验证方案Keepmixing

继续混合BatchRecordAndProcessValidationProtocol批记录工艺验证方案Equipmentisoutofcleaningstatus

设备没有处于清洁状态LHPotentialcritical

潜在关键Checkbeforeusing

使用前检查Cleaningandwithincleaningexpiration

应干净清洁、在清洁有效期内CompileSOP制定SOPRe-clean重新清洗BatchRecordandCleaningRecord批记录清洗记录4Drymixing

(ClassD)

干混（D级区）加粘合剂前混合8minWrongmixingtimeandrotationalspeed

预混时间、转速不正确，混合时间、转速不正确LHPotentialcritical

潜在关键Doublecheck采取双人复核Time:8min

Rotationalspeed:80rpm

时间：8min转速：80rpmCompileSOP制定SOPMaterialscannotbereleased.禁止放行BatchRecordAndProcessValidationProtocol批记录工艺方案Equipmentisoutofcleaningstatus

设备没有处于清洁状态LHPotentialcritical

潜在关键Checkingbeforeusing

使用前检查Cleaningandwithincleaningexpiration

应干净清洁、在清洁有效期内CompileSOP制定SOPRe-clean重新清洗BatchRecordandCleaningRecord批记录清洗记录Contentuniformity

含量均匀性HMCCPSamplingandtest

取样检测RSD≤20%Validatewhenmanufacture

生产中验证Resetthetimeandspeed

调整时间和转速BatchRecord批记录5Adhesivepreparation（GradeD）

粘合剂配制（D级区）Partialsyrupandappropriateamountofwatertomakebond

部分糖浆和适量水配成糖浆做粘合剂使用Equipmentisoutofcleaningstatus

设备没有处于清洁状态LHPotentialcritical

潜在关键Checkingbeforeusing

使用前检查Cleaningandwithincleaningexpiration

应干净清洁、在清洁有效期内CompileSOP制定SOPRe-clean重新清洗BatchRecordandCleaningRecord批记录清洗记录Didnotdissolvecompletely

没有完全溶解MHCCPVisuallycheck

目视检查Dissolvecompletelyandnoextraneousmatter

应溶解完全，无异物Validateduringprocessvalidation

工艺验证中进行验证Keepdissolving

继续溶解Batchrecordandprocessvalidationrecord

批记录工艺验证记录UnqualifiedPW

纯化水不合格LHPotentialcritical

潜在关键Routinemonitoring

日常监控PWstandard

纯化水标准CompileSOP制定SOPMaterialscannotbeused.禁止使用BatchRecord批记录6Granulation

(ClassDarea)

制粒（D级区）Addingbondandappropriatewatermakesoftmasstosmallandtightlywetgranule

加入粘合剂和适量水将软材制成小而紧实的湿颗粒Solutionsprayspeed

喷液速度不合适MMPotentialcritical

潜在关键Observationduringprocess

工艺过程中观察N/AProcessValidationProtocol工艺验证方案N/ABatchRecordAndProcessValidationProtocol批记录和工艺验证方案Badqualityofgranulesoftmass

制得的颗粒软材质量不好MHCCPObservationduringprocess

工艺过程中观察Smallandtight

小而紧实Validateduringvalidationprocess

工艺验证中进行验证Materialscannotbeused.禁止使用BatchRecordAndProcessValidationProtocol批记录和工艺验证方案7Wetsorting

(ClassD)

湿法整粒（D级区）Wetsortingthroughwetgranulatemachine,8*8meshsievingtomakegranulesizeuniformly

将湿颗粒通过湿法整粒机，8*8目筛网整粒，使颗粒大小基本一致Equipmentisoutofcleaningstatus

设备没有处于清洁状态LHPotentialcritical

潜在关键Checkingbeforeusing

使用前检查Cle