HACCP風(fēng)險(xiǎn)評(píng)估報(bào)告樣板

DocumentN/Ame文件名稱RiskAssessmentReportforPediatricSulfamethoxazole,SulfdiazineandTrimethoprimGranulesProcess

小兒雙磺甲氧芐啶顆粒工藝風(fēng)險(xiǎn)評(píng)估報(bào)告DocumentNo.文件號(hào)Page頁(yè)碼RA-001-00PagePAGE15ofNUMPAGES63RiskAssessmentReportforPediatricSulfamethoxazoleSulfdiazineandTrimethoprimGranulesProcess小兒雙磺甲氧芐啶顆粒工藝風(fēng)險(xiǎn)評(píng)估報(bào)告ReportApproval報(bào)告批準(zhǔn)Company/Title公司/職務(wù)Name姓名Signature簽名Date日期Writtenby編寫Austar/ValidationEngineer奧星/驗(yàn)證工程師智曉日Reviewedby審核Approvedby

批準(zhǔn)RevisionHistory版本修訂索引Rev.版本Date日期RevisionReasons修訂原因00InitialIssue首次頒布

Index目錄TOC\o"1-2"\h\z\u1 Purpose目的 42 Scope范圍 43 Responsibility職責(zé) 44 RegulationandGuidance法規(guī)和指南 65 Abbreviations縮略語(yǔ) 76 SystemDescription系統(tǒng)描述 86.1PlantDescription車間概述 86.2ProductInformation產(chǎn)品信息 87 ReferenceDocuments參考文件 188 RiskAssessmentMethod風(fēng)險(xiǎn)評(píng)估方法 198.1ConductaHazardAnalysis進(jìn)行危害分析 198.2DeterminetheCriticalControlpoints(CCPs)關(guān)鍵控制點(diǎn)的確認(rèn) 228.3EstablishTargetLevelsandCriticalLimits建立目標(biāo)水平和關(guān)鍵限值 238.4EstablishSystem(s)tomonitoringCCP建立CCP監(jiān)測(cè)系統(tǒng) 248.5EstablishanappropriateCorrectiveActionPlan建立適當(dāng)?shù)募m正計(jì)劃 248.6EstablishProcedures建立規(guī)程 258.7EstablishDocumentationandkeeprecords建立文件并保留記錄 269 RiskAssessmentMatrix風(fēng)險(xiǎn)評(píng)估矩陣 2810 Conclusion結(jié)論&建議 66

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

本工藝風(fēng)險(xiǎn)評(píng)估的目的是應(yīng)用ICHQ9（質(zhì)量風(fēng)險(xiǎn)管理）的原則以及使用危害分析和關(guān)鍵控制點(diǎn)（HACCP）的風(fēng)險(xiǎn)管理工具評(píng)估確定出XXX公司口服制劑車間小兒雙磺甲氧芐啶顆粒生產(chǎn)工藝中所有的潛在危險(xiǎn)和關(guān)鍵控制點(diǎn)，并記錄在文件中。以保證具有適宜的控制，并以安全的方式生產(chǎn)該產(chǎn)品。這種評(píng)估行為針對(duì)小兒雙磺甲氧芐啶顆粒的生產(chǎn)工藝關(guān)鍵控制點(diǎn)的制定提供了支持。Scope范圍TheriskassessmentscopeisthePediatricSulfamethoxazole,SulfdiazineandTrimethoprimGranulesProcessinOralDosagePlantofXXXX.TheProductCode:1594.

本工藝風(fēng)險(xiǎn)評(píng)估的范圍為XXXX車間小兒雙磺甲氧芐啶顆粒，產(chǎn)品代碼為1594。Responsibility職責(zé)Austarresponsibility奧星的職責(zé)：Riskassessmentexecution

進(jìn)行風(fēng)險(xiǎn)評(píng)估RiskAssessmentReportcompilation

風(fēng)險(xiǎn)評(píng)估報(bào)告的編寫XXXresponsibilityXXX的職責(zé)：ToassurethatdetailedknowledgeandspecificskilloftheproductareavailableforeffectivelydevelopingtheHACCPplanfordisciplineteams.Teammembersshouldrepresentalltherelevantdisciplines,suchasresearchanddevelopment,production,qualitycontrol,qualityassurance,microbiology,engineeringandshipmentorothersasapplicablewiththeabilityto:確保具有產(chǎn)品的詳細(xì)知識(shí)和專業(yè)技術(shù)，用以各專業(yè)組開(kāi)發(fā)有效地危害分析和關(guān)鍵工藝控制點(diǎn)的計(jì)劃。小組成員應(yīng)代表研發(fā)，生產(chǎn)，質(zhì)量控制，質(zhì)量保證，微生物學(xué)，工程和發(fā)貨以及其他相關(guān)領(lǐng)域能力。Conductahazardanalysis

實(shí)施危害分析Identifypotentialhazards

識(shí)別潛在的危害Identifyhazardswhichshouldbecontrolled

識(shí)別應(yīng)該控制的危害Recommendcontrolsandcriticallimits

建議的控制和關(guān)鍵限度Designproceduresformonitoringandverification

監(jiān)測(cè)和確認(rèn)的設(shè)計(jì)程序Recommendappropriatecorrectiveactionforoccurreddeviation

對(duì)發(fā)生的偏差推薦合適的糾正措施verifytheHACCPplan

確認(rèn)危害分析和關(guān)鍵控制點(diǎn)計(jì)劃Otherresponsibilities:其它職責(zé)Informationcollection

信息的收集Supplyallprocedure,data,manuals,drawinganddocumentationnecessaryforthecompletionoffinalreport

提供為報(bào)告編寫所需要的所有的規(guī)程、數(shù)據(jù)、手冊(cè)、圖紙和文件TakingpartintheRA

參與風(fēng)險(xiǎn)評(píng)估Reviewandapprovethereport

報(bào)告的審核和批準(zhǔn)RegulationandGuidance法規(guī)和指南(CFDA)GMP(2010Revision)

(CFDA)GMP(2010年修訂版)ICHHarmonizedTripartiteGuidelineQualityRiskManagementQ9

ICH質(zhì)量風(fēng)險(xiǎn)管理三方協(xié)調(diào)指導(dǎo)原則Q9ISPEGuidelineVolume7,Risk-BasedManufactureofPharmaceuticalProducts,1stEdition,2010ISPE指南7“基于風(fēng)險(xiǎn)分析的制藥產(chǎn)品生產(chǎn)”，2010年第一版WHOTechnicalReportseriesNo.908,2003,Annex7WHO技術(shù)報(bào)告系列No.908，2003，附錄7

Abbreviations縮略語(yǔ)Abbreviations縮略語(yǔ)Definition定義RARiskAssessment

風(fēng)險(xiǎn)分析QRMQualityRiskManagement質(zhì)量風(fēng)險(xiǎn)管理HACCPHazardAnalysisandCriticalControlPoints危害分析和關(guān)鍵控制點(diǎn)CCPCriticalControlPoints關(guān)鍵控制點(diǎn)SOPStandardOperatingProcedure標(biāo)準(zhǔn)操作規(guī)程PWPurifiedWater純化水

SystemDescription系統(tǒng)描述6.1PlantDescription車間概述XXXX6.2ProductInformation產(chǎn)品信息6.2.1ProductName產(chǎn)品名稱：GeneralName:PediatricSulfamethoxazole,SulfdiazineandTrimethoprimGranules通用名稱：小兒雙磺甲氧芐啶顆粒EnglishName:PediatricSulfamethoxazole,SulfdiazineandTrimethoprimGranules英文名稱：小兒雙磺甲氧芐啶顆粒Pinyin:Xiao’erShuanghuangjiayangbiandingKeli漢語(yǔ)拼音：Xiao’erShuanghuangjiayangbiandingKeliDosage:Granules劑型：顆粒劑6.2.2Description描述：ActivityingredientsofthisproductareSulfamethoxazole(SMZ),Sulfadiazine(SD),Trimethoprim(TMP).本品主要成份為磺胺甲噁唑(SMZ)，磺胺嘧啶(SD)，甲氧芐啶(TMP)。Chemicalstructuralformula化學(xué)結(jié)構(gòu)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.

性狀：本品為白色的顆粒。6.2.4Methodofcleaning.Donotusecleanagent,andusePWdriect.

不使用清潔劑，直接用純化水沖洗。6.2.5GrindingandsievingThreerawmaterialsshouldbegrindingandsievingwith80meshsieve,andsucroseneedbegrindingseperatelyandsievingwith80meshsieve.AlltheotherexcipientsexceptSilicashouldbesievingwith80meshsieveseperately.

本品3種原料需經(jīng)粉碎并80目篩，蔗糖需單獨(dú)粉碎并過(guò)80目篩，除二氧化硅外其他輔料篩分過(guò)80目篩。6.2.6PVerifythattheper-blendingoperationsareconformingtotheGMPrequirementsand10-12minper-blendingcanensurethecontentuniformityofgranuleisconformingtotherequirements.確認(rèn)預(yù)混過(guò)程符合GMP的要求，預(yù)先混合10-12min以保證最終顆粒的含量均勻性達(dá)到要求。6.2.7SolutionPreparationAddthesameamountsofPWandsugar，essenceusedforsolutionpreparationintojacketedpot,andheatingthemwithsteam.Thenletitcooldowntoroomtemperatureandpouritintostainlesssteelbucketforuse.

將漿用蔗糖、香精和等量純化水倒入夾層鍋，通蒸汽加熱配漿，然后放冷至室溫，倒入潔凈不銹鋼桶中待用。6.2.8DryingSuckthewetgranulesaftersortingintoboilinggranulatorandturnonheatwindtokeeptemperatureinsideofthefluidbedwithin38~60℃inordertodrythegranules,testwatercontentofthedehydratedgranuletocheckthedehydrationefficacy.

將整粒后的濕顆粒吸入沸騰制粒機(jī)，開(kāi)啟熱風(fēng)保持床內(nèi)溫度38~60℃烘干顆粒并對(duì)水分進(jìn)行測(cè)定，以確定顆粒的干燥效果。6.2.9BlendingMixingrotationalspeedis8rpm，andmixingtimeisvalidatedduringprocessvalidationwhichtakeassaysampleat5min,10min,15mintovalidatebestmixingtime.

混合轉(zhuǎn)速為8rpm，混合時(shí)間在工藝階段進(jìn)行驗(yàn)證，可在5min,10min,15min分別取樣檢測(cè)含量以確定最佳混合時(shí)間。6.2.10PIncludinginnerpackagingandexternalpackaging.InnerpackagingwillbeperformedunderclassDcleanarea.Fillblendinggranulesintocomplexfilmbagsbygranulesfillingmachine,andduringfillingprocessfilledquantityandapperancewillbechecked.Externalpackagingincludingcartonning,strapping,sealingandpacking,willbeperformedundergeneralarea.

包裝分內(nèi)包和外包。內(nèi)包在D級(jí)潔凈區(qū)完成，使用顆粒分裝機(jī)把總混后的顆粒裝入復(fù)合膜小袋中，分裝期間對(duì)裝量、外觀進(jìn)行檢測(cè)。外包在一般區(qū)進(jìn)行，完成裝盒、捆扎、封箱、打包。6.2.11Semi-finishedproductstoredinstainlesssteelbucket,whichlabeledwithstatusidentification,andkeptunderclassDcleanarea.Sulfadiazineshallbeprotectedfromlightduringgrindingandweighingprocess.

中間產(chǎn)品在不銹鋼桶中密封，掛好狀態(tài)標(biāo)示牌，D級(jí)潔凈區(qū)保存?；前粪奏ぴ诜鬯?、稱量過(guò)程中要避光。

6.2.12Items項(xiàng)目Specification規(guī)格Strength規(guī)格containing0.1gsulfamethoxazole(SMZ),0.1gsulfadiazineand40mgmethoxybenzylaminopyrimidine

磺胺甲噁唑0.1g，磺胺嘧啶0.1g,甲氧嘧啶40mgPackageMaterials包裝材料Pharmaceuticalcomplexfilmsmallbagforsealing

藥用復(fù)合膜小袋封裝ExpiryDate有效期Temporary24months暫定24個(gè)月NationalMedicinePermitNo.:國(guó)藥準(zhǔn)字H13023581ProductCode產(chǎn)品代碼1594Specification執(zhí)行標(biāo)準(zhǔn)TheNationaldrugstandardsoftheSFDA：QS-10001-(HD-1065)-2002國(guó)家藥品監(jiān)督管理局國(guó)家藥品標(biāo)準(zhǔn)WS-10001-(HD-1065)-20026.2.13IntendeduseTotreatUrinarytractinfection,enteralinfection,respiratorytractInfection,meningitis,tympanitis,furuncleandsepticemiacausedbysensitivebacteria.用于敏感菌所致的尿路感染、腸道感染、呼吸道感染以及腦膜炎、中耳炎、癰腫及敗血癥等。

6.2.14TestItems檢驗(yàn)項(xiàng)目In-house內(nèi)控標(biāo)準(zhǔn)Q/HYGJ03.05.1001-2001TheNationaldrugstandardsoftheSFDA：WS-10001-(HD-1065)-2002國(guó)家藥品監(jiān)督管理局國(guó)家藥品標(biāo)準(zhǔn)WS-10001-(HD-1065)-2002Character

形狀Whitegranules

本品為白色的顆粒Whitegranules

本品為白色的顆粒Identification1

鑒別1Formedorangeredprecipitation

應(yīng)生產(chǎn)橙紅色沉淀Formedorangeredprecipitation

應(yīng)生產(chǎn)橙紅色沉淀Identification2

鑒別2Appearedscarlet

應(yīng)顯深紅色Appearedscarlet

應(yīng)顯深紅色I(xiàn)dentification2

鑒別3Theretentiontimeofmainpeaksofsulfamethoxazole(SMZ),sulfadiazineandmethoxybenzylaminopyrimidineinsampleshouldbecorrespondingtotheoneofreferencesubstance.

供試品中磺胺甲噁唑、磺胺嘧啶、甲氧芐啶主峰的保留時(shí)間應(yīng)與對(duì)照品主峰的保留時(shí)間一致Theretentiontimeofmainpeaksofsulfamethoxazole(SMZ),sulfadiazineandmethoxybenzylaminopyrimidineinsampleshouldbecorrespondingtotheoneofreferencesubstance.

供試品中磺胺甲噁唑、磺胺嘧啶、甲氧芐啶主峰的保留時(shí)間應(yīng)與對(duì)照品主峰的保留時(shí)間一致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

甲氧芐啶含量93.0~107.0%90.0~110.0%Lossondrying%

干燥失重%≤1.7≤2.0Contentuniformity%

裝量差異%±6.5±7Particlesize

粒度%≤13≤15Bacterial

細(xì)菌數(shù)≤500cfu/g≤1000cfu/gFungiandmolds

霉菌和酵母菌數(shù)≤50cfu/g≤100cfu/gE.coli

大腸埃希菌Absent

不得檢出Absent

不得檢出Moldyandacarid

霉變、活螨Absent

不得檢出Absent

不得檢出6.2.15FlowChart

磺胺甲噁唑磺胺嘧啶甲氧芐啶枸櫞酸鈉粉碎稱量80目磺胺甲噁唑磺胺嘧啶甲氧芐啶枸櫞酸鈉粉碎稱量80目處理后物料二氧化硅篩分稱量處理后物料40目混合機(jī)預(yù)混10-12min預(yù)混物料瓊脂、甜菊素、篩分稱量80目處理后物料蔗糖糖粉稱量粉碎80目濕法制粒機(jī)混合5-8min混合物蔗糖、香精純化水糖漿夾層鍋配漿80目過(guò)篩濕法制粒機(jī)制粒3-10min濕顆粒濕法整粒機(jī)整粒8.0×8濕整后顆粒干顆粒沸騰制粒機(jī)38℃~6振蕩篩篩分12:60目整粒后顆粒小袋小盒包裝小盒、說(shuō)明書捆扎機(jī)捆扎捆扎膜顆粒分裝機(jī)分裝、控制裝量差異中包裝成品裝箱、稱重、打包箱皮總混后顆?；旌蠙C(jī)混合10min裝盒機(jī)裝盒復(fù)合膜稱量粉碎、80目氯化鈉sodiumchlorideSulfamethoxazole;sodiumchlorideSulfamethoxazole;Suafadiazin;trimethoprimSodiumcitratecrushdispensing80meshmaterialafterdealwithSilica;Siftingdispensingmaterialafterdealwith40meshMixerPre-mix10-12minMatrialafterpre-mixsiftingdispensing80meshmaterialafterdealwithsugarSugarcrushdispensing80meshWetgranulatorMixingfor5-8minMixedmaterialSugaressencepurifiedwatersyrupJacketedKettleMakesyrupsieving80meshWetguanulator3-10minWetgranuleWetsievingaperture8*8mmSievinggranuleDrygranuleFBD38~60sieving12:60meshQualifiedgranuleBagsCartonCarton,leafletStrappingmachineStrapfilmpackingInterproductFinishedproductBoxing,weightingBoxskinFinalgranulemixing10minCartonermachineComplexfilmAgarSteviosincrushdispensing80mesh6.3Equipments/SystemList設(shè)備/系統(tǒng)清單No.序號(hào)EquipmentName設(shè)備名稱TypeMode規(guī)格型號(hào)Quantity數(shù)量1Sievingmachine

篩分機(jī)S2012Grindingmachine

粉碎機(jī)DWM10013Grindingandweighingintegrativemachine

粉碎稱量一體機(jī)50B-1.5t14Jacketedpot

夾層鍋150L-B15Wetgranulator

濕法制粒機(jī)HSZ600B16Boilinggranulator

沸騰制粒機(jī)FS300B17Vibrationsievingmachine

震蕩篩分機(jī)ZS80018Pyramidblender

方錐混合機(jī)HF-300019Granulebagfillingmachine

顆粒條包分裝機(jī)TM80-12110Cartonningmachine

裝盒機(jī)C200111Boxcheckweigher

小盒檢重秤Versaweigh112Strappingmachine

捆扎機(jī)PEWO-Pack250CK113Sealing,weighingandpackingmachine

封箱稱重打包機(jī)N/A1

ReferenceDocuments參考文件DocumentName

文件名稱DocumentNo.

文件號(hào)Pediatricsulfamethoxazolesulfadiazineandtrimethoprimgranulein-housestandard

小兒雙磺甲氧芐啶顆粒企業(yè)標(biāo)準(zhǔn)Q/HYGJ03.05.1001-2011sFDAdrugstandard

國(guó)家藥品監(jiān)督管理局國(guó)家藥品標(biāo)準(zhǔn)WS-10001-(HD-1065)-2002Pediatricsulfamethoxazolesulfadiazineandtrimethoprimgranuleprocessprocedure

小兒雙磺甲氧芐啶顆粒工藝規(guī)程Q/HYGJ05.01.1001-2011Semi-finishedproductspecificationforpediatricsulfamethoxazolesulfadiazineandtrimethoprimgranule

小兒雙磺甲氧芐啶顆粒中間產(chǎn)品質(zhì)量標(biāo)準(zhǔn)Q/HYGJ06.02.1001-2011VMPoforaldosageplant

口服制劑車間驗(yàn)證主計(jì)劃VMP-KF-2011-00

RiskAssessmentMethod風(fēng)險(xiǎn)評(píng)估方法8.1ConductaHazardAnalysis進(jìn)行危害分析Riskevaluationcomparestheidentifiedandanalyzedriskagainstgivenriskcriteria.Itdeterminesthequalityoftheoutput.風(fēng)險(xiǎn)評(píng)估將所識(shí)別和分析的風(fēng)險(xiǎn)與給定的風(fēng)險(xiǎn)標(biāo)準(zhǔn)進(jìn)行對(duì)比，確定生產(chǎn)產(chǎn)品的質(zhì)量。8.1.1HazardIdentificationIdentifyallpotentialhazardsthatmaybereasonablyexpectedtooccurateachstepfromproduction,testinganddistributiontothepointofuse.對(duì)各個(gè)生產(chǎn)工序中所有可能發(fā)生的偏差進(jìn)行識(shí)別。8.1.2HazardAnalysis危害分析Atwo-stagehazardanalysisistobecarriedout.Duringthefirststage,theteamwillreviewthematerials,activities,equipment,storage,distributionandintendeduseoftheproduct.Alistofthepotentialhazards(biological,chemicalandphysical)whichmaybeintroduced,increasedorcontrolledineachstepwillbedrawnup.開(kāi)展兩個(gè)階段的危害分析，在第一階段中，評(píng)估團(tuán)隊(duì)將審核產(chǎn)品的物料，活動(dòng)，設(shè)備，儲(chǔ)存，分發(fā)和預(yù)計(jì)用途。每一步驟將寫出可能引入、增加或控制的潛在的危害（生物、化學(xué)和物料）的清單。Inthehazardanalysis,thefollowingshouldbeincludedwhereverpossible:在危害分析中，可能包括下述問(wèn)題：theprobableoccurrenceofhazardsandtheseverityoftheiradversehealtheffects;可能發(fā)生的危害及其危害健康的嚴(yán)重性；thequalitativeand/orquantitativeevaluationofthepresenceofhazards;危害存在的定性和/或定量評(píng)估；thesurvivalormultiplicationofmicroorganismsofconcern;相關(guān)微生物的殘存或繁殖；theproductionorpresentindrugsoftoxins,chemicalsorphysicalagents;毒性，物理或化學(xué)試劑的生產(chǎn)或在藥品中的殘留；theconditionsleadingtotheabove.上述內(nèi)容的引導(dǎo)條件。Duringthesecondstage,ahazardevaluationwillbeconducted,i.e.theseverityofthepotentialhazardsandtheprobabilityoftheiroccurrencewillbeestimated.第二階段，危害評(píng)估的執(zhí)行，即，潛在危害的嚴(yán)重性和發(fā)生的可能性的評(píng)估。TheteamwillthendecidewhichpotentialhazardswillbeaddressedintheHACCPplan,andwhatcontrolmeasures,ifany,existthatcanbeappliedforeachhazard.Morethanonecontrolmeasuremayberequiredtocontrolaspecifichazard(s)andmorethanonehazardmaybecontrolledbyaspecifiedcontrolmeasure.評(píng)估團(tuán)隊(duì)將決定在關(guān)鍵工藝控制點(diǎn)計(jì)劃中說(shuō)明存在有哪些潛在的危害，采取什么控制措施，如果存在，可以應(yīng)用于每個(gè)危害?？刂埔粋€(gè)具體的危害可能要求至少一個(gè)控制措施，一個(gè)具體的控制措施可能控制多個(gè)危害。Potentialhazardsinrelationtoatleastthefollowingistobeconsidered:潛在的危害至少要考慮以下因素：materialsandingredients;原輔料；physicalcharacteristicsandcompositionoftheproduct;物理特性和產(chǎn)品的組成；processingprocedures;加工過(guò)程；microbiallimits,whereapplicable;微生物限度，如果適用；premises;廠房設(shè)施；equipment;設(shè)備；packaging;包裝；sanitationandhygiene;消毒和衛(wèi)生；personnel;人員；riskofexplosions;暴露風(fēng)險(xiǎn)；mix-ups.混淆。8.1.2.1HazardEvaluation

危害評(píng)估Possibility可能性Possibilityofhazard,likedeviationordefect

發(fā)生偏差或缺陷等危害的可能性。High:operationrangeisclosetosettinglimit,orparameterrangeisnarrow,andparameterisdifficulttocontrol.Deviationfromtherangemayoccurevenundernormalcondition.高：操作范圍接近于設(shè)定范圍，或參數(shù)范圍比較窄，參數(shù)本身較難控制。正常情況下也可能會(huì)偏離范圍。Medium:operationrangeisclosetosettinglimit,orparameterrangeiswide,andparameteriseasytocontrol.Deviationfromtherangemayoccuronlyunderabnormalcondition.中：操作范圍接近于設(shè)定范圍，或參數(shù)范圍比較寬，參數(shù)本身比較容易控制。異常情況下才會(huì)偏離范圍。Low:operationrangeisfarnarrowtosettinglimit,orparameterrangeiswide.Deviationfromtherangemayoccuronlyunderemergencycondition.低：操作范圍遠(yuǎn)比設(shè)定范圍窄，或參數(shù)范圍比較寬，緊急情況下才會(huì)偏離設(shè)計(jì)空間。SeverityRating嚴(yán)重性Impactofhazardonproductquality發(fā)生危害后對(duì)產(chǎn)品質(zhì)量的影響程度。High:impacttoproductquality,whichmustbecontrolledstrictlytoensurethequality.Deviationfromparameterrangeiscriticaldeviation高：對(duì)產(chǎn)品質(zhì)量有影響，必須嚴(yán)格控制才能保證質(zhì)量，參數(shù)偏離范圍為重大偏差。Medium:middleimpacttoproductquality,maindeviationmayoccurunlessstrictlycontrolistaken.中：對(duì)產(chǎn)品質(zhì)量可能有影響。不嚴(yán)格控制會(huì)出現(xiàn)主要偏差。Low:minorimpacttoproductquality,deviationfromparameterrangeisminordeviation.低:對(duì)產(chǎn)品質(zhì)量影響很小，參數(shù)偏離范圍為次要偏差。Theseverityandprobabilityratingwillbecombinedtoevaluatecriticality.Thefollowingmethodwillbeusedtodefinethecriticality.將把嚴(yán)重性和可能性合在一起來(lái)評(píng)價(jià)關(guān)鍵性。將采用如下方法來(lái)確定關(guān)鍵性：HighSeverity嚴(yán)重性高Potential-Critical潛在關(guān)鍵Critical關(guān)鍵Critical關(guān)鍵MediumSeverity嚴(yán)重性中等Non-Critical非關(guān)鍵Potential-Critical潛在關(guān)鍵Critical關(guān)鍵LowSeverity嚴(yán)重性低Non-Critical非關(guān)鍵Non-Critical非關(guān)鍵Potential-Critical潛在關(guān)鍵LowPossibility可能性低MediumPossibility可能性中等HighPossibility可能性高Thepurposedofevaluationistodefinecritical,potential-criticalandnoncriticalforeachcriticalprocessandfacility.Areasonableproposalshouldbegivenforcriticalandpotential-criticalcontrolpoints,appropriatecontrolmethodmustbedecidedforcriticalcontrolpoint.評(píng)估的目的，是對(duì)每個(gè)關(guān)鍵工序和設(shè)施中確定關(guān)鍵、潛在關(guān)鍵和非關(guān)鍵。關(guān)鍵控制點(diǎn)和潛在關(guān)鍵控制點(diǎn)需要給出合理建議，關(guān)鍵控制點(diǎn)需確定適宜的控制方法。8.2DeterminetheCriticalControlpoints(CCPs)關(guān)鍵控制點(diǎn)的確認(rèn)DeterminationofCCPwilldependontheoperationconcerned,e.g.production,packing,reprocessing,storage,distribution.Ifahazardhasbeenidentifiedatastepwherecontrolisnecessaryforsafety,andnocontrolmeasureexistsatthatstep,oranyother,theproductorprocessshouldbemodifiedatthatstep,oratanearlierorlaterstage,toincludesuchacontrolmeasure.關(guān)鍵控制點(diǎn)的確認(rèn)將取決于相關(guān)的操作，例如，生產(chǎn)、包裝、再加工、儲(chǔ)存、發(fā)放。如果已經(jīng)在一個(gè)步驟中識(shí)別出危害需要安全方面的控制措施，并且在這步驟中并不存在控制措施，或者在其他情況下，產(chǎn)品和工藝在那一步驟中需要修改，或在早期或晚期階段，也應(yīng)該包括這樣的控制措施。8.3EstablishTargetLevelsandCriticalLimits建立目標(biāo)水平和關(guān)鍵限值Criticallimitswillbespecifiedandverified,ifpossible,foreachcriticalcontrolpoint.Morethanonecriticallimitmaysometimesbeelaboratedataparticularstep.Thecriteriausedusuallyincludemeasurementsoftemperature,time,moisturelevel,pH,andsensoryparameters,suchasvisualappearanceandtexture.Criticallimitswillbebasedonscience.將對(duì)關(guān)鍵限度進(jìn)行規(guī)定和確認(rèn)，如果可能的話，對(duì)每一個(gè)關(guān)鍵控制點(diǎn)進(jìn)行確認(rèn)。在一個(gè)特殊的步驟有時(shí)可能超過(guò)一個(gè)關(guān)鍵限度，通常使用的標(biāo)準(zhǔn)包括溫度、時(shí)間、水分、pH，和感官參數(shù)，例如外觀和質(zhì)感。關(guān)鍵限度必須基于科學(xué)的原理。TargetLevelsandCriticalLimitsmustbeestablishedforcriticalcontrolpoints.對(duì)判定為關(guān)鍵的控制點(diǎn)必須建立目標(biāo)水平和關(guān)鍵限值。8.4EstablishSystem(s)tomonitoringCCP建立CCP監(jiān)測(cè)系統(tǒng)ThemonitoringproceduresusedmustbeabletodetectthecontroldeficiencyofCCP,andthisinformationshouldbeavailableintimetomakeadjustmentstoensurecontroloftheprocessandpreventviolationsofthecriticallimits.However,processadjustmentsshouldbemadewhenmonitoringresultsindicateatrendtowardslossofcontrolataCCP.Theseadjustmentsshouldbemadebeforeadeviationoccurs.采用的檢測(cè)程序必須能檢測(cè)到關(guān)鍵控制點(diǎn)控制的缺失，并且應(yīng)能及時(shí)了解這些信息進(jìn)行調(diào)整，以確保工藝的控制和避免超出關(guān)鍵限度。然而，當(dāng)監(jiān)測(cè)到關(guān)鍵控制點(diǎn)缺失的趨勢(shì)出現(xiàn)時(shí)，應(yīng)該調(diào)整工藝，這些調(diào)整應(yīng)該在偏差發(fā)生前進(jìn)行。MonitoringDatamustbeevaluatedbyadesignatedpersonwiththeknowledgeandauthoritytocarryoutcorrectiveactionswhenindicated.監(jiān)測(cè)的數(shù)據(jù)必須由指定的具有專業(yè)知識(shí)和授權(quán)的，執(zhí)行糾正措施的人進(jìn)行評(píng)估。Monitoringmeasureforcriticalcontrolpointmustbedefinedandperformed.AllrecordsanddocumentsassociatedwithmonitoringCCPsmustbesignedanddatedbytheperson(s)carryingoutthemonitoringandbyaresponsiblereviewingperson(s)ofthecompany.對(duì)關(guān)鍵控制點(diǎn)制定監(jiān)控措施并執(zhí)行。所有的監(jiān)測(cè)關(guān)鍵控制點(diǎn)的相關(guān)記錄和文件必須由執(zhí)行監(jiān)測(cè)的人員和審核人員簽名和日期。8.5EstablishanappropriateCorrectiveActionPlan建立適當(dāng)?shù)募m正計(jì)劃SpecificcorrectiveactionsshouldbedevelopedforeachCCPinordertodealwithdeviationswhentheyoccur.TheseactionsshouldensurethattheCCPisundercontrol.為了在偏差發(fā)生時(shí)能夠及時(shí)進(jìn)行處理，必須開(kāi)發(fā)每一個(gè)關(guān)鍵控制點(diǎn)的具體的糾正措施，這些措施應(yīng)該確保關(guān)鍵控制點(diǎn)在控制中。Correctiveactionsshouldincludeatleastthefollowing:糾正措施應(yīng)該至少包括以下內(nèi)容：(a)verificationandcorrectionofthecauseofnon-compliance;(a)不符合性原因的確認(rèn)和糾正；(b)verificationofthedispositionoftherejectedproduct;(b)不合格產(chǎn)品處理的確認(rèn)；(c)recordsofthecorrectiveactionsthathavebeentaken.(c)已經(jīng)采取的糾正措施的記錄。Appropriatecorrectiveactionforeachcriticalcontrolpointshouldbeestablishedtoensuredeviationoccurredincriticalcontrolpointcanbecorrectedintime.應(yīng)當(dāng)對(duì)建立的每一個(gè)關(guān)鍵控制點(diǎn)制定糾正措施，關(guān)鍵控制點(diǎn)出現(xiàn)偏差時(shí)能及時(shí)的被糾正。8.6EstablishProcedures建立規(guī)程ProcedureofmonitoringmeasureshallbedraftedtoensuretheeffectiveoperationofHACCPsystem.Verificationandauditingmethods,proceduresandtests,includingrandomsamplingandanalysis,canbeusedtodeterminewhetherthesystemisworkingcorrectly.Thefrequencyofverificationshouldbesufficienttoconfirmtheproperfunctioningofthesystem.應(yīng)該起草危害分析分析和關(guān)鍵控制點(diǎn)系統(tǒng)監(jiān)測(cè)措施程序，以確保其有效的運(yùn)行。確認(rèn)和審計(jì)方法，程序和測(cè)試，包括隨機(jī)取樣和分析，可以用于確認(rèn)系統(tǒng)是否正常的工作。應(yīng)該有充分的確認(rèn)頻率以確保系統(tǒng)功能的正確性。Examplesofverificationactivitiesmayinclude,butnotlimitedto:確認(rèn)活動(dòng)的例子可能包括，但不局限于：reviewoftheHACCPsystemanditsrecords;危害分析和關(guān)鍵控制點(diǎn)系統(tǒng)及其記錄的審核；reviewofdeviationsandproductdispositions;產(chǎn)品處理和偏差的審核；confirmationthatCCPsarekeptundercontrol.關(guān)鍵控制點(diǎn)的確認(rèn)必須在控制中進(jìn)行。8.7EstablishDocumentationandkeeprecords建立文件并保留記錄Efficientandaccuratedocumentationandrecordshouldbekept.Examplesofactivitiesforwhichdocumentationisrequiredmayinclude,butnotlimitedto:應(yīng)該保留有效的和精確的文件和記錄。文件要求的活動(dòng)的例子可能包括，但不限于：hazardanalysis;危害分析；CCPdetermination;關(guān)鍵控制點(diǎn)的確認(rèn)；HACCPplan;危害分析和關(guān)鍵控制點(diǎn)計(jì)劃；criticallimitdetermination.關(guān)鍵限度的確認(rèn)。Examplesofactivitiesforwhichrecordsarerequiredinclude:

要求記錄的活動(dòng)的例子包括：CCPmonitoringactivities;關(guān)鍵控制點(diǎn)監(jiān)測(cè)活動(dòng)；processsteps;工藝步驟；associatedhazards;相關(guān)的危害；criticallimits;關(guān)鍵的限度；verificationproceduresandschedule;程序和時(shí)間表的確認(rèn)；deviations;偏差；associatedcorrectiveactions;相關(guān)的糾正措施；modificationstotheHACCPsystem.危害分析和關(guān)鍵控制點(diǎn)體系的修改。Relevantprocedureshallbefollowedforqualityriskmanagementactivities,andrelevantdocumentationandrecordshallbekeptastheevidenceofimplementation.應(yīng)當(dāng)按照規(guī)程進(jìn)行質(zhì)量風(fēng)險(xiǎn)管理工作并保留文件和記錄來(lái)證明實(shí)施了風(fēng)險(xiǎn)控制措施。DocumentN/Ame文件名稱RiskAssessmentReportforPediatricSulfamethoxazole,SulfdiazineandTrimethoprimGranulesProcess

小兒雙磺甲氧芐啶顆粒工藝風(fēng)險(xiǎn)評(píng)估報(bào)告DocumentNo.文件號(hào)Page頁(yè)碼RA-001-00PagePAGE61ofNUMPAGES61RiskAssessmentMatrix風(fēng)險(xiǎn)評(píng)估矩陣No.序號(hào)ProcessStep(Area)工藝步驟（區(qū)域）Description描述PossibleDeviation可能發(fā)生的偏差SPCriticality關(guān)鍵性ControlMeasure控制措施ControlRange/Limit控制范圍/限度MonitoringProcedure監(jiān)測(cè)程序CorrectiveAction糾正措施Document&Record文件和記錄備料1Grindingandsieving(ClassDarea)

粉碎、過(guò)篩（D級(jí)區(qū)）Therawmaterialandsugarshouldgrindwith80meshsieve.theothermaterialexceptSilicaonlysievedwith80mesh.

原料、蔗糖均粉碎過(guò)80目篩。其他輔料,除二氧化硅過(guò)40目，過(guò)80目篩Contaminatedduringexposureprocess

暴露過(guò)程污染產(chǎn)品MMPotentialcritical

潛在關(guān)鍵Controlpressuredifferentialandcleanness

控制房間壓差及房間潔凈度ClassDstandard

D級(jí)潔凈區(qū)標(biāo)準(zhǔn)CompileSOP制定SOPMaterialsdispensingisnotapproved

禁止投料Batchrecordandsuperviserecord

批記錄監(jiān)控記錄Sievebreakingaftergrindingandsieving

粉碎、過(guò)篩后篩網(wǎng)損壞MHCCPCheckingbeforeandaftergrindingandsieving

粉碎、過(guò)篩前后均檢查。Integrityandnobreakage

完整、無(wú)破損CompileSOP制定SOPMaterialsdispensingisnotapproved禁止投料BatchRecord批記錄Wrongsievingmeshspecification

篩網(wǎng)規(guī)格錯(cuò)誤LHPotentialcritical

潛在關(guān)鍵Checkingsievingmesh

檢查篩網(wǎng)目數(shù)80目CompileSOP制定SOPMaterialsdispensingisnotapproved禁止投料BatchRecord批記錄Wrongmaterials

原輔料錯(cuò)誤LHPotentialcritical

潛在關(guān)鍵Checkingbeforeusing

使用前檢查NACompileSOP制定SOPMaterialsdispensingisnotapproved禁止投料BatchRecord

Inletandoutletoftransfermaterialsrecord批記錄中轉(zhuǎn)物料進(jìn)出記錄Noprotectionfromlightduringsulfapyridineproducingprocess

磺胺嘧啶沒(méi)有采取避光操作MMPotentialcritical

潛在關(guān)鍵Reducelightbrightnessorreplacethelight

降低燈光亮度、或更換照具N/ACompileSOP制定SOPStopproductionandadoptlight-keepingmeasure

立即停止生產(chǎn)，采取避光措施Batchrecord

批記錄Equipmentisoutofcleaningstatus

設(shè)備沒(méi)有處于清潔狀態(tài)LHPotentialcritical

潛在關(guān)鍵Checkingbeforeusing

使用前檢查Cleaningandwithincleaningexpiration

應(yīng)干凈清潔、在清潔有效期內(nèi)CompileSOP制定SOPRe-clean重新清洗BatchRecordandCleaningRecord批記錄清洗記錄2Weighing(ClassDarea)

稱量（D級(jí)區(qū)）Weighingmaterialsafterprocessingseparatelyaccordingtodispensing

處理好的物料按每料投料量分別稱量Contaminatedunderexposingprocess

暴露過(guò)程污染產(chǎn)品LLNon-critical

非關(guān)鍵N/AN/AN/AN/AN/A稱量器具沒(méi)有清潔Weighingutensilisoutofcleaningstatus

稱量器具沒(méi)有處于清潔狀態(tài)LHPotentialcritical

潛在關(guān)鍵Checkingbeforeusing

使用前檢查Cleaningandundercleaningexpiration

應(yīng)干凈清潔、在清潔有效期內(nèi)CompileSOP制定SOPRe-clean重新清洗Cross-contamination

交叉污染LHPotentialcritical

潛在關(guān)鍵Weighinginstrictaccordancewithweighingprocedure

嚴(yán)格按照物料稱量程序進(jìn)行N/ACompileSOP制定SOPMaterialscannotbereleased.禁止放行Batchrecord

weighingrecord

批記錄稱量記錄Noprotectionfromlightduringsulfapyridineproducingprocess

磺胺嘧啶沒(méi)有采取避光操作MMPotentialcritical

潛在關(guān)鍵Reducelightbrightnessorreplacethelight

降低燈光亮度、或更換照具N/ACompileSOP制定SOPStopproductionandprotectedfromlight

立即停止生產(chǎn)，采取避光措施Batchrecord

批記錄Inaccuracyweighing

稱量不準(zhǔn)確MHCCPDoublecheck采取雙人復(fù)核Formulatedamount

處方量CompileSOP制定SOPMaterialscannotbereleased.禁止放行Batchrecord

批記錄Weighingsystemdidnotcalibrate

稱重系統(tǒng)沒(méi)有校驗(yàn)LHPotentialcritical

潛在關(guān)鍵Timelycalibrated

應(yīng)及時(shí)校驗(yàn)Routinecalibration:beforeandafterproduction

Periodicallycalibration:AccordingtoSOP

日常校驗(yàn)：生產(chǎn)前后周期性校驗(yàn)：按照SOPCompileSOP制定SOPSystemcannotbeused.禁止使用BatchRecord批記錄BatchRecord校驗(yàn)記錄Wrongmaterialsstatus

原輔料狀態(tài)不正確MHCCPConfirmthename,batchno.,strength,quantityofmaterialwhichwaitingfordispensing確認(rèn)待投料原輔料品名、批號(hào)、規(guī)格、數(shù)量N/ACompileSOP制定SOPMaterialsdispensingisnotapproved禁止投料BatchRecord批記錄yieldandrecocilation物料收率及物料平衡率MHCCPPersonneltraining

人員培訓(xùn)物料收率：91.0～100.0%物料平衡率：98.0～100.0%Validateduringprocessvalidation

工藝驗(yàn)證中進(jìn)行驗(yàn)證Increasetraining

加強(qiáng)培訓(xùn)Batchrecordandprocessvalidationprotocol

批記錄工藝驗(yàn)證方案3Pre-mixing(ClassDarea)

預(yù)混（D級(jí)區(qū)）Pre-mixingrawmaterials,silicondioxideandsodiumcitratefor15mininthemixingmachine

濕法制粒前原料需和二氧化硅、枸櫞酸鈉在混合機(jī)預(yù)混10-12minWrongpre-mixingtimeandrotationalspeed

預(yù)混時(shí)間、轉(zhuǎn)速不正確HLPotentialcritical

潛在關(guān)鍵Doublecheck采取雙人復(fù)核Time:10min

Rotationalspeed:8rpm

時(shí)間：10min轉(zhuǎn)速：8rpmCompileSOP制定SOPMaterialscannotbereleased.禁止放行BatchRecordAndProcessValidationProtocol批記錄工藝方案Unevenmixing

混合不均勻HMCCPCheckaftermixing

混合完成后檢查Uniformcolor

顏色均一Processvalidationprotocol

工藝驗(yàn)證方案Keepmixing

繼續(xù)混合BatchRecordAndProcessValidationProtocol批記錄工藝驗(yàn)證方案Equipmentisoutofcleaningstatus

設(shè)備沒(méi)有處于清潔狀態(tài)LHPotentialcritical

潛在關(guān)鍵Checkbeforeusing

使用前檢查Cleaningandwithincleaningexpiration

應(yīng)干凈清潔、在清潔有效期內(nèi)CompileSOP制定SOPRe-clean重新清洗BatchRecordandCleaningRecord批記錄清洗記錄4Drymixing

(ClassD)

干混（D級(jí)區(qū)）加粘合劑前混合8minWrongmixingtimeandrotationalspeed

預(yù)混時(shí)間、轉(zhuǎn)速不正確，混合時(shí)間、轉(zhuǎn)速不正確LHPotentialcritical

潛在關(guān)鍵Doublecheck采取雙人復(fù)核Time:8min

Rotationalspeed:80rpm

時(shí)間：8min轉(zhuǎn)速：80rpmCompileSOP制定SOPMaterialscannotbereleased.禁止放行BatchRecordAndProcessValidationProtocol批記錄工藝方案Equipmentisoutofcleaningstatus

設(shè)備沒(méi)有處于清潔狀態(tài)LHPotentialcritical

潛在關(guān)鍵Checkingbeforeusing

使用前檢查Cleaningandwithincleaningexpiration

應(yīng)干凈清潔、在清潔有效期內(nèi)CompileSOP制定SOPRe-clean重新清洗BatchRecordandCleaningRecord批記錄清洗記錄Contentuniformity

含量均勻性HMCCPSamplingandtest

取樣檢測(cè)RSD≤20%Validatewhenmanufacture

生產(chǎn)中驗(yàn)證Resetthetimeandspeed

調(diào)整時(shí)間和轉(zhuǎn)速BatchRecord批記錄5Adhesivepreparation（GradeD）

粘合劑配制（D級(jí)區(qū)）Partialsyrupandappropriateamountofwatertomakebond

部分糖漿和適量水配成糖漿做粘合劑使用Equipmentisoutofcleaningstatus

設(shè)備沒(méi)有處于清潔狀態(tài)LHPotentialcritical

潛在關(guān)鍵Checkingbeforeusing

使用前檢查Cleaningandwithincleaningexpiration

應(yīng)干凈清潔、在清潔有效期內(nèi)CompileSOP制定SOPRe-clean重新清洗BatchRecordandCleaningRecord批記錄清洗記錄Didnotdissolvecompletely

沒(méi)有完全溶解MHCCPVisuallycheck

目視檢查Dissolvecompletelyandnoextraneousmatter

應(yīng)溶解完全，無(wú)異物Validateduringprocessvalidation

工藝驗(yàn)證中進(jìn)行驗(yàn)證Keepdissolving

繼續(xù)溶解Batchrecordandprocessvalidationrecord

批記錄工藝驗(yàn)證記錄UnqualifiedPW

純化水不合格LHPotentialcritical

潛在關(guān)鍵Routinemonitoring

日常監(jiān)控PWstandard

純化水標(biāo)準(zhǔn)CompileSOP制定SOPMaterialscannotbeused.禁止使用BatchRecord批記錄6Granulation

(ClassDarea)

制粒（D級(jí)區(qū)）Addingbondandappropriatewatermakesoftmasstosmallandtightlywetgranule

加入粘合劑和適量水將軟材制成小而緊實(shí)的濕顆粒Solutionsprayspeed

噴液速度不合適MMPotentialcritical

潛在關(guān)鍵Observationduringprocess

工藝過(guò)程中觀察N/AProcessValidationProtocol工藝驗(yàn)證方案N/ABatchRecordAndProcessValidationProtocol批記錄和工藝驗(yàn)證方案Badqualityofgranulesoftmass

制得的顆粒軟材質(zhì)量不好MHCCPObservationduringprocess

工藝過(guò)程中觀察Smallandtight

小而緊實(shí)Validateduringvalidationprocess

工藝驗(yàn)證中進(jìn)行驗(yàn)證Materialscannotbeused.禁止使用BatchRecordAndProcessValidationProtocol批記錄和工藝驗(yàn)證方案7Wetsorting

(ClassD)

濕法整粒（D級(jí)區(qū)）Wetsortingthroughwetgranulatemachine,8*8meshsievingtomakegranulesizeuniformly

將濕顆粒通過(guò)濕法整粒機(jī)，8*8目篩網(wǎng)整粒，使顆粒大小基本一致Equipmentisoutofcleaningstatus

設(shè)備沒(méi)有處于清潔狀態(tài)LHPotentialcritical

潛在關(guān)鍵Checkingbeforeusing

使用前檢查Cle