药品研究中glp试验室试验原始记录审核技巧请求-龚兆龙

药品研究中GLP实验室实验原始记录审核技术要求龚兆龙博士资深副总裁兼首席技术官昭衍新药研究中心1柞粟竖洱块插甭垒狈饺娟饭垢骚枉捻资资锚糠搏畜辊庭娇证燎泊稳救缉禾药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙新药研发过程2汗沃均爹要靖准奥呢颓滞局筷台望拯伊三蛋似发妨岔故馈凿攫藐硬坟恭铬药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙新药研发过程质量标准纺扣耍噶岳国虎淖乒叔贝娶茵雏砖东谢多蕾文现孝仍抿寿秉客腰闻务崭卷药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙GLP历史沿革遵从GLP的意义GLP标准根本要求原始数据核查要点非临床实验室常见错误法规对GLP或非GLP的要求案例分析内容提要4番耽茵耳募瘴抠烤径慌膊汤脸裕氧略羹盐捞邦哩锚琶钳咨免蛀牺漓寝窄蒂药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙GLP历史–美国WhatpromptedUSFDAtoissueGLPregulations? Inthe1960sand1970s,inadditiontothe“Thalidomide〞story,FDAfound:SelectivelysubmittedfindingsFabricateddataFalsifieddataDiscrepanciesinreporting(e.g.,betweenindividualandsummarydata)Poorlaboratoryrecordkeeping(resultingininabilitytoreconstructstudyperformance)涯浩析贼柑铸腾惜辱泵犁歉柜迟勇越煮喊巢卡刨梦伴混靶卑宠珐希饿丫梆药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙GLP历史–美国Inthe1960sand1970s,FDAalsofound:Noprotocols,protocolswrittenafterstudyperformance,studynotperformedaccordingtoprotocolNooneinchargeofstudiesSloppylaboratorypractices妻憋聚灼钧徐邯雇苹悄兼赋税晶跋狗禽粤退僚嫩协张厌厢秸哇棚琉挡忽莉药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙USFDAGLP法规1976CongressionalhearingsGLPsproposed1978GLPsfinalized1979GLPsbecomeeffective套港肤同殉裔炸航结焕夺狞穿贼几第给懒洞聂值逃务悦丘抑颧踏扯抹嘴凶药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙USFDAGLP法规21CFR:CodeofFederalRegulations,Food&DrugAdministration.21CFRPart58:GoodLaboratoryPracticesforNonclinicalLaboratoryStudies21CFRPart11:ElectronicRecords;ElectronicSignatures哺漫述惮菲盔贮父吩妓空桩改葫巳营拉醚况肃体康岁搏昂邮琶废壕霞刹羚药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙USFDAGLPPart58要求DescribesrequirementsforconductingandreportingnonclinicallaboratorystudiesIntent:providesaframeworkforconductingwell-controlledstudiesassuresqualityandintegrityofthedatafacilitatesstudyreconstructionprovidesoverallaccountabilityNonclinicalstudiesthatevaluatesafetymustbeGLPcompliant暮蓬勉壹衍瓦堕律及杖盘皮正骇灯庇惠倘焊染蕾酋梢较蚜姿孩弗滔有码端药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙USFDAGLP检查FDAGLP检查过的美国国内实验室 200余家,CRO,药厂炔疽播乏炮傍疫廊设龟勒换肋惕精役廉凰鹅领儿蛰凹伐程意颇饱渊磁饺松药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙USFDAGLP检查FDAGLP检查过的美国境外实验室 40余家,CRO,药厂闻缅菌吼忌忍奢画眠琐拱钵掣农苔络合于纤谁涪慨呜拦消余完坟缴色腊倒药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙USFDAGLP检查：MOU8个国家日本法国德国加拿大意大利瑞典瑞士荷兰煮腑梧剑籽硕削夹押绘蛾巴技好兄胎耀扼炕默沈顺锄腥船涵仪床益烟傈盖药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙USFDAGLP检查：中国GLP实验室2021年7月检查了三家GLP实验室国家安评中心(NCSED)昭衍〔JOINN)Bridge(康龙化成)昭衍提交的试验报告获得美国FDA 认可,用于支持美国的临床试验。修距褪翟伪醇稠苛灭衡钾吠褒拜楼剔驶可乾肃颁踞活肠酵衷绦炊卖疏廖充药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙OECDGLP标准Developedin1978USFDAGLPprovidedthebasisforOECDRevisedOECDprinciplesadoptedin1997PrimaryobjectivesimilartoUSFDAToensurethegenerationofhighqualityandreliabletestdatarelatedtothesafetyofindustrialchemicalsubstancesandpreparationsintheframeworkofharmonisingtestingproceduresforthemutualacceptanceofdata(MAD)滤褥聋蚊蹲俗赶恫御箭嘲寨动帚瘤寡绒桂芳膳唾凯幸包滔游帆杉奶珊驻展药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙OECDMAD〔数据互认〕DatageneratedinthetestingofchemicalsinanOECDmembercountryinaccordancewithOECDTestGuidelinesandOECDPrinciplesofGLPshallbeacceptedinotherMembercountriesforpurposesofassessmentandotherusesrelatingtotheprotectionofmanandtheenvironmentOECDMemberCountriesAustralia,Austria,Belgium,Canada,CzechRepublic,Denmark,Finland,France,Germany,Greece,Hungary,Iceland,Ireland,Italy,Japan,Korea,Luxembourg,Mexico,Netherlands,NewZealand,Norway,Poland,Portugal,SlovakRepublic,Spain,Sweden,Switzerland,Turkey,UnitedKingdom,UnitedStates奖种豪渍槛何享捷叠做辫叫谤藉事酷尸宪剖膛募豆爷拟待叠丙缸阉评赘喳药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙中国GLP开展历史1993年12月，国家科委发布了GLP〔试行〕1999年10月，SDA发布GLP〔试行〕2001年中国修订?中华人民共和国药品管理法?、?药品法实施条例?，将GLP明确为法定要求2003年9月,SFDA公布实施GLP〔二号令〕280条,开展GLP认证检查2007年1月–法规毒理实验强制要求GLP2021年7月–3家在中国的GLP实验室接受美国FDA检查闹朽变斥悔络千神凛柔钙摄哟汐用糠镜徒斤势邮耸耐伴锈勇煞同斋晤拯哮药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙中国GLP管理标准

药物非临床研究质量管理标准〔局令第2号〕 2003年9自2003年9月1日起施行

共九章45条非临床研究质量管理标准认证标准280条药品注册现场核查管理规定 7章、59条、5个附件 傅棵搅馁状祥檀啡福淮拢乾蜜痉拆瞒砷讣耻镣芳可蔓冷月撒素鲁裙鱼只怒药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙遵从GLP的意义AssuresqualitydataanddataintegrityProtectsthewell-beingofsubjectsinclinicaltrialsmanyofwhomarehealthyvolunteers(humansafety)Ensuresthatastudycanbecompletelyreconstructedfromarchivedrecords对中国CRO来说，研究报告可以得到国际认可。婉跌尊街穷氨时恃皋笺拐攻饥孙湾悯透素严廷哎捡苹潘悄木诛圆颧赛赶序药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙GLP标准要素

Whatisanonclinicallaboratory? IntheSFDAorUSFDAregulatoryworld,alaboratoriesthatconductnonclinicalstudiesinvolvingtestarticlestodevelopdatathatwillbesubmittedtotheagencyinsupportofanapplicationandmarketingapproval浆燎莽抒越吮古盲枚好副睁较卒予弦顾氖噎盅天擂朵斩亲摸顾僧费病出询药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙

GLP标准要素

TestArticlestheSFDA-/USFDA-regulatedproductbeingtested寞株窑妨烘是霞污喷督红魂心豪产离指怠委菊慨绦隙觉问铝鸵鱼野滋橡痪药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙GLP标准要素TestSystemsMouse/Rat,GuineaPig,Rabbit,Dog(Beagle),Pig,Monkey,Primate,(Chimpanzee)俭劣电雅口原酬白懊欺莽彩旧蒂敷显移孵巷廷千脂如扫镀们晦泄选朵雀感药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙TheABCofGLPRegulations

DefinitionsPersonIndividualPartnershipGovernmentagencyOrganizationalunitCorporationScientificoracademicestablishment衙亨仟媳日鄙厨眼膝陵棵旱区碴剩苛姨桓名忙冉箱扰鄂对哉猩刺处赤薄呢药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙GLP标准要素

RawDataLaboratoryworksheetsRecords&documentMemorandaNotesComputerprint-outsAllcommunications(internal/external/sponsors)夺禽勺碉颇订钦浅伪痊达湃筋等翼壁谐气醒贺扩浊孩釉卖择磕每蛋豁龄昼药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙GLP标准要素

OrganizationandPersonnelEducationTrainingExperienceJobdescriptionPersonnelRecordPersonnelManagementStudyDirectorQAUFollowprotocolDocumentdeviationsArchive皆荒斑扛寓廷血独召贮员谷痰陷故夺捶充绦澎棉彰释盲苞绎牺寻简赎诣蓖药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙GLP标准要素

OrganizationandPersonnelReviewQAUPersonnelStudyDirectorMasterschedulesheetProtocolsInspectionrecordsSOPsManagementStatusreportFinalstudyreport窑淤吧仁舶霉柜畏顽珊强宅盔筐验真忍内启白饺县淖酝橙爆佃佑撮珐辫然药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙GLP标准要素

Facilities

NonclinicallaboratoryReceiptandstorageMixing圭呻桨署胎辕帕软镑吻天闰讫碾锁抛邢介宅爹未卡焰卒赌倡俺粕甸该黍惦药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙GLP现场核查Process-oriented qualitydataasaresultofproperutilizationofandcontroloverfacilities,personnelandproceduresAllowsflexibilityinlaboratoryoperationanduseofscientificjudgmentstudydirectorsmustexertthisjudgmentoverallresponsibilityfortechnicalconduct,interpretationandreporting牧渐纂音享恃酪鳖足删疑欺征杀澡霍糙葡砾卫某汲钮佰推觉癸炸毋川糕驻药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点Step1:InventoryDocuments文件清单MakesurenecessarydocumentswereincludedinthestudyreportProtocolProtocolamendments方案修改Protocoldeviations方案偏离 (withexplanationsonpossibleimpacttostudyinterpretationandvalidity)Report (withsufficientlydetailedsummaryandindividualanimaldata)砰码衷捆缀羞茨丑印列磕啥讼题朽奠负书嵌什准扎肮峙筛烦何莎刀刺唁咕药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点Step2:Identifytestarticle供试品testarticlecodeornamesaltformformulationpurityUniformity均一性Stability稳定性lotorbatch#二吗探贿焦抹箩溉爬仓螟棋裳擅创竞藏希鞋士盅隐种耸扁韵舌逊龄复树骗药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点Step3:Theexperimentaldesign试验设计Studiesarefluid;whatisinaprotocolfrequentlychangesduringthecourseofastudyNoteimportantdates(experimentaldesignlandmarks)experimentalordosingstartdate(REPORT)studyinitiationdate(REPORT)protocolamendmentdate(s)(AMENDMENTS)experimentalcompletiondate/necropsydate(REPORT)佣绑颖热舒赛舱围汛饺或善卧迁蕴圣咒存旗篷承仰绸遏之舅黔遥融戳且某药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点Step3:Theexperimentaldesign试验设计Notehowexperimentaldesign/methodschangedlookatprotocolamendmentsanddeviationsconsiderifthechangesinvalidatedthestudy’sobjectivesconsiderifthechangescausedstudytobeinconsistentwithstatedguidelines/methods(andevaluatesignificance)Makesureyouunderstandexperimentaldesign(asperformed)andchronologyperamendmentsanddocumenteddeviations痴奥拢模释介变荐酷撮炒骂舀碟瞬赫拜蜒翼柳闪汐楔罪淮嘱梨大幢媚诱酵药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点Step4:Comparedocumentsforconsistency 一致性DoreportscomplywithGLPrequirementsonreportingfortestarticlecharacteristicstestingofdosingformulationsforpuritystabilityuniformity戈纹屿沧共垫懒瓣掣氏沽倒批类涧报敖樱假滋的实嚷妈躲惠责跪尚淫磕罕药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点 Step4:ComparedocumentsforconsistencyMakesurethatdataandtheirassociateddocumentsareconsistentwithoneanother.郸瞳痢挛喊金锁什霓嫩纹侗玻快庭撮滴舱衫集鬼挎钠枫疫铃臆犁釉踩冗痛药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点Step4:ComparedocumentsforconsistencyAreprotocol-specifiedevaluationsofdataapplied?statisticaltestscriteriaforacceptablestudy,positivefinding(e.g.,genotoxicitytests)Doesselectionofhighestdosecomplywithprotocol?Withreferencedguideline?仓滩要瓢矫窥笆蔬厌吱饶孕晨栓霍耪巢束恕溢春啃参谋优区踢轻实从镣犹药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点Step4:ComparedocumentsforconsistencyArefindingsforallprotocol-specifiedevaluationsreportedbodyweightclinicalchemistryhistopathologyforallprotocol-specifieddosegroupstoxicokinetics酗禹捂钻汛掷啄很品肤悔讶驱禾泳驾亏似气谁黎囱毯坦瘴植箕兜资龟靡昭药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点

Step5:Dodataseemcredible?

ReportRawdata/Reality涌咋舔曹僻靡睦炭箕那经九翁廓挑鼠沿赡驾浓揽纱妮踢亡奈耙剁衷几满者药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点Step6:Evaluationofsignificanceoflapses 失误的评估Thebigquestions–Didproblemsinstudydocumentsresultinyourinabilitytodrawmeaningfulconclusionsfromthestudy(withrespecttostudy’sstatedobjective)?Didinconsistenciesinthispartofthesubmission,relativetootherpartsofthesubmission,makeyouhavelessfaithintheintegrityofotherportionsofthesubmission?Intheconclusionsofotherstudies?蕾索死踪律祝寞荧捂眷勘壹留篱郊韧葵婿针秩那么白怒轨食缅黔环推庙缘急药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点 NotalllapsesprecludedrawingconclusionsfromastudymistakescanhappeninperformingastudyindescribingfactsometimesfactisnotconvenientTheevaluationofmistakesrequiresanevalutionoftheirmagnitudeandnature.Areerrorswidespread?Limited?Doerrorsoccurinreportingofendpointsthatarecriticaltoscientificinterpretation?Doerrorsspeakforareport-specificproblemorsomethingthatisasystemicproblem

?醒捎军饵嚣友痘谓邵串萧液酥队籍尼岂危勉裸毖辙硅程刹都窗岿擅殃雄受药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙

现场核查要点：职责

TESTINGFACILITYMANAGEMENT:Overalllaboratorymanagementandadministrativefunctionsdesignatesstudydirectorbeforestudyisinitiatedreplacesstudydirector(promptly),ifnecessaryassuresthereisaqualityassuranceunit(QAU)assurestestandcontrolarticleshavebeenappropriatelyevaluatedforidentity,strength,purity,stabilityanduniformity(asapplicable)脸纸腻续镀春盏兵勉荧状魄妙凯疫悠丫袱嘘征糠翠豹灼谨吉驼实稍秀洁残药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点：职责TESTINGFACILITYMANAGEMENT:(cont’d)assuresappropriatestaffing,facilities,equipmentandmaterialsareavailableforscheduledtestsassuresthatstaffunderstandsthefunctionstheyaretoperformassuresdeviationsreportedbyQAUarepromptlyreportedtostudydirector匿淋座粹吸玩仇灸宣轩倦始漱拦址倾钝缚嗣懒汹借绪店匪幽噎点箔住邱鸵药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点：职责STUDYDIRECTORSinglepointofstudycontrolhasoverallresponsibilityfor:ProtocolpreparationtechnicalconductofstudyinterpretationofresultsanalysisofresultsdocumentationofresultsreportingofresultsArchiving浚铺嗓颂盘电脉骆役逞敬绚醚挥咳晰禹倦竭懂腿亚啄巩史碟蔚恫酚转委铂药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点：职责STUDYDIRECTOR:(cont’d)Protocolpreparation滩逸培砍蛮硒臼暴涵盈混愤杀软衰控姐添刨渠养蔑路戌悯眼击氧撞澳沧娜药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点：职责

STUDYDIRECTOR:(cont’d)ContributorsOphthalmologyCardiologyImmunologyAnalyticalFormulationanalysisBioanalyticalStatisticalanalysisSpecialists/Consultants Antibodies Bonemarrowdifferentialcounts Specializedclinicalpathology SpermAnalysis票沁投七鹏剂剂钙掘缄歌忌异锌堑展捆换十昂奖撑认寝字安烘鸽爷绪蓝部药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点：职责

STUDYDIRECTOR:(cont’d)SpecialProceduresConsiderationsArethereSOPsinplace?Arethestaffappropriatelytrained? Isthistrainingdocumented?Areliteraturesearchesnecessary? IACUCimplications?Doyouneedtouseaconsultant/PIforthework?枝展缠偷谣粒索衙拱浸哥总盐佬僵要寸猎瓶铅异降怀殆绞朔缨荡埠雷母娱药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点：职责

STUDYDIRECTOR:(cont’d)Multi-SiteStudies*Work(i.e.phaseofaGLPstudy)performedatageographicallydistinctsite(NotaFDAGLPterm)AssignaPItoensurecompliancewithGLPsWillsignan"AcceptanceofResponsibilities"formWillsignastatementtothisfactuponcompletionoftheworkStudydirectorremainsthesinglepointofcontrolandmaintainsresponsibilityforoverallconductQualityassuranceofthetestsite*OECDrequirement防曾煤婿腔灯狸据课孵扣弗确眉寓炮哉丙徊楼申授珍匣雨罚颤菊凋挤闲罢药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点：职责

STUDYDIRECTOR:(cont’d)StudySchedulingConsiderationsTestarticleavailabilityAnimalavailability/orderingHousingTrainedstaffAnalyticalchemistryClinicalpathologyNecropsyReports鸵抿颓讲艾黑重歹碌垃醒霹吠焉拥涵溪忧棍盼痢苞惕扔纹现大痛仔驶趋检药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点：职责

STUDYDIRECTOR:(cont’d)TestArticleCalculations-Howmuchwillyouneed?Whenisitavailable?Finaldoses?AnalyticalConfirmationStorage/handlingconditionsCertificateofAnalysis(COA),MSDS,purity,stabilityIsthereadoseformulation?椰佯蹄视索遂呢股壹送零滨距楞垢友舜池澡靴头硬幅唐挤兰癸警厨盲机簧药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点：职责

STUDYDIRECTOR:(cont’d)Protocol–Review&ApprovalManagementSDSponsor(ifdonebyCRO)ScientificcontributorsandlaboratorystaffReportpreparationstaffQAUIACUC安唇密莫萝筒叙倘症馈奄获样摸红坞账二亚脏途奄床焦抚埠萍侨愿抡笛艳药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点：职责STUDYDIRECTOR:(cont’d)OvetsightofStudyConductObserveanimalsandproceduresReviewdataCommunicatewithscientificcontributorsandtechnicalstaffQAaudits–internalandexternalInteractionswithcontributors/PIsSubmissionofsamplesReceipt/reviewofreportRespondtounexpectedevents御孤叔钦村貉梧娃确铣臀罐溢匙樟诺貌贪拯俏眯额抱识撵睁蛙云特明伞乳药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点：职责STUDYDIRECTOR:(cont’d)OversightofStudyConductProtocolamendments-aplannedchangeProtocoldeviations–notplanned;impactonstudymustbedeterminedSOPdeviations弗弊肿誊式潭角入瞅伯扣民嚎铝眠彝幽三报瑚尘喝遭布肘验仗咀票架得洱药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点：职责STUDYDIRECTOR:(cont’d)ExampleofDocumentationProtocol/protocolamendmentProtocol/SOPdeviationsAnimalorderTestarticlereceipt/informationTestarticlepreparationprocedureDoseaccountability(outofrange?)StudyfilenotesVeterinaryrequests/approvaloftreatmentEnvironmentaldeviations(e.g.light/darkcycleandhumidity)observationsofanimals/proceduresDatareviewCorrespondenceemail,fax,letter,telephonecallsReports路靳陷微钳博晶罩拱块穴派哎榴诬箱豆轴经睦枕逢兰肝圭葵酌睹琐甄铬胡药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点：职责STUDYDIRECTOR:(cont’d)ReportPreparation玖摘掣斧圣眩澡变样娶癸烷蹿兹疯触贫捆惊魁藕践骗馒拥怨环桃缺滋洪怎药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点：职责STUDYDIRECTOR:(cont’d)ArchivingProtocol/amendmentsRawdataDocumentationSpecimensFinalreport针锣近惧栖命抨庚郸泣疡慰捧帘歹丸酒拌孰泅巡剔五纂帧匠根钵杯邓挪绒药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点：职责STUDYDIRECTOR:(cont’d)SDResponsibilitiesforaFinalReportDatainterpretationPreliminarydraft–audited?unaudited?Integrationoftoxicology,pathology,TKandothersupportivedataContributingScientist/PIreportsStopped/suspendedprogramsGLPcomplianceDeviationsandimpactondata凿拳嗡剂螺缔但旗淤躬埔徘晋鸵十哭铅韦打残恕椭星憎屏霹中衬兜项屉死药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点：职责STUDYDIRECTOR:(cont’d)assuresthat:protocol,includinganychanges,isapprovedasspecifiedinGLPs,andisfollowedallexperimentaldata,includingobservationsofunanticipatedresponsesofthetestsystem,areaccuratelyrecordedandverifiedunforeseencircumstances,thatmayaffectthequalityandintegrityofthestudy,arenotedwhentheyoccur,andthatcorrectiveactionistakenanddocumented和畅居摔佩涝淆区鳖志鞘帅帜音卜霄计涣斤疲裳婪秤遣沈硝涯惋稀待遂旨药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点：职责QUALITYASSURANCEUNIT(QAU):OverseesGLPComplianceinlaboratoryresponsibleformonitoringeachstudyforGLPcomplianceorganizationally,QAUreportstotestfacilitymanagementindependentofthepersonnelengagedinthedirectionandconductofindividualstudiesassuresthatfacilities,equipment,personnel,methods,practices,records,andcontrolsareinconformancewiththeGLPs招蛊朔遣壶狮彼秩朽捍留厨侍瓶套金奴回急哪嘿婶剔峡扁贰盆薛辆偷嘶冕药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点：职责QUALITYASSURANCEUNIT(QAU):(cont’d)OverseesGLPcomplianceinlaboratorykeepsup-to-daterecordsofallstudiesscheduled/performedwithmasterscheduleatlabmaintainscopiesofallstudyprotocols穷坯赌篡扼震翰浮史虎懒魂悍二良听碟剪打哆窃堰小蟹冲派资环喷树腑敷药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点：职责QUALITYASSURANCEUNIT(QAU):(cont’d)Inspectsstudiesatintervalsadequatetoassuretheintegrityofthestudymaintainswrittenandproperlysignedrecordsateachinspectionidentifyingdateofinspectionthestudyinspectedphaseorsegmentofstudyinspectedpersonperforminginspection耳探涌屿驰琉能趾流糟秃总失久父了菌抿幌鹃焰久吧王吓眉雇钓芝身盅秋药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点：职责QUALITYASSURANCEUNIT(QAU):(cont’d)maintainswrittenandproperlysignedrecords ateachinspectionidentifyingfindingsandproblemsobservedduringinspectionscheduleddateforreinspection,ifapplicableproblemsmustimmediatelybebroughttoattentionofstudydirectorandmanagement服谜旦佐骗摇咱煞教祁委铬凶远以锌兑筏直毋烙桐拳拙琅孪臻玻巫驼风病药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点：职责QUALITYASSURANCEUNIT(QAU):(cont’d)submitsperiodicstatusreportsoneachstudytomanagementandstudydirectornotesproblemsnotescorrectiveactionstakendeterminesthatnodeviationfromapprovedprotocolsorstandardsoperatingproceduresweremadewithoutproperauthorizationanddocumentation接遗邻话舔蓝垃烩侵型辰磕掳好脸胚洛桅嘿造尘熄攫禽护仲载眨锻展谨萄药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点：职责QUALITYASSURANCEUNIT(QAU):(cont’d)Reviewsfinalstudyreporttoassurethat:reportaccuratelydescribesmethodsandstandardoperatingproceduresreportedresultsaccuratelyreflectthestudy’srawdataPreparesandsignsstatementstobeincludedwiththefinalreportspecifyingdetailsoninspections界吴痉俐剩块慕壁期称棍腕乡造瘦卤呛唾初互赛挣腐灭量隋芽喝绑在桔剑药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙现场核查要点：职责FacilityOperationsStandardoperatingprocedures(SOP)CompleteandcomprehensiveUptodateSoundscienceandpracticalReagentsandsolutionsIdentity,titer/concentration,storagerequirements,andexpirationdateAnimalcareandIACUC瞥犯迫培讥虾纂瘦功纠咒胶捉谴纵獭肾舰追唬孝离拧辣构净湖拆仰垢芽瘦药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙Majorissuesofdataaudit

WhatdowelookforwhileauditingaGLPlabStudyDirectorFacilityManagementQualityAssuranceChemistryPathology(Clinicalandanatomical)TechnicalStaffReportwritingSponsorAccountingSubcontractors介扫幂漱慰砒颊烃尤租际洼严锭挨竿介麻苛素敲涅庐偶饭角进紧饼骸仑租药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙非临床实验室常见错误StudydirectorFailuretofollowprotocol Mostcommonbecauseeverythingisdrivenbyprotocol.Examples:TAStabilitydeterminationEnvironmentalconditionsExposuretotestarticle(dosing)处怯代日团爹针丰煮隅穗登林团尺础块星掐范呻竖吓指姓必谈部员匆傅搂药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙非临床实验室常见错误Studydirector(cont’d)FinalReport Commonlyseefailurestoaddressissuesthatoccurredduringstudythatcouldaffectoutcomes涵瓢珠迭宿歹当搔任且纫画滔媚愚吧钾宿须互括应弹风钮藻声络焉镣昏长药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙非临床实验室常见错误Studydirector(cont’d)Failuretorecordalldataandverify Formulation Dosing舌朴命鬼赣从煞滓兼扬突夏跌信届芜最劳寝棺歇墨仰促留队辗宦硬勒娥虑药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙非临床实验室常见错误Studydirector(cont’d)DocumentationissuesBestway,protocolamendment.Mustbedonebeforeaction(signedbySDandalsoQA,managementandsponsor).Secondbest,deviationreport(deviationfromprotocolorSOP).Completedafter-the-factbypersonmakingtheobservation(signedbySDandalsoQAandmanagement).Deviationisnotedinstudyreportalongwithdescriptionoftheimpactthedeviationhasonstudyintegrity.问盆醒洲霉败梧诺械仗傻丸僻瞧贯傈色狡韭硒匝侧高谴刹往印显屉疯兆漓药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙非临床实验室常见错误InconsistencieswithinaprotocolorbetweenprotocolandSOPOmissionofnecessaryinformationfromprotocolLateentriesinstudybooksNonGLPcorrectionsFailuretosignanddateentriesExpiredreagents靴综疆姨痢偏锭捧媚桅胀耻诫俗盯袄锤驯束蚁交敏逻拒杭辉辛颐置荚梁既药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙非临床实验室常见错误FailuretoissuetimelyprotocolamendmentsanddeviationreportsPaperworkmissingfromstudybookInconsistenciesbetweenprotocolandreportorrawdataandreport.状左姑乖墓瓦植哆困津吞拈刻附染宝吱臃仕眶插闭瘸筷忿蹬帐擞硕砰恩粘药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙非临床实验室常见错误QAUfailstoauthorizedeviationDeviationsnotdetectedbytheQAU,butshouldhavebeen高缩鉴胞适孝聋冻橙代愤涤柯派攒汰巷晋南霉砂滔蛇存忱随玄霸暖您恐保药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙非临床实验室常见错误 Transferofdata,specimens,recordstoarchivesAtcompletionofstudyNotallrecordstransferred锑官瘸素镇迹哲藻轨咀正诫须缆仔咬瘁嘻列大瑟嚣她撒龟俗竿冲绞雾侠惹药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙非临床实验室常见错误DidnotfollowSOPsforrequiredauditingInappropriatetrainingrecordkeepingEquipmentcalibrationissuesSanitation–cage/roomdisinfectantsWatersystemattachedtocagerack椎怨寅荤送诊放答沸创鸦逸扦叁徒尘哪账擦奔铭早鸥批进然蛊卿亢薯浇澳药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙GLPornotGLPSafetyPharmacologystudies,Core/GLP,followupstudiesdependingonthedesign/nonGLPPrimaryPharmacodynamic/non-GLP,SecondaryPD/nonGLPunlesscontributetothesafetyevaluationBridgingstudies,GLPQTstudies,Guidance/GLP,datanotrequiredforregulatorysubmission/nonGLPInVitro,ifpivotal,genotox/GLP,efficacy,MOA,metabolism/nonGLP聚巾凛像马腆开戳绵熟祟唱卸畴硕植找亏藻尼堕星蒜交毒嫁傻嗽哦暗讫范药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙GLPornotGLP StudiesthatarenotwithinthescopeofGLPregulationsInclude(USdomesticonly):EfficacyChemicalassaysforqualitycontrolStabilitytestsConformancepharmacopeiastandardsPharmacologyandeffectivenessNewmethodologyfortoxicologyexperimentationExploratorystudiesonvirusesandcellbiologyModeofaction,synthesis,analysisStudiescoveredbyGMPs延振滩凌饵肾总联屿让越棋蓄酷碳窗秦飘挝掐诱棉脐乞絮介卷荚状濒乡斌药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙GLPornotGLPDiseaseModelBiologicSystems,Pharmacology,Transgenicanimals,efficacy/nonGLP,Carc/GLPAnimalRule,Efficacy/GLPImmunotoxicitystudies,GuidancedoesnotmentionGLP,notpivotalforsafetyandmosttestsroutinelynotconductedaccordingtoGLPExcipients,GLP椅记椿角管寐恤钉阂宇至详孩队逻翻嫩熄庐窝器逆近桐猖群业匝嗽旦挫肿药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙GLPornotGLP TheStandardisGLP…WhenisFDA“morelikely〞toacceptnonGLP(USdomesticonly)?Oncology(safetydataisfrompublishedliterature)Biologics(smallcompanies,university,NIH,NCI)tissuecrossreactivitystudiesAIDSDrugs(earlydays,studiesdonebyAcademicians)BotanicalsubmissionsKnownclassofdrugsOlddrugs,changeofrouteofadministrationtoalesshazardousexposure(bridgingstudies)Drugsmarketedoverseas,toxstudiesperformedinUSbutnotGLPs(antimalarial,parasiticdrugs)谅殉敞黔温氦靴陆户锰兵杭袒亏斑跨助键涤坐老醚煮溯筹啸较判从庙诉椽药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙GLPornotGLP However,forstudiessubmittedfromoverseasinsupportofsafetyassessment,theFDAmostlikelyacceptonlyGLPcompliantdata:ShouldbeGLP,OECDguidelinesacceptedJapaneseGLPOrcountrieswithOECDMutualAcceptanceofData(MAD)盅搀屯剁残舱伶斤清斜伊廖漓邑膊绘酒剖许在师钻聋趁忿耕样冠池蛮戎唆药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙GLPornotGLPIffromoverseasandnotGLPUsuallymorestrictStudiesfromnon-traditionalsources,nonICHcountries,requestinspectionMOU,memorandumofunderstandingwithdifferentcountriesRequestpermissiontodoinspectionfromtheentitydoingthestudyCountriesacceptinspectionbyDSIormightnotAcceptanceofthesestudiesisuptothereviewer/DivisioninCDER妇罚孵半汛捻举彼托科准陨儿镜钧癌京拳膝方扇弟寥刮拧釜芳增黎曳澎硫药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙案例分析(1)RCC：Findingsinaratreprotoxstudyaudited:Onlyoneabnormality/variation/developmentaldelay,horacicandabdominalvisceraoffetusesfromcontrolortreatedanimalsinthreestudies •Possiblyfewerthanexpecteda/v/ddinskeletons •Almostnoviscerala/v/ddinhistoricalcontrols,butskeletalratesreasonableQuestion: Wereobservationthresholdssufficientlysensitive?非禄蚌肃缉握饭足梭事西鸳封挞氟晤坠粒蛀密加惟怕彤维呸胆椿媚辰愤哪药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙Inspectionalfindings TheStudyDirectorandheadofthereprotoxdepartmenthadonlyahighschooldiplomaandafewmonthsofon-the-jobtraining,mostlyforskeletalevaluations.Theleadtechnicianhadlessthanelementaryschooleducation.BeforecomingtoRCC,hisbutcherbusinesshadfailed.Technicianhadon-the-jobtrainingatRCC.SOPswereOKforcranial/skeletal,weakforvisceral.Recordedcranial/skeletaldatafairlyrepresentedthespecimens.Externalfindingswerereasonable,comparableto literature. NosatisfactoryexplanationforthelowratesINSOFTTISSUES案例分析(1)鉴契宣襄郡钡殿蓬肿功阔琐栋咆冶吝逼呜巷柬届邯掺颠鸦节朗执惯瓦啦业药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙案例分析(1)Q:whatisthedeficiencyofthisGLPreprotoxstudyauditedvsregulations?Isdataacceptableforsupportingsafetyevaluation?敲风产爆荷藤邑液斌拓扬关乐经尺刊榨尼膛假设沟峻兔据型稍粱跨促枷酋辟药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙案例分析(1)A:whatisthedeficiencyofthisGLPreprotoxstudyauditedvsregulations?人员资质培训Isdataacceptableforsupportingsafetyevaluation?NO！！闭薯嘲戚厚劫酶姚搞价别剔设篇搏涣风职擞戚轧蛔针候凸霍侨撇癣毒忍前药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙药品研究中GLP实验室实验原始记录审核技术要求-龚兆龙案例分析(2)InspectionatABCCompany