药品研究中GLP实验室实验原始记录审核技术要求.ppt

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1、,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,新药研发过程,2,新药研发过程质量规范,GLP 历史沿革 遵从 GLP 的意义GLP 规范基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,GLP 历史 美国,What prompted US FDA to issue GLP regulations?In the 1960s and 1970s,in addition to the“Thalidomide”story,FDA found:Selectively submitted find

2、ingsFabricated dataFalsified dataDiscrepancies in reporting(e.g.,between individual and summary data)Poor laboratory recordkeeping(resulting in inability to reconstruct study performance),GLP 历史 美国,In the 1960s and 1970s,FDA also found:No protocols,protocols written after study performance,study not

3、 performed according to protocolNo one in charge of studiesSloppy laboratory practices,US FDA GLP 法规,1976Congressional hearingsGLPs proposed1978GLPs finalized1979GLPs become effective,US FDA GLP 法规,21 CFR:Code of Federal Regulations,Food Electronic Signatures,US FDA GLP Part 58 要求,Describes requirem

4、ents for conducting and reporting nonclinical laboratory studiesIntent:provides a framework for conducting well-controlled studiesassures quality and integrity of the datafacilitates study reconstructionprovides overall accountability Nonclinical studies that evaluate safety must be GLP compliant,US

5、 FDA GLP 检查,FDA GLP检查过的美国国内实验室200余家,CRO,药厂,US FDA GLP 检查,FDA GLP检查过的美国境外实验室40余家,CRO,药厂,US FDA GLP 检查：MOU,8 个国家日本法国德国加拿大意大利瑞典瑞士荷兰,US FDA GLP 检查：中国GLP实验室,2009 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。,OECD GLP 规范,Developed in 1978 USFDA GLP provided the basis for

6、 OECDRevised OECD principles adopted in 1997Primary objective similar to USFDATo ensure the generation of high quality and reliable test data related to the safety of industrial chemical substances and preparations in the framework of harmonising testing procedures for the mutual acceptance of data(

7、MAD),OECD MAD（数据互认）,Data generated in the testing of chemicals in an OECD member country in accordance with OECD Test Guidelines and OECD Principles of GLP shall be accepted in other Member countries for purposes of assessment and other uses relating to the protection of man and the environmentOECD

8、Member CountriesAustralia,Austria,Belgium,Canada,Czech Republic,Denmark,Finland,France,Germany,Greece,Hungary,Iceland,Ireland,Italy,Japan,Korea,Luxembourg,Mexico,Netherlands,New Zealand,Norway,Poland,Portugal,Slovak Republic,Spain,Sweden,Switzerland,Turkey,United Kingdom,United States,中国GLP发展历史,1993

9、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颁布实施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GLP 2009年7月 3家在中国的GLP 实验室接受美国FDA检查,中国GLP管理规范,药物非临床研究质量管理规范（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规范认证标准280条 药品注册现场核查管理规定7章、59条、5个附件,遵从 GLP 的意义,Assures qualit

10、y data and data integrityProtects the well-being of subjects in clinical trials many of whom are healthy volunteers(human safety)Ensures that a study can be completely reconstructed from archived records对中国CRO来说，研究报告可以得到国际认可。,GLP 规范要素,What is a nonclinical laboratory?In the SFDA or USFDA regulatory

11、world,a laboratories that conduct nonclinical studies involving test articles to develop data that will be submitted to the agency in support of an application and marketing approval,GLP 规范要素,Test Articlesthe SFDA-/USFDA-regulated product being tested,GLP 规范要素,Test Systems Mouse/Rat,Guinea Pig,Rabbi

12、t,Dog(Beagle),Pig,Monkey,Primate,(Chimpanzee),The ABC of GLP Regulations Definitions,Person,Individual,Partnership,Government agency,Organizational unit,Corporation,Scientific or academic establishment,GLP 规范要素Raw Data,Laboratory worksheetsRecords&documentMemorandaNotesComputer print-outsAll communi

13、cations(internal/external/sponsors),GLP 规范要素Organization and Personnel,EducationTrainingExperienceJob description,Personnel Record,Personnel,Management,Study Director,QAU,Follow protocolDocument deviationsArchive,GLP 规范要素Organization and Personnel,Review,QAU,Personnel,Study Director,Master schedule

14、sheetProtocolsInspection recordsSOPs,Management,Status report,Final study report,GLP 规范要素Facilities,Nonclinical laboratory,Receipt and storageMixing,GLP现场核查,Process-oriented quality data as a result of proper utilization of and control over facilities,personnel and proceduresAllows flexibility in la

15、boratory operation and use of scientific judgment study directors must exert this judgment overall responsibility for technical conduct,interpretation and reporting,现场核查要点,Step 1:Inventory Documents 文件清单Make sure necessary documents were included in the study reportProtocolProtocol amendments 方案修改Pr

16、otocol deviations 方案偏离(with explanations on possible impact to study interpretation and validity)Report(with sufficiently detailed summary and individual animal data),现场核查要点,Step 2:Identify test article 供试品test article code or namesalt formformulationpurityUniformity 均一性Stability 稳定性lot or batch#,现场

17、核查要点,Step 3:The experimental design 试验设计Studies are fluid;what is in a protocol frequently changes during the course of a studyNote important dates(experimental design landmarks)experimental or dosing start date(REPORT)study initiation date(REPORT)protocol amendment date(s)(AMENDMENTS)experimental c

18、ompletion date/necropsy date(REPORT),现场核查要点,Step 3:The experimental design 试验设计Note how experimental design/methods changedlook at protocol amendments and deviationsconsider if the changes invalidated the studys objectivesconsider if the changes caused study to be inconsistent with stated guidelines

19、/methods(and evaluate significance)Make sure you understand experimental design(as performed)and chronology per amendments and documented deviations,现场核查要点,Step 4:Compare documents for consistency 一致性Do reports comply with GLP requirements on reporting fortest article characteristicstesting of dosin

20、g formulations forpuritystabilityuniformity,现场核查要点,Step 4:Compare documents for consistency Make sure that data and their associated documents are consistent with one another.,现场核查要点,Step 4:Compare documents for consistency Are protocol-specified evaluations of data applied?statistical testscriteria

21、 for acceptable study,positive finding(e.g.,genotoxicity tests)Does selection of highest dose comply with protocol?With referenced guideline?,现场核查要点,Step 4:Compare documents for consistencyAre findings for all protocol-specified evaluations reportedbody weightclinical chemistryhistopathology for all

22、 protocol-specified dose groupstoxicokinetics,现场核查要点Step 5:Do data seem credible?Report Raw data/Reality,现场核查要点,Step 6:Evaluation of significance of lapses 失误的评估The big questions Did problems in study documents result in your inability to draw meaningful conclusions from the study(with respect to st

23、udys stated objective)?Did inconsistencies in this part of the submission,relative to other parts of the submission,make you have less faith in the integrity of other portions of the submission?In the conclusions of other studies?,现场核查要点,Not all lapses preclude drawing conclusions from a studymistak

24、es can happen in performing a studyin describing fact sometimes fact is not convenient The evaluation of mistakes requires an evalution of their magnitude and nature.Are errors widespread?Limited?Do errors occur in reporting of endpoints that are critical to scientific interpretation?Do errors speak

25、 for a report-specific problem or something that is a systemic problem?,现场核查要点：职责,TESTING FACILITY MANAGEMENT:Overall laboratory management and administrative functionsdesignates study director before study is initiatedreplaces study director(promptly),if necessaryassures there is a quality assuranc

26、e unit(QAU)assures test and control articles have been appropriately evaluated for identity,strength,purity,stability and uniformity(as applicable),现场核查要点：职责,TESTING FACILITY MANAGEMENT:(contd)assures appropriate staffing,facilities,equipment and materials are available for scheduled testsassures th

27、at staff understands the functions they are to performassures deviations reported by QAU are promptly reported to study director,现场核查要点：职责,STUDY DIRECTOR Single point of study controlhas overall responsibility for:Protocol preparationtechnical conduct of studyinterpretation of resultsanalysis of res

28、ultsdocumentation of resultsreporting of resultsArchiving,现场核查要点：职责,STUDY DIRECTOR:(contd)Protocol preparation,现场核查要点：职责,STUDY DIRECTOR:(contd)Contributors Ophthalmology Cardiology ImmunologyAnalyticalFormulation analysisBioanalyticalStatistical analysis,Specialists/Consultants AntibodiesBone marrow

29、 differential countsSpecialized clinical pathologySperm Analysis,现场核查要点：职责,STUDY DIRECTOR:(contd)Special Procedures Considerations Are there SOPs in place?Are the staff appropriately trained?Is this training documented?Are literature searches necessary?IACUC implications?Do you need to use a consult

30、ant/PI for the work?,现场核查要点：职责,STUDY DIRECTOR:(contd)Multi-Site Studies*Work(i.e.phase of a GLP study)performed at a geographically distinct site(Not a FDA GLP term)Assign a PI to ensure compliance with GLPsWill sign an Acceptance of Responsibilities formWill sign a statement to this fact upon compl

31、etion of the work Study director remains the single point of control and maintains responsibility for overall conductQuality assurance of the test site*OECD requirement,现场核查要点：职责,STUDY DIRECTOR:(contd)Study Scheduling Considerations Test article availability Animal availability/orderingHousingTraine

32、d staffAnalytical chemistryClinical pathologyNecropsyReports,现场核查要点：职责,STUDY DIRECTOR:(contd)Test Article Calculations-How much will you need?When is it available?Final doses?Analytical ConfirmationStorage/handling conditionsCertificate of Analysis(COA),MSDS,purity,stabilityIs there a dose formulati

33、on?,现场核查要点：职责,STUDY DIRECTOR:(contd)Protocol Review&ApprovalManagement SDSponsor(if done by CRO)Scientific contributors and laboratory staff Report preparation staffQAUIACUC,现场核查要点：职责,STUDY DIRECTOR:(contd)Ovetsight of Study Conduct Observe animals and proceduresReview dataCommunicate with scientifi

34、c contributors and technical staff QA audits internal and externalInteractions with contributors/PIsSubmission of samplesReceipt/review of reportRespond to unexpected events,现场核查要点：职责,STUDY DIRECTOR:(contd)Oversight of Study Conduct Protocol amendments-a planned changeProtocol deviations not planned

35、;impact on study must be determinedSOP deviations,现场核查要点：职责,STUDY DIRECTOR:(contd)Example of DocumentationProtocol/protocol amendment Protocol/SOP deviationsAnimal order Test article receipt/information Test article preparation procedureDose accountability(out of range?)Study file notesVeterinary re

36、quests/approval of treatmentEnvironmental deviations(e.g.light/dark cycle and humidity)observations of animals/procedures Data reviewCorrespondence email,fax,letter,telephone callsReports,现场核查要点：职责,STUDY DIRECTOR:(contd)Report Preparation,现场核查要点：职责,STUDY DIRECTOR:(contd)ArchivingProtocol/amendmentsR

37、aw data DocumentationSpecimensFinal report,现场核查要点：职责,STUDY DIRECTOR:(contd)SD Responsibilities for a Final ReportData interpretationPreliminary draft audited?unaudited?Integration of toxicology,pathology,TK and other supportive dataContributing Scientist/PI reportsStopped/suspended programsGLP compl

38、iance Deviations and impact on data,现场核查要点：职责,STUDY DIRECTOR:(contd)assures that:protocol,including any changes,is approved as specified in GLPs,and is followedall experimental data,including observations of unanticipated responses of the test system,are accurately recorded and verifiedunforeseen ci

39、rcumstances,that may affect the quality and integrity of the study,are noted when they occur,and that corrective action is taken and documented,现场核查要点：职责,QUALITY ASSURANCE UNIT(QAU):Oversees GLP Compliance in laboratoryresponsible for monitoring each study for GLP complianceorganizationally,QAU repo

40、rts to test facility managementindependent of the personnel engaged in the direction and conduct of individual studiesassures that facilities,equipment,personnel,methods,practices,records,and controls are in conformance with the GLPs,现场核查要点：职责,QUALITY ASSURANCE UNIT(QAU):(contd)Oversees GLP complian

41、ce in laboratorykeeps up-to-date records of all studies scheduled/performed with master schedule at labmaintains copies of all study protocols,现场核查要点：职责,QUALITY ASSURANCE UNIT(QAU):(contd)Inspects studiesat intervals adequate to assure the integrity of the studymaintains written and properly signed

42、records at each inspection identifyingdate of inspectionthe study inspectedphase or segment of study inspectedperson performing inspection,现场核查要点：职责,QUALITY ASSURANCE UNIT(QAU):(contd)maintains written and properly signed records at each inspection identifyingfindings and problems observed during in

43、spectionscheduled date for reinspection,if applicableproblems must immediately be brought to attention of study director and management,现场核查要点：职责,QUALITY ASSURANCE UNIT(QAU):(contd)submits periodic status reports on each study to management and study directornotes problemsnotes corrective actions ta

44、kendetermines that no deviation from approved protocols or standards operating procedures were made without proper authorization and documentation,现场核查要点：职责,QUALITY ASSURANCE UNIT(QAU):(contd)Reviews final study report to assure that:report accurately describes methods and standard operating procedu

45、resreported results accurately reflect the studys raw dataPrepares and signs statements to be included with the final report specifying details on inspections,现场核查要点：职责,Facility OperationsStandard operating procedures(SOP)Complete and comprehensiveUp to dateSound science and practicalReagents and so

46、lutionsIdentity,titer/concentration,storage requirements,and expiration dateAnimal care and IACUC,Major issues of data auditWhat do we look for while auditing a GLP lab,Study Director,Facility Management,Quality Assurance,Chemistry,Pathology(Clinical and anatomical),Technical Staff,Report writing,Sp

47、onsor,Accounting,Subcontractors,非临床实验室常见错误,Study directorFailure to follow protocolMost common because everything is driven by protocol.Examples:TA Stability determinationEnvironmental conditionsExposure to test article(dosing),非临床实验室常见错误,Study director(contd)Final ReportCommonly see failures to add

48、ress issues that occurred during study that could affect outcomes,非临床实验室常见错误,Study director(contd)Failure to record all data and verifyFormulationDosing,非临床实验室常见错误,Study director(contd)Documentation issuesBest way,protocol amendment.Must be done before action(signed by SD and also QA,management and

49、sponsor).Second best,deviation report(deviation from protocol or SOP).Completed after-the-fact by person making the observation(signed by SD and also QA and management).Deviation is noted in study report along with description of the impact the deviation has on study integrity.,非临床实验室常见错误,Inconsiste

50、ncies within a protocol or between protocol and SOPOmission of necessary information from protocolLate entries in study booksNon GLP correctionsFailure to sign and date entriesExpired reagents,非临床实验室常见错误,Failure to issue timely protocol amendments and deviation reportsPaperwork missing from study bo