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
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