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
2、submitted findings Fabricated data Falsified data Discrepancies 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 stu
3、dy performance, study not performed according to protocol No one in charge of studies Sloppy laboratory practices,US FDA GLP 法规,1976 Congressional hearings GLPs proposed 1978 GLPs finalized 1979 GLPs become effective,US FDA GLP 法规,21 CFR: Code of Federal Regulations, Food Electronic Signatures,US FD
4、A GLP Part 58 要求,Describes requirements for conducting and reporting nonclinical laboratory studies Intent: provides a framework for conducting well-controlled studies assures quality and integrity of the data facilitates study reconstruction provides overall accountability Nonclinical studies that
5、evaluate safety must be GLP compliant,US 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。,O
6、ECD GLP 规范,Developed in 1978 USFDA GLP provided the basis for OECD Revised OECD principles adopted in 1997 Primary objective similar to USFDA To ensure the generation of high quality and reliable test data related to the safety of industrial chemical substances and preparations in the framework of h
7、armonising testing procedures for the mutual acceptance of data (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 oth
8、er uses relating to the protection of man and the environment OECD Member Countries Australia, Austria, Belgium, Canada, Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Japan, Korea, Luxembourg, Mexico, Netherlands, New Zealand, Norway, Poland, Portugal,
9、Slovak Republic, Spain, Sweden, Switzerland, Turkey, United Kingdom, United States,中国GLP发展历史,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
10、(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 quality data and data integrity Protects 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 arch
11、ived 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 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
12、范要素,Test Articles the SFDA-/USFDA-regulated product being tested,GLP 规范要素,Test Systems Mouse/Rat, Guinea Pig, Rabbit, Dog (Beagle), Pig, Monkey, Primate, (Chimpanzee),The ABC of GLP Regulations Definitions,Person,Individual,Partnership,Government agency,Organizational unit,Corporation,Scientific or
13、academic establishment,GLP 规范要素 Raw Data,Laboratory worksheets Records & document Memoranda Notes Computer print-outs All communications (internal/external/sponsors),GLP 规范要素 Organization and Personnel,Education Training Experience Job description,Personnel Record,Personnel,Management,Study Director
14、,QAU,Follow protocol Document deviations Archive,GLP 规范要素 Organization and Personnel,Review,QAU,Personnel,Study Director,Master schedule sheet Protocols Inspection records SOPs,Management,Status report,Final study report,GLP 规范要素 Facilities,Nonclinical laboratory,Receipt and storage Mixing,GLP现场核查,P
15、rocess-oriented quality data as a result of proper utilization of and control over facilities, personnel and procedures Allows flexibility in laboratory operation and use of scientific judgment study directors must exert this judgment overall responsibility for technical conduct, interpretation and
16、reporting,现场核查要点,Step 1: Inventory Documents 文件清单 Make sure necessary documents were included in the study report Protocol Protocol amendments 方案修改 Protocol deviations 方案偏离 (with explanations on possible impact to study interpretation and validity) Report (with sufficiently detailed summary and indi
17、vidual animal data),现场核查要点,Step 2: Identify test article 供试品 test article code or name salt form formulation purity Uniformity 均一性 Stability 稳定性 lot or batch#,现场核查要点,Step 3: The experimental design 试验设计 Studies are fluid; what is in a protocol frequently changes during the course of a study Note imp
18、ortant dates (experimental design landmarks) experimental or dosing start date (REPORT) study initiation date (REPORT) protocol amendment date(s) (AMENDMENTS) experimental completion date/necropsy date (REPORT),现场核查要点,Step 3: The experimental design 试验设计 Note how experimental design/methods changed
19、look at protocol amendments and deviations consider if the changes invalidated the studys objectives consider if the changes caused study to be inconsistent with stated guidelines/methods (and evaluate significance) Make sure you understand experimental design (as performed) and chronology per amend
20、ments 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 for test article characteristics testing of dosing formulations for purity stability uniformity,现场核查要点,Step 4: Compare documents for consistency Make sure that da
21、ta 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 tests criteria for acceptable study, positive finding (e.g., genotoxicity tests) Does selection of highest dose comply w
22、ith protocol? With referenced guideline?,现场核查要点,Step 4: Compare documents for consistency Are findings for all protocol-specified evaluations reported body weight clinical chemistry histopathology for all protocol-specified dose groups toxicokinetics,现场核查要点 Step 5: Do data seem credible? Report Raw
23、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 studys stated objective)? Did inconsistencies in this part of the submission, relative to o
24、ther 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 study mistakes can happen in performing a study in describing fact sometimes fact is not conveni
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