最新品研究实验原始记录审核技术要求PPT课件.ppt

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1、2新药研发过程新药研发过程US FDA GLP Part 58 要求要求 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 Noncl

2、inical studies that evaluate safety must be GLP compliantUS FDA GLP 检查检查 FDA GLP检查过的美国国内实验室检查过的美国国内实验室200余家余家, CRO, 药厂药厂US FDA GLP 检查检查 FDA GLP检查过的美国境外实验室检查过的美国境外实验室40余家余家, CRO, 药厂药厂US FDA GLP 检查：检查：MOU 8 个国家个国家日本日本法国法国德国德国加拿大加拿大意大利意大利瑞典瑞典瑞士瑞士荷兰荷兰US FDA GLP 检查：中国检查：中国GLP实验室实验室 2009 年年7月检查了三家月检查了三家GL

3、P实验室实验室 国家安评中心国家安评中心 (NCSED) 昭衍（昭衍（JOINN) Bridge (康龙化成康龙化成) 昭衍提交的试验报告获得美国昭衍提交的试验报告获得美国FDA认可认可, 用于支持美国的临床试验。用于支持美国的临床试验。OECD GLP 规范规范 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 qua

4、lity 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 (MAD)OECD MAD （数据互认）（数据互认） Data generated in the testing of chemicals in an OECD member country in accordance with

5、 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 environment OECD Member Countries Australia, Austria, Belgium, Canada, Czech Republic, Denmark, Finland, France, Germany, G

6、reece, Hungary, Iceland, Ireland, Italy, Japan, Korea, Luxembourg, Mexico, Netherlands, New Zealand, Norway, Poland, Portugal, Slovak Republic, Spain, Sweden, Switzerland, Turkey, United Kingdom, United States中国中国GLP发展历史发展历史 1993年年12月，国家科委发布了月，国家科委发布了GLP（试行）（试行） 1999年年10月，月，SDA发布发布GLP（试行）（试行） 2001年中

7、国修订年中国修订中华人民共和国药品管理法中华人民共和国药品管理法、 药品法实施条例药品法实施条例，将，将GLP明确为法定要求明确为法定要求 2003年年9月月,SFDA颁布实施颁布实施GLP（二号令）（二号令）280 条条, 开展开展GLP认证检查认证检查 2007年年1月月 法规毒理实验强制要求法规毒理实验强制要求GLP 2009年年7月月 3家在中国的家在中国的GLP 实验室接受美国实验室接受美国FDA检查检查中国中国GLP管理规范管理规范药物非临床研究质量管理规范（局令第药物非临床研究质量管理规范（局令第2号）号）2003年年9自自2003年年9月月1日起施行日起施行 共九章共九章45条

8、条 非临床研究质量管理规范认证标准非临床研究质量管理规范认证标准280条条 药品注册现场核查管理规定药品注册现场核查管理规定7章、章、59条、条、5个附件个附件遵从遵从 GLP 的意义的意义 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

9、archived records 对中国对中国CRO来说，研究报告可以得到国际来说，研究报告可以得到国际认可。认可。GLP 规范要素规范要素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

10、 marketing approvalGLP 规范要素规范要素Test Articles the SFDA-/USFDA-regulated product being testedGLP 规范要素规范要素 Test Systems Mouse/Rat, Guinea Pig, Rabbit, Dog (Beagle), Pig, Monkey, Primate, (Chimpanzee)The ABC of GLP Regulations DefinitionsPersonIndividualPartnershipGovernment agencyOrganizational unitCor

11、porationScientific or academic establishmentGLP 规范要素规范要素Raw Data Laboratory worksheets Records & document Memoranda Notes Computer print-outs All communications (internal/external/sponsors)GLP 规范要素规范要素Organization and PersonnelEducationTrainingExperienceJob descriptionPersonnel RecordPersonnelManage

12、mentStudy DirectorQAUFollow protocolDocument deviationsArchiveGLP 规范要素规范要素Organization and PersonnelReviewQAUPersonnelStudy DirectorMaster schedule sheetProtocolsInspection recordsSOPsManagementStatus reportFinal study reportGLP 规范要素规范要素FacilitiesNonclinical laboratoryReceipt and storageMixingGLP现场核

13、查现场核查Process-oriented quality data as a result of proper utilization of and control over facilities, personnel and proceduresAllows flexibility in laboratory operation and use of scientific judgment study directors must exert this judgment overall responsibility for technical conduct, interpretation

14、 and reporting现场核查要点现场核查要点Step 1: Inventory Documents 文件清单文件清单 Make sure necessary documents were included in the study report Protocol Protocol amendments 方案修改方案修改 Protocol deviations 方案偏离方案偏离(with explanations on possible impact to study interpretation and validity) Report (with sufficiently detai

15、led summary and individual animal data)现场核查要点现场核查要点Step 2: Identify test article 供试品供试品 test article code or name salt form formulation purity Uniformity 均一性均一性 Stability 稳定性稳定性 lot or batch#现场核查要点现场核查要点Step 3: The experimental design 试验设计试验设计 Studies are fluid; what is in a protocol frequently chan

16、ges during the course of a study Note important 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)现场核查要点现场核查要点Step 3: The experimental design 试验设计试

17、验设计 Note how experimental design/methods changed 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 experiment

18、al design (as performed) and chronology per amendments and documented deviations现场核查要点现场核查要点Step 4: Compare documents for consistency 一致性一致性 Do reports comply with GLP requirements on reporting for test article characteristics testing of dosing formulations for purity stability uniformity现场核查要点现场核查要

19、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 (

20、e.g., genotoxicity tests) Does selection of highest dose comply with protocol? With referenced guideline?现场核查要点现场核查要点Step 4: Compare documents for consistency Are findings for all protocol-specified evaluations reported body weight clinical chemistry histopathology for all protocol-specified dose gr

21、oups toxicokinetics现场核查要点现场核查要点Step 5: Do data seem credible?Report Raw data/Reality现场核查要点现场核查要点Step 6: Evaluation of significance of lapses 失误的评估失误的评估The big questions Did problems in study documents result in your inability to draw meaningful conclusions from the study (with respect to studys stat

22、ed 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?现场核查要点现场核查要点Not all lapses preclude drawing conclusions from a study mistak

23、es can happen in performing a study in 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

24、speak for a report-specific problem or something that is a systemic problem ?现场核查要点：职责现场核查要点：职责 TESTING FACILITY MANAGEMENT: Overall laboratory management and administrative functions designates study director before study is initiated replaces study director (promptly), if necessary assures there i

25、s a quality assurance 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：职责现场核查要点：职责TESTING FACILITY MANAGEMENT: (contd) assures appropriate staffing, facilities, equipment and materials are av

26、ailable for scheduled tests assures that staff understands the functions they are to perform assures deviations reported by QAU are promptly reported to study director现场核查要点：职责现场核查要点：职责STUDY DIRECTOR Single point of study controlhas overall responsibility for: Protocol preparation technical conduct

27、of study interpretation of results analysis of results documentation of results reporting of results Archiving现场核查要点：职责现场核查要点：职责STUDY DIRECTOR: (contd)Protocol preparation现场核查要点：职责现场核查要点：职责 STUDY DIRECTOR: (contd)Contributors Ophthalmology Cardiology Immunology Analytical Formulation analysis Bioana

28、lyticalStatistical analysis Specialists/Consultants AntibodiesBone marrow differential countsSpecialized clinical pathologySperm Analysis 现场核查要点：职责现场核查要点：职责 STUDY DIRECTOR: (contd)Special Procedures Considerations Are there SOPs in place? Are the staff appropriately trained? Is this training documen

29、ted? Are literature searches necessary?IACUC implications? Do you need to use a consultant/PI for the work? 现场核查要点：职责现场核查要点：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

30、 with GLPs Will sign an Acceptance of Responsibilities form Will sign a statement to this fact upon completion of the work Study director remains the single point of control and maintains responsibility for overall conduct Quality assurance of the test site*OECD requirement 现场核查要点：职责现场核查要点：职责 STUDY

31、DIRECTOR: (contd)Study Scheduling Considerations Test article availability Animal availability/ordering Housing Trained staff Analytical chemistry Clinical pathology Necropsy Reports 现场核查要点：职责现场核查要点：职责 STUDY DIRECTOR: (contd)Test Article Calculations - How much will you need? When is it available? F

32、inal doses? Analytical Confirmation Storage/handling conditions Certificate of Analysis (COA), MSDS, purity, stability Is there a dose formulation? 现场核查要点：职责现场核查要点：职责 STUDY DIRECTOR: (contd)Protocol Review & Approval Management SD Sponsor (if done by CRO) Scientific contributors and laboratory staff

33、 Report preparation staff QAU IACUC 现场核查要点：职责现场核查要点：职责STUDY DIRECTOR: (contd)Ovetsight of Study Conduct Observe animals and procedures Review data Communicate with scientific contributors and technical staff QA audits internal and external Interactions with contributors/ PIs Submission of samples Re

34、ceipt/review of report Respond to unexpected events现场核查要点：职责现场核查要点：职责STUDY DIRECTOR: (contd)Oversight of Study Conduct Protocol amendments - a planned change Protocol deviations not planned; impact on study must be determined SOP deviations 现场核查要点：职责现场核查要点：职责STUDY DIRECTOR: (contd)Example of Documen

35、tationProtocol/protocol amendment Protocol/SOP deviationsAnimal order Test article receipt/information Test article preparation procedureDose accountability (out of range?)Study file notesVeterinary requests/approval of treatmentEnvironmental deviations (e.g. light/dark cycle and humidity) observati

36、ons of animals/procedures Data reviewCorrespondence email, fax, letter, telephone callsReports 现场核查要点：职责现场核查要点：职责STUDY DIRECTOR: (contd)Report Preparation现场核查要点：职责现场核查要点：职责STUDY DIRECTOR: (contd)Archiving Protocol/amendments Raw data Documentation Specimens Final report 现场核查要点：职责现场核查要点：职责STUDY DIREC

37、TOR: (contd)SD Responsibilities for a Final Report Data interpretation Preliminary draft audited? unaudited? Integration of toxicology, pathology, TK and other supportive data Contributing Scientist/PI reports Stopped/suspended programs GLP compliance Deviations and impact on data 现场核查要点：职责现场核查要点：职责

38、STUDY DIRECTOR: (contd) assures that: protocol, including any changes, is approved as specified in GLPs, and is followed all experimental data, including observations of unanticipated responses of the test system, are accurately recorded and verified unforeseen circumstances, that may affect the qua

39、lity and integrity of the study, are noted when they occur, and that corrective action is taken and documented现场核查要点：职责现场核查要点：职责QUALITY ASSURANCE UNIT (QAU):Oversees GLP Compliance in laboratory responsible for monitoring each study for GLP compliance organizationally, QAU reports to test facility m

40、anagement independent of the personnel engaged in the direction and conduct of individual studies assures that facilities, equipment, personnel, methods, practices, records, and controls are in conformance with the GLPs现场核查要点：职责现场核查要点：职责QUALITY ASSURANCE UNIT (QAU): (contd)Oversees GLP compliance in

41、 laboratory keeps up-to-date records of all studies scheduled/performed with master schedule at lab maintains copies of all study protocols现场核查要点：职责现场核查要点：职责QUALITY ASSURANCE UNIT (QAU): (contd) Inspects studies at intervals adequate to assure the integrity of the study maintains written and properl

42、y signed records at each inspection identifying date of inspection the study inspected phase or segment of study inspected person performing inspection现场核查要点：职责现场核查要点：职责QUALITY ASSURANCE UNIT (QAU): (contd) maintains written and properly signed records at each inspection identifying findings and pro

43、blems observed during inspection scheduled date for reinspection, if applicable problems must immediately be brought to attention of study director and management现场核查要点：职责现场核查要点：职责QUALITY ASSURANCE UNIT (QAU): (contd) submits periodic status reports on each study to management and study director not

44、es problems notes corrective actions taken determines that no deviation from approved protocols or standards operating procedures were made without proper authorization and documentation现场核查要点：职责现场核查要点：职责QUALITY ASSURANCE UNIT (QAU): (contd) Reviews final study report to assure that: report accurate

45、ly describes methods and standard operating procedures reported results accurately reflect the studys raw data Prepares and signs statements to be included with the final report specifying details on inspections现场核查要点：职责现场核查要点：职责Facility Operations Standard operating procedures (SOP) Complete and co

46、mprehensive Up to date Sound science and practical Reagents and solutions Identity, titer/concentration, storage requirements, and expiration date Animal care and IACUCMajor issues of data auditWhat do we look for while auditing a GLP labStudy DirectorFacility ManagementQuality AssuranceChemistryPat

47、hology(Clinical and anatomical)Technical StaffReport writingSponsorAccountingSubcontractors非临床实验室常见错误非临床实验室常见错误Study director Failure to follow protocolMost common because everything is driven by protocol. Examples: TA Stability determination Environmental conditions Exposure to test article (dosing

48、)非临床实验室常见错误非临床实验室常见错误Study director (contd) Final ReportCommonly see failures to address issues that occurred during study that could affect outcomes非临床实验室常见错误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非临床实验室常见错误Study director (contd) Documentati

49、on issues Best way, protocol amendment. Must be done before action (signed by SD and also QA, management and 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 not

50、ed 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非临床实验室常见错误 Inconsistencies within a protocol or between protocol and SOP Omission of necessary information from protocol Late entries in study books Non GLP corrections Failure to sign and date ent