1、1,美国FDA验证高级培训Denis Kluba 博士吴培栋 博士,2,目录Table Of Contents,验证定义CGMP对验证的要求验证历史与期望验证综述验证主方案与规划实施验证的方法验证的技术内容要求执行验证方案工作流程改变控制再验证总结,3,Part One: What is Validation?,?,第一部分：验证定义,4,What is Validation?,For this Seminar it refers to two things:1. The USA FDA requirements that must be met in order to successfull
2、y and continually sell drug products in the USA2. Activities that will contribute to the success of the company in the manufacture of drug products,验证的含义？,5,Validation,“Anything which you cannot understand is indistinguishable from magic.” Arthur C. Clark“Validation may not be magic!” C. Edwards,业内对
3、验证的理解,6,Validation Is.,“Documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes.”,FDA对验证的定义,7,To Consistently Produce A Desired Known Product,Why Do We Validate?,ConfirmD
4、esign,Establish OperatingBoundaries,Establish Baselines,ProductCompliance,Test withinSpecification,验证的作用/目的,8,How Do We Validate?,Details Will Follow But This is the General Model,Identify EquipmentSystems,Develop Tests,Write Protocols,Conduct Tests,Evaluate Data,Report Results,Results OK?,yes,No,Am
5、endProtocol,AmendTest,Collect Data,Validated System,System Modified?,验证流程图,9,First three steps to CGMP compliance,documentdocumentdocument,符合CGMP要求的头三步,10,Boundaries of Validation,Engineering,COMMISSIONING START-UP TROUBLE SHOOTING TRIAL RUNS CYCLE DEVELOPMENT PROCESS DEVELOPMENT ENGINEERING STUDIES
6、 VENDOR SERVICE REPORTS FACTORY ACCEPTANCE TEST “AS-BUILT” DRAWINGS,STANDARD OPERATING PROCEDURES MFG BATCH RECORDS PERSONNEL TRAINING CALIBRATION PREVENTATIVE MTCE CHANGE CONTROL COMPLIANCE VENDOR AUDITS ANNUAL REVIEWS COMPLAINTS SAFETY,Operations / QA,Validation,验证的界限/范围,11,Validation Life Cycle A
7、pproach,Prospective / Concurrent,Define SpecificationsEquipment Process Requirements,Procedures,Design/Specify Equipment,Define Process,Develop Procedure Spec.,Install Equipment,Verify Procedure Specifications,Qualify Equipment,Develop ValidationProtocol,Obtain Data on Process,Obtain Data on Process
8、,Validation Report,Three LotsProspective,Acceptance,OngoingEvaluation,Change Control,New / Revised Process / Product,验证生命周期:新的/修改过的工艺/产品,12,Validation Life Cycle Approach,Retrospective,Define SystemSpecificationsEquipment Procedures,QualifyEquipment,Review Process Capability,Specifications, Procedur
9、es,Operating Instructions,Develop ValidationProtocol,Validation Report,Acceptance,OngoingEvaluation,Data,Conduct Testing(If Needed),Change Control,Existing Process / Product,验证生命周期:现有工艺/产品,13,Benefits of Validation,Increased ThroughputReduction In Rejections and ReworksReduction In Utility CostsAvoi
10、dance Of Capital ExpendituresFewer Complaints About Process Related FailuresReduced Testing In-process and Finished GoodsMore Rapid / Accurate Investigations Into Process UpsetsMore Rapid and Reliable Startup Of New EquipmentEasier Scale-up From Development WorkEasier Maintenance Of The EquipmentImp
11、roved Employee Awareness Of ProcessesMore Rapid Automation,验证带来的好处,14,Elements Of Contemporary Validation In The US,Equipment Calibration - Process and Validation EquipmentEquipment Qualification - Installation and OperationalProcess DevelopmentProcess DocumentationPerformance Qualification - Valida
12、tionMaintenance of Validation - Process and Equipment Change Control,当今美国验证包含的内容,15,cGMP and ISO-9000 - Similarities,Aimed at QualityRequire DocumentationRequire Specific Quality ProgramQA and QC Included,CGMP和 ISO 9000的相似之处,16,cGMP and ISO-9000 - Differences,cGMP Aimed at ProductISO-9000 Includes D
13、esign and Service, as wellcGMP Covers Activities Directly Related to ManufacturingISO-9000 Covers Broader Range of Activities (e.g. Purchasing)cGMP Requires Formal ValidationISO-9000 Requires Applicable Statistical Methods,CGMP和 ISO 9000的不同之处,17,Benefits of the Systems Approach to Validation,More Ri
14、gorous Control Over OperationsCentralized Planning for all Validation Related AspectsTies Existing Sub-elements into Cohesive SystemEstablishes Validation as a Program, not a ProjectProvides for Continuity of ApproachAffirms Validation as a Discipline Much like OthersAllows For Personnel Growth with
15、in the Validation ExpertiseUsually Results in Centralization of Validation ExpertiseMore Compatible with the Accomplishment of a Corporate Objective for Validation,系统验证方法的好处,18,The Validation Program,Establish Goals and Objectives as to What Must be ValidatedQualify or Re-qualify the EquipmentEstabl
16、ish Validation Protocols for each, and obtain Approval of the ProtocolsEstablish Personnel Requirements and Training Records ProcedureDesign and Conduct Experiments. Collect DataEvaluate the DataPrepare Summary Reports Outlining the Results of the Experiments. Obtain the Necessary ApprovalsEstablish
17、 and Maintain Validation Files Including Raw DataInstitute a Change Control Procedure to Insure the Ongoing Acceptability of the Work,验证项目/规划,19,Part Two: GMP Requirements,第二部分：GMP对验证的要求,20,GMP requirements,Part 211: Current good manufacturing practice for finished pharmaceuticals 211.68 - Automatic
18、, mechanical, and electronic equipment. 211.84 - Testing and approval or rejection of components, drug product containers, and closures. 211.110 - Sampling and testing of in-process materials and drug products. 211.113 - Control of microbiological contamination. 211.165 - Testing and release for dis
19、tribution. 211.166 - Stability testing.,GMP要求,21,cGMP in the Pharmaceutical Industry,GMP is the abbreviation of “Good Manufacturing Practice” which is adopted by the medical and health related industries including the pharmaceutical industry in an effort to maintain the highest standards of quality
20、in the development, manufacture and control of medicinal products. Since the industry standards are subject to continuous improvement, the letter c in the abbreviation “cGMP” refers more specifically to the current or the latest version of the GMP requirements.,制药行业的cGMP,22,Regulatory Requirements f
21、or Validation.,The requirement of process validation is implicit in the language of 21 CFR 211.100 of the Current Good Manufacturing regulations which states:“There shall be written procedures for product and process control to assure that drug products have the identity, strength, quality, and puri
22、ty they purport or are represented to possess.,监管部门对验证的要求,23,GMP Regulatory Requirements for Cleaning Validation,1978 cGMP Regulations (part 211.67(a) Equipment cleaning and maintenance states: “Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent ma
23、lfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements”.,GMP条例对清洗验证的要求,24,GMP Regulatory Requirements for Test Method Validation,Laboratory Controls 21 CFR 211.165(e) states: The accura
24、cy, sensitivity, specificity and reproducibility of test methods employed by the firm shall be established and documented. Such validation and documentation may be accomplished in accordance with Part 211.194(a)(2).,GMP条例对化验方法验证的要求,25,GMP Regulatory Requirements for Test Method Validation,Part 211.1
25、94(a)(2) states: A statement of each method used. . . shall indicate the location of data that establish that the methods used in the testing of the sample meet proper standards of accuracy and reliability as applied to the product tested. The suitability of all testing methods used shall be verifie
26、d under actual conditions of use.,GMP条例对化验方法验证的要求,26,GMP Regulatory Requirements for Test Method Validation,U.S. Federal Court decision: United States vs Barr Labs Cleaning Validation: . . . it was ruled for cleaning to be effective, the specific test methods had to be shown to be effective.,GMP条例对化
27、验方法验证的要求,27,PROCESS VALIDATION,21 CFR 211.110“such control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product”,工艺验证,2
28、8,Part Three: History and Expectations,As applied by the FDA and Implemented by Industry,第三部分：验证历史与FDA和制药行业对验证的期望,29,History and expectations,Learn for the experiences of the USA manufacturers and industry organizations Current applicationsPast citationsIndustry guidelinesICH Q7AISPEPDAEtc.,历史与期望,30
29、,Validation Targets,Early YearsSterilizationAseptic OperationsMiddle YearsNon-sterile ProcessesOral Dosage Forms,Recent YearsBiological ProcessesBulk Organic SynthesisDevelopmental and Pilot OperationsSupporting ServicesCurrentlyTotal OperationsReview by SystemsQuality System Production System Labor
30、atory ControlsPackaging and Labeling, Materials and FacilitiesEquipment Manufacturing.,验证目标,31,History of Validation,Validation in The Early Years - 1972 to 1978Regulatory Based to Satisfy FDA PressuresDefensive to Protect Product LineValidation in Its Adolescence - 1978 To 1983Primarily DefensiveSo
31、me Efforts at Process OptimizationIncludes Some Peripheral ConcernsValidation in the US Today - 1983 to PresentNon- Regulatory in Many Areas Geared Towards Optimization and focused on Systems,验证历史,32,validation vs. VALIDATION,validationDefensiveTesting OrientedCostlyQuality ControlNarrow Focus,VALID
32、ATIONOptimizationTotal Process ControlCost EffectiveQuality AssuranceDiverse Application,如何正确理解验证,33,Elements of Contemporary Validation in the US,Equipment Calibration - Process and Validation EquipmentEquipment Qualification - Installation and OperationalProcess DevelopmentProcess DocumentationPer
33、formance Qualification - ValidationMaintenance of Validation -Process and Equipment Change Control,当今美国验证所包含的内容/要素,34,Expectations,Validation is a Program not a ProjectValidation Contributes to the Stability of the OperationsValidation is not Someone Elses Job!,对验证的期望,35,Part Four: Validation,An Ove
34、rview,第四部分：验证概述,36,Who Validates?,Validation Staff,Engineering,Quality Assurance,Quality Control,Manufacturing,谁进行验证？,37,Validation,v,Design,Testing,Operation,验证,运作,38,Validation,v,Vendor,SystemsIntegrator,Owner/User,验证,系统集成者,39,Validation,v,EngineeringR&D,Validation TeamMaintenance,ManufacturingQua
35、lity Assurance,验证,制造质量保障,40,Write Protocols,起草方案,41,Example Data Sheets,数据单样品,42,Conduct Testing,Chemical Tests,Careful Review andMarkup of Prints, Specs,MicrobiologicalTests,Physical Tests(Temp., Press., Flow),Computer Tests,进行测试,43,Installation Qualification (IQ),IQ documents thatsystem is install
36、ed in accordance with approved design, specification and regulatory codesmanufacturers installation recommendation have been taken into considerationIQs implemented concurrently with construction of each system,安装合格确认,44,Operational Qualification (OQ),OQ documents that the equipment:can operate as d
37、esigned and intendedis capable of repeatable operation over the entire operating range of process variablesOQ executed when equipment can be started up,运转/运作合格确认,45,Process Qualification (PQ),PQ documentscritical systems which can be challengedtest proceduresproduct quality attributes to be evaluate
38、dacceptance criteriaalert/action levelssystem validated under worst case conditionsgenerally 3 consecutive successful runs required,工艺合格确认,46,Definition of Process Validation,1978,Validation is: Documented evidence that provides a high degree of assurance that a specific process will consistently pr
39、oduce a product of a certain predetermined quality.,工艺验证定义,47,Definition of Process Validation,In addition to documented evidence that a process will perform reliably and repeatedly, validation, in its highest form, provides an understanding of why.,1993,工艺验证定义,48,Stages of the Life-Cycle,R&D,Design
40、,Construction,Testing,SOPs/Maintenance,Change Control,生命周期的阶段,49,Benefits of Validation,Increased ThroughputReduction in Rejections and ReworksReduction in Utility CostsAvoidance Of Capital ExpendituresFewer Complaints About Process Related FailuresReduced Testing In-process and Finished GoodsMore R
41、apid / Accurate Investigations Into Process UpsetsMore Rapid and Reliable Startup Of New EquipmentEasier Scale-up From Development WorkEasier Maintenance Of The EquipmentImproved Employee Awareness Of ProcessesMore Rapid Automation,验证的好处,50,Documentation of Validation,Master PlanProtocolData SheetsR
42、eportProcedures,验证文件,51,Validation Protocols,Provide an Outline of the Validation EffortInclude a Clear Definition of What Will Be ValidatedIs Uniquely IdentifiedIs DatedApproved By Competent Individuals In Responsible AreasAre Suitable For Review By Regulatory Agencies,验证方案,52,Validation Protocol E
43、ssential Elements,Introduction/AbstractDescription of Process or SystemTest PlanResponsibilitiesAcceptance CriteriaApprovalsAppend Data Sheets, Etc.,验证方案的核心要素,53,Validation Reports Functions,Restrict to One Task or SubjectHas a Unique IdentificationIs DatedFormally Reviewed and ApprovedIdentifies Pr
44、otocol(s) Used in the StudyIs Suitable for Review by FDA,验证报告功能,54,Validation Report - Contents,Abstract Or Summary ConclusionPlan Of StudyExperimentalResultsConclusionsProtocol ReferenceDiagramsAny Miscellaneous InformationApprovals,验证报告内容,55,Installation Qualification (IQ),IQ Documents That The:Sy
45、stem is Installed in Accordance with Approved Design, Specifications and Regulatory CodesManufacturers Installation Recommendations have been taken into ConsiderationIQ is Implemented Concurrently with Construction of Each System,安装合格确认,56,Design Documentation,Design and Procurement Documentation Su
46、pport of IQ:PFDs/P&IDsCritical System Installation Drawings (E.G. Water System Isometrics, Sanitary Duct Drawings)Purchase and Installation SpecificationsVendor Manuals and PrintsComputer Software Documentation,设计文件,57,Construction Documentation,Construction Documents In Support Of IQ:Slope ChecksPi
47、ping Pressure Test ReportsMotor Checkout ReportsWeld Inspection ReportsCleaning, Passivation and Sanitization Procedures and ReportsHVAC Test and Balance ReportsOther Appropriate Construction Documentation,建造文件,58,The P&ID,(Piping & Instrumentation Diagram, Engineering Flow Diagram),Process EquipmentSupport VesselsInterconnecting LinesUtility LinesInstruments/Instrument FunctionsSchematicNo Scale - Not Spatially PreciseShows Relationships and Relative Position,管线和仪器图,
