美國fda驗(yàn)證高級培訓(xùn)

1、1,,美國FDA驗(yàn)證高級培訓(xùn)Denis Kluba 博士吳培棟 博士,,,2,目錄Table Of Contents,驗(yàn)證定義CGMP對驗(yàn)證的要求驗(yàn)證歷史與期望驗(yàn)證綜述驗(yàn)證主方案與規(guī)劃實(shí)施驗(yàn)證的方法驗(yàn)證的技術(shù)內(nèi)容要求執(zhí)行驗(yàn)證方案工作流程改變控制再驗(yàn)證總結(jié),3,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Part One: What is Validation?,

2、?,第一部分：驗(yàn)證定義,4,What is Validation?,For this Seminar it refers to two things:1. The USA FDA requirements that must be met in order to successfully and continually sell drug products in the USA2. Activities that will co

3、ntribute to the success of the company in the manufacture of drug products,驗(yàn)證的含義？,5,Validation,“Anything which you cannot understand is indistinguishable from magic.” Arthur C. Clark“Validation may not be mag

4、ic!” C. Edwards,業(yè)內(nèi)對驗(yàn)證的理解,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

5、 and quality attributes.”,FDA對驗(yàn)證的定義,7,To Consistently Produce A Desired Known Product,Why Do We Validate?,ConfirmDesign,Establish OperatingBoundaries,Establish Baselines,ProductCompliance,Test withinSpecification,驗(yàn)

6、證的作用/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,AmendProtocol,Amend

7、Test,,,,Collect Data,,,,,,,,,,,,,,Validated System,,System Modified?,,,,,,,,,,,,驗(yàn)證流程圖,9,First three steps to CGMP compliance,documentdocumentdocument,符合CGMP要求的頭三步,10,Boundaries of Validation,,,,Engineering,,,COMMISSIO

8、NING START-UP TROUBLE SHOOTING TRIAL RUNS CYCLE DEVELOPMENT PROCESS DEVELOPMENT ENGINEERING STUDIES VENDOR SERVICE REPORTS FACTORY ACCEPTANCE TEST “AS-BUILT”

9、DRAWINGS,STANDARD OPERATING PROCEDURES MFG BATCH RECORDS PERSONNEL TRAINING CALIBRATION PREVENTATIVE MTCE CHANGE CONTROL COMP

10、LIANCE VENDOR AUDITS ANNUAL REVIEWS COMPLAINTS SAFETY,Operations / QA,Validation,驗(yàn)證的界限/范圍,11,Validation Life Cycle Approach,Prospective / Concurrent,Define SpecificationsEquipment Process Requir

11、ements,Procedures,Design/Specify Equipment,Define Process,Develop Procedure Spec.,Install Equipment,Verify Procedure Specifications,Qualify Equipment,Develop ValidationProtocol,Obtain Data on Process

12、,Obtain Data on Process,Validation Report,Three LotsProspective,Acceptance,OngoingEvaluation,Change Control,New / Revised Process / Product,驗(yàn)證生命周期:新的/修改過的工藝/產(chǎn)品,12,Validation Life Cycle Approach,Retrospective

13、,Define SystemSpecificationsEquipment Procedures,QualifyEquipment,Review Process Capability,Specifications, Procedures,Operating Instructions,Develop ValidationProtocol,Validation Report,Acceptance,OngoingEval

14、uation,Data,Conduct Testing(If Needed),Change Control,Existing Process / Product,驗(yàn)證生命周期:現(xiàn)有工藝/產(chǎn)品,13,Benefits of Validation,Increased ThroughputReduction In Rejections and ReworksReduction In Utility CostsAvoidance Of

15、 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 Equipm

16、entEasier Scale-up From Development WorkEasier Maintenance Of The EquipmentImproved Employee Awareness Of ProcessesMore Rapid Automation,驗(yàn)證帶來的好處,14,Elements Of Contemporary Validation In The US,Equipment Calibration

17、- Process and Validation EquipmentEquipment Qualification - Installation and OperationalProcess DevelopmentProcess DocumentationPerformance Qualification - "Validation"Maintenance of Validation - Process a

18、nd Equipment Change Control,當(dāng)今美國驗(yàn)證包含的內(nèi)容,15,cGMP and ISO-9000 - Similarities,Aimed at QualityRequire DocumentationRequire Specific Quality ProgramQA and QC Included,CGMP和 ISO 9000的相似之處,16,cGMP and ISO-9000 - Differen

19、ces,cGMP Aimed at ProductISO-9000 Includes Design and Service, as wellcGMP Covers Activities Directly Related to ManufacturingISO-9000 Covers Broader Range of Activities (e.g.. Purchasing)cGMP Requires Formal Valid

20、ationISO-9000 Requires Applicable Statistical Methods,CGMP和 ISO 9000的不同之處,17,Benefits of the Systems Approach to Validation,More Rigorous Control Over OperationsCentralized Planning for all Validation Related AspectsT

21、ies 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 within

22、 the Validation ExpertiseUsually Results in Centralization of Validation ExpertiseMore Compatible with the Accomplishment of a Corporate Objective for Validation,系統(tǒng)驗(yàn)證方法的好處,18,The Validation Program,Establish Goals and

23、Objectives as to What Must be ValidatedQualify or Re-qualify the EquipmentEstablish Validation Protocols for each, and obtain Approval of the ProtocolsEstablish Personnel Requirements and Training Records ProcedureD

24、esign and Conduct Experiments. Collect DataEvaluate the DataPrepare Summary Reports Outlining the Results of the Experiments. Obtain the Necessary ApprovalsEstablish and Maintain Validation Files Including Raw Dat

25、aInstitute a Change Control Procedure to Insure the Ongoing Acceptability of the Work,驗(yàn)證項(xiàng)目/規(guī)劃,19,Part Two: GMP Requirements,第二部分：GMP對驗(yàn)證的要求,20,GMP requirements,Part 211: Current good manufacturing practice for finished p

26、harmaceuticals   §211.68 - Automatic, mechanical, and electronic equipment.   §211.84 - Testing and approval or rejection of components, drug product containers, and closures.   

27、;§211.110 - Sampling and testing of in-process materials and drug products.   §211.113 - Control of microbiological contamination.   §211.165 - Testing and release for distribution.

28、  §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

29、 the pharmaceutical industry in an effort to maintain the highest standards of quality in the development, manufacture and control of medicinal products. Since the industry standards are subject to continuous improvemen

30、t, the letter ‘c’ in the abbreviation “cGMP” refers more specifically to the current or the latest version of the GMP requirements.,制藥行業(yè)的cGMP,22,Regulatory Requirements for Validation.....,The requirement of process vali

31、dation 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 id

32、entity, strength, quality, and purity they purport or are represented to possess.",監(jiān)管部門對驗(yàn)證的要求,23,GMP Regulatory Requirements for Cleaning Validation,1978 cGMP Regulations (part 211.67(a)) Equipment cleaning and mai

33、ntenance states: “Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or puri

34、ty of the drug product beyond the official or other established requirements”.,GMP條例對清洗驗(yàn)證的要求,24,GMP Regulatory Requirements for Test Method Validation,Laboratory Controls 21 CFR 211.165(e) states: The accuracy, s

35、ensitivity, 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條例對化

36、驗(yàn)方法驗(yàn)證的要求,25,GMP Regulatory Requirements for Test Method Validation,Part 211.194(a)(2) states: A statement of each method used. . . shall indicate the location of data that establish that the methods used in the

37、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 verified under actual conditions of use.,GMP條例對化驗(yàn)方法驗(yàn)證的要求,26,

38、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 te

39、st methods had to be shown to be effective.,GMP條例對化驗(yàn)方法驗(yàn)證的要求,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

40、processes that may be responsible for causing variability in the characteristics of in-process material and the drug product”,工藝驗(yàn)證,28,Part Three: History and Expectations,As applied by the FDA and Implemented by Industry

41、,第三部分：驗(yàn)證歷史與FDA和制藥行業(yè)對驗(yàn)證的期望,29,History and expectations,Learn for the experiences of the USA manufacturers and industry organizations Current applicationsPast citationsIndustry guidelinesICH Q7AISPEPDAEtc.,歷史與期望,30

42、,Validation Targets,Early YearsSterilizationAseptic OperationsMiddle YearsNon-sterile ProcessesOral Dosage Forms,Recent YearsBiological ProcessesBulk Organic SynthesisDevelopmental and Pilot Operations

43、Supporting ServicesCurrentlyTotal OperationsReview by SystemsQuality System Production System Laboratory ControlsPackaging and Labeling, Materials and FacilitiesEquipment Manufacturing.,驗(yàn)證目標(biāo),31,History

44、 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 DefensiveSome Eff

45、orts at Process OptimizationIncludes Some Peripheral ConcernsValidation in the US Today - 1983 to PresentNon- Regulatory in Many Areas Geared Towards Optimization and focused on Systems,驗(yàn)證歷史,32,"validation&quo

46、t; vs. "VALIDATION","validation"DefensiveTesting OrientedCostlyQuality ControlNarrow Focus,"VALIDATION"OptimizationTotal Process ControlCost EffectiveQuality AssuranceDiv

47、erse Application,如何正確理解驗(yàn)證,33,Elements of Contemporary Validation in the US,Equipment Calibration - Process and Validation EquipmentEquipment Qualification - Installation and OperationalProcess DevelopmentProcess Docum

48、entationPerformance Qualification - "Validation"Maintenance of Validation -Process and Equipment Change Control,當(dāng)今美國驗(yàn)證所包含的內(nèi)容/要素,34,Expectations,Validation is a Program not a ProjectValidation Contributes to

49、 the Stability of the OperationsValidation is not Someone Else's Job!,對驗(yàn)證的期望,35,Part Four: Validation,An Overview,第四部分：驗(yàn)證概述,36,Who Validates?,Validation Staff,Engineering,Quality Assurance,Quality Control,Manufactur

50、ing,誰進(jìn)行驗(yàn)證？,37,Validation,v,Design,Testing,Operation,驗(yàn)證,運(yùn)作,38,Validation,v,,Vendor,SystemsIntegrator,Owner/User,驗(yàn)證,系統(tǒng)集成者,39,Validation,v,EngineeringR&D,Validation TeamMaintenance,ManufacturingQuality Assurance,驗(yàn)證,

51、制造質(zhì)量保障,40,Write Protocols,起草方案,41,Example Data Sheets,數(shù)據(jù)單樣品,42,Conduct Testing,,Chemical Tests,Careful Review andMarkup of Prints, Specs,MicrobiologicalTests,Physical Tests(Temp., Press., Flow),Computer Tests,進(jìn)行測試,43,

52、Installation Qualification (IQ),IQ documents thatsystem is installed in accordance with approved design, specification and regulatory codesmanufacturers installation recommendation have been taken into considerationIQ

53、s implemented concurrently with construction of each system,安裝合格確認(rèn),44,Operational Qualification (OQ),OQ documents that the equipment:can operate as designed and intendedis capable of repeatable operation over the entir

54、e operating range of process variablesOQ executed when equipment can be started up,運(yùn)轉(zhuǎn)/運(yùn)作合格確認(rèn),45,Process Qualification (PQ),PQ documentscritical systems which can be challengedtest proceduresproduct quality attribute

55、s to be evaluatedacceptance criteriaalert/action levelssystem validated under "worst case conditions"generally 3 consecutive successful runs required,工藝合格確認(rèn),46,Definition of Process Validation,,,,,,,,,,,,,,

56、,,,1978,Validation is: Documented evidence that provides a high degree of assurance that a specific process will consistently produce a product of a certain predetermined quality.,工藝驗(yàn)證定義,47,Definition of Process Validat

57、ion,In addition to documented evidence that a process will perform reliably and repeatedly, validation, in its highest form, provides an understanding of why.,1993,工藝驗(yàn)證定義,48,Stages of the Life-Cycle,R&D,Design,Constr

58、uction,Testing,SOPs/Maintenance,,,,,,,,,,Change Control,生命周期的階段,49,Benefits of Validation,Increased ThroughputReduction in Rejections and ReworksReduction in Utility CostsAvoidance Of Capital ExpendituresFewer Compl

59、aints 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 Developm

60、ent WorkEasier Maintenance Of The EquipmentImproved Employee Awareness Of ProcessesMore Rapid Automation,驗(yàn)證的好處,50,Documentation of Validation,Master PlanProtocolData SheetsReportProcedures,驗(yàn)證文件,51,Validation Proto

61、cols,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 Regu

62、latory Agencies,驗(yàn)證方案,52,Validation Protocol Essential Elements,Introduction/AbstractDescription of Process or SystemTest PlanResponsibilitiesAcceptance CriteriaApprovalsAppend Data Sheets, Etc.,驗(yàn)證方案的核心要素,53,Validat

63、ion Reports – Functions,Restrict to One Task or SubjectHas a Unique IdentificationIs DatedFormally Reviewed and ApprovedIdentifies Protocol(s) Used in the StudyIs Suitable for Review by FDA,驗(yàn)證報(bào)告－功能,54,Validation Rep

64、ort - Contents,Abstract Or Summary ConclusionPlan Of StudyExperimentalResultsConclusionsProtocol ReferenceDiagramsAny Miscellaneous InformationApprovals,驗(yàn)證報(bào)告－內(nèi)容,55,Installation Qualification (IQ),IQ Documents Tha

65、t The:System is Installed in Accordance with Approved Design, Specifications and Regulatory CodesManufacturers Installation Recommendations have been taken into ConsiderationIQ is Implemented Concurrently with Constr

66、uction of Each System,安裝合格確認(rèn),56,Design Documentation,Design and Procurement Documentation Support of IQ:PFDs/P&IDsCritical System Installation Drawings (E.G. Water System Isometrics, Sanitary Duct Drawings)Purcha

67、se and Installation SpecificationsVendor Manuals and PrintsComputer Software Documentation,設(shè)計(jì)文件,57,Construction Documentation,Construction Documents In Support Of IQ:Slope ChecksPiping Pressure Test ReportsMotor Ch

68、eckout 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 & Instrumen

69、tation Diagram, Engineering Flow Diagram),Process EquipmentSupport VesselsInterconnecting LinesUtility LinesInstruments/Instrument FunctionsSchematicNo Scale - Not Spatially PreciseShows Relationships and Relative