国际上不同分析方法验证准则概述

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1、国际国际上不同分析方法上不同分析方法验证验证的准的准则概则概述述7/8/20107/8/2010蔡磊明蔡磊明 分析方法验证是论证某一分析方法适用于其用途分析方法验证是论证某一分析方法适用于其用途的过程。的过程。Analytical method validation is the process to confirm that the analytical procedure employed for a specific test is suitable for its intended use.分析方法验证分析方法验证Method Validation 7/8/20107/8/2010Sl

2、ide 3Criteria for Method ValidationLimit of detectionLimit of quantitation Precision(Intermediate precision)Accuracy Linearity/RangeSelectivity/SpecificityRuggednessRobustnessActual validation effort depends on the analysis problemProof suitability for intended useDefinition Method ScopeDefine Valid

3、ation CriteriaTestDefine Routine TestsValidation of Analytical MethodslSample matrixlCompoundslEquipment,LocationlOptimize method parameterslDefine performance characteristicslAcceptance criterialDevelop test caseslPreliminary testslFinal testslSOPslSystem Suitability testslAnalytical quality contro

4、lSlide 5Scope of the MethodCompounds,Sample matrixQualitative/quantitative informationOperating range(concentration)Performance characteristicsInstrument(specific brand,product e.g.,Agilent 1200 Series)Location(specific lab,specific site,global)Specific regulatory/standards requirements(e.g.,part 21

5、 CFR Part 11,ISO17025)International regulatory bodies and their guidelines on different aspects of MVBodyFull nameGuidance onEurachemFocus for Analytical Chemistry in EuropeMethod validationCITACCooperation of International Traceability in Analytical ChemistryProficiency testingQuality AssuranceEAEu

6、ropean Cooperation for AccreditationAccreditationCENEuropean Committee for NormalizationStandardizationIUPACInternational Union of Pure&Applied Chem.Method validationISOInternational Standardization OrganisationStandardisationAOACILACAssociation of Official Analytical ChemistsInternational Laborator

7、y Accreditation Cooperat.Internal qual.ControlProficiency testingAccreditation FDAUS Food and Drug AdministrationMethod validationUSPUnited States PharmacopoeiaMethod validationICHInternational Conference on HarmonizationMethod validationExamples of Methods That Require Validation DocumentationChrom

8、atographic Methods-HPLC,GC,TLC,GC/MS,etc.Pharmaceutical Analysis-In support of CMC.Bioanalytical Analysis-In support of PK/PD/Clinical Studies.Spectrophotometric Methods UV/VIS,IR,NIR,AA,NMR,XRD,MSCapillary Electrophoresis Methods-Zone,Isoelectric Focusing Particle Size Analysis Methods-Laser,Micros

9、copic,Sieving,SEC,etc.Automated Analytical Methods-Robots,Automated Analysis.77/8/20107/8/2010Considerations Prior to Method ValidationSuitability of Instrument vStatus of Qualification and Calibration Suitability of Materials vStatus of Reference Standards,Reagents,Placebo Lots Suitability of Analy

10、st vStatus of Training and Qualification Records Suitability of Documentation vWritten analytical procedure and proper approved protocol with pre-established acceptance criteria87/8/20107/8/2010Validation Step Define the application,purpose and scope of the method.Analytes?Concentration?Sample matri

11、ces?Develop a analytical method.Develop a validation protocol.Qualification of instrument.Qualify/train operator Qualification of material.Perform pre-validation experiments.Adjust method parameters and/or acceptance criteria if necessary.Perform full validation experiments.Develop SOP for executing

12、 the method in routine analysis.Document validation experiments and results in the validation report.97/8/20107/8/2010Purpose of Method ValidationIdentification of Sources and Quantitation of Potential errorsDetermination if Method is Acceptable for Intended UseEstablish Proof that a Method Can be U

13、sed for Decision MakingSatisfy Regulatory RequirementsValidation Reporttype of compounds and matrixdetailed chemicals,reagents,reference standards and control sample preparationsprocedures for quality checks of standards and chemicals usedsafety considerationsmethod parameterscritical parameters ind

14、icated from robustness testinglisting of equipment and its functional and performance requirements,e.g.cell dimensions,baseline noise,column temperature rangedetailed conditions on how the experiments were conducted,including sample preparationstatistical procedures and representative calculationspr

15、ocedures for quality control in the routine(e.g.,system suitability tests)representative plots,e.g.chromatograms,spectra and calibration curvesmethod acceptance limit performance datathe expected uncertainty of measurement resultscriteria for revalidationperson who developed and initially validated

16、the methodsummary and conclusionsUS FDA Validation GuidelinesFDA Guidance for Industry:Analytical Procedures and Methods Validation(DRAFT),August 2000 FDA Policy guide:Requesting Methods Validation for Abbreviated New Drug Applications(ANDAs),May 1998 FDA Guidance for Industry:Bioanalytical Method V

17、alidation,May 2001 FDA Guidance:Mass,Spectrometry for Confirmation of the Identity of Animal Drug Residues(Draft),FDA Guidance:Guideline for Submitting Samples and Analytical Data for Methods Validation FDA Guidance:Protocol for the Conduct of Method Transfer for Type C Medicated Feed Assay Methods,

18、May 2007US FDA Validation GuidelinesFDA Guidance for Industry:Analytical Procedures and Methods Validation(DRAFT),August 2000 FDA Policy guide:Requesting Methods Validation for Abbreviated New Drug Applications(ANDAs),May 1998 FDA Guidance for Industry:Bioanalytical Method Validation,May 2001 FDA Gu

19、idance:Mass,Spectrometry for Confirmation of the Identity of Animal Drug Residues(Draft),FDA Guidance:Guideline for Submitting Samples and Analytical Data for Methods Validation FDA Guidance:Protocol for the Conduct of Method Transfer for Type C Medicated Feed Assay Methods,May 2007ICH Validation Gu

20、idelinesICH-Guidance for Industry:Q2A-Text on Validation of Analytical Procedures ICH-Guidance for Industry:Q2B-Validation of Analytical Procedures-MethodologyEU Validation GuidelinesEURACHEM The Fitness for Purpose of Analytical Methods Probably the most detailed official document for method valida

21、tion,1998EMEA Guide Residues:Guidance for generating and reporting methods of analysis in support of pre-registration data requirements for Annex II(part A,Section 4)and Annex III(part A,Section 5)of Directive 91/414,Nov.2000Australian Validation Guidelines TGA Guide(Australia)-Starting Material Ana

22、lytical Procedure Validation for Complimentary Medicines,March 2006 NATA Technical Note#17-Guidelines for the Validation and Verification of Chemical Test Methods,April 2009US EPA Validation GuidelinesUS EPA Guide to Method Flexibility and Approval of EPA Water Methods 40 CFR Part 136 Guidelines Est

23、ablishing Test Procedures for the Analysis of Pollutants;Analytical Methods for Biological Pollutants in Ambient Water;Final Rule,Jan.31,200340 CFR Parts 136 and 503 Guidelines Establishing Test Procedures for the Analysis of Pollutants;Analytical Methods for Biological Pollutants in Wastewater and

24、Sewage Sludge:March 26,2007 US EPA,Guidance for methods development and methods validation for the Resource Conservation and Recovery Act(RCRA)Program,Washington,1995Validation GuidelinesIUPAC Technical Report:Harmonized Guidelines for Single Laboratory Validation of Methods of Analysis Pure Appl.Ch

25、em.,Vol.74,No.5,pp.835-855,2002AOAC How to Meet ISO 17025 Requirements for Method Verification.Prepared by AOAC INTERNATIONAL 481 N.Frederick Ave,Suite 500,2007United States Pharmacopeia,Validation of Compendial Methods,e.g.,XXVI,Rockville,MD,2002 2149/2152(Chapter 1225),1999Regulatory and Complianc

26、e Requirements Reviewn FDA regulations such as GMP,GLP and GCP and qualitFDA regulations such as GMP,GLP and GCP and quality standards such as ISO17025 require analytical methoy standards such as ISO17025 require analytical methods to be validated before and during routine use.ds to be validated bef

27、ore and during routine use.n There are no specific regulations on method validations There are no specific regulations on method validations but the FDA,other agencies and industry task forces hbut the FDA,other agencies and industry task forces have developed guidelines for method validation.ave de

28、veloped guidelines for method validation.Validation Requirements&Parameters ICH/USP Validation Requirements&Parameters SpecificityLinearityRangeAccuracyPrecision RepeatabilityIntermediate PrecisionReproducibilityLimit of DetectionLimit of QuantitationICHICHUSPUSPUSP Categories Category 1:Quantitatio

29、n of major components or active ingredients Category 2:Determination of impurities or degradation products Category 3:Determination of performance characteristicsUSP Data Elements Required For Assay ValidationAnalytical Analytical PerformancePerformanceParameterParameterAssay CategAssay Category 1or

30、y 1Assay Category 2Assay Category 2Assay CateAssay Category 3gory 3QuantitativeQuantitativeLimit TestsLimit TestsAccuracyAccuracyYesYesYesYes*PrecisionPrecisionYesYesYesYesNoNoYesYesSpecificitySpecificityYesYesYesYesYesYes*LODLODNoNoNoNoYesYes*LOQLOQNoNoYesYesNoNo*LinearityLinearityYesYesYesYesNoNo*

31、RangeRangeYesYesYesYes*RuggednessRuggednessYesYesYesYesYesYesYesYes*May be required,depending on the nature of the specific test.May be required,depending on the nature of the specific test.ICH Validation Characteristics vs.Type of Analytical ProcedureType of AnalytiType of Analytical cal ProcedureP

32、rocedureIdentificationIdentificationImpurity testingImpurity testingAssayAssayQuantitativeQuantitativeLimit TestsLimit TestsAccuracyAccuracyNoNoYesYesNoNoYesYesPrecisionPrecision Repeatability RepeatabilityNoNoYesYesNoNoYesYes Interm.Prec.Interm.Prec.NoNoYesYesNoNoYesYesSpecificitySpecificityYesYesY

33、esYesYesYesYesYesLODLODNoNoNoNoYesYesNoNoLOQLOQNoNoYesYesNoNoNoNoLinearityLinearityNoNoYesYesNoNoYesYesRangeRangeNoNoYesYesNoNoYesYesAOAC Categories of Chemical MethodsCategory 1:Confirmation of IdentityCategory 2:Quantifying an analyte at a low concentration Category 3:Determining if an analyte is

34、present above or below a specified,low concentration(often called a Limit Test).The specified concentration is close to the LOQ.Category 4:Quantifying an analyte at a high concentrationCategory 5:Determining if an analyte is present above or below a specified,high concentration(often called a Limit

35、Test).The specified concentration is substantially above the LOQ.Category 6:Qualitative test.AOAC Validation Characteristics vs.Type of Analytical ProcedureType of AnaType of Analytical lytical ProcedureProcedurePerformance Characteristics Included in a ValidationPerformance Characteristics Included

36、 in a ValidationCategory Category 1 1CategoryCategory 2 2CategoryCategory 3 3CategoryCategory 4 4CategoryCategory 5 5CategoryCategory 6 6AccuracyAccuracyNoNoYesYesNoNoYesYesYesYesNoNoPrecisionPrecisionNoNoYesYesNoNoYesYesYesYesNoNoSpecificitySpecificityYesYesYesYesYesYesYesYesYesYesYesYesLODLODNoNoY

37、esYesYesYesYesYes/NoNoNoNoNoNoLOQLOQNoNoYesYesNoNoYesYes/NoNoNoNoNoNoRuggednessRuggednessNoNoYesYesNoNoYesYesNoNoNoNoLinearity/RangeLinearity/RangeNoNoYesYesNoNoYesYesNoNoNoNoAOAC Validation Characteristics-Analyte concentration versus precision within orbetween daysAOAC Validation Characteristics-A

38、nalyte recovery at different concentrationsHow do we Know the expectations of the FDA?FDA Form 483 FDA Warning Letters Personal Experiences483 Observations There was inadequate method validation specificity data to demonstrate that each method was capable of distinguishing the active ingredient from

39、 its impurities and degradation products.Specificity studies did not include the minimum stress conditions of acid and base hydrolysis,oxidation,thermal degradation and photolysis,degradation schematic for the active ingredient that identifies the major degradation products was not included for each

40、 product.3020092009FDA Waning LetterOn addition to the example of modifying both compendial methods and customer supplied methods,we also observed the use of unvalidated in-house methods as well as unvalidated modifications to in-house methods.A statement indicating that the method has not been vali

41、dated in the particular formulation was included in the certificate of analysis foruse of this statement does not absolvefrom using valid,accurate,and reproducible methods.(June 2000)3120092009FDA Systems Based Inspection:Laboratory System32Method Method ValidationValidation13%13%Training/Qual.Train

42、ing/Qual.4%4%Stability Program Stability Program 21%21%InadequateInadequateRecordsRecords27%27%Controls.GeneralControls.General35%35%Feb Feb July 2002:212 Inspections(US)July 2002:212 Inspections(US)*Reference:Albinus D Reference:Albinus D Sa,FDA,CDER Office of Compliance,from AAPS,Nov.2002 presentation.Sa,FDA,CDER Office of Compliance,from AAPS,Nov.2002 presentation.20092009Related Site