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1、国际上不同分析方法验证的准则概述,7/8/2010,蔡磊明,分析方法验证是论证某一分析方法适用于其用途的过程。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Method Validation,7/8/2010,Slide 3,Criteria for Method Validation,Limit of detectionLimit o
2、f quantitation Precision(Intermediate precision)Accuracy Linearity/RangeSelectivity/SpecificityRuggednessRobustness,Actual validation effort depends on the analysis problem,Proof suitability for intended use,Definition Method Scope,Define Validation Criteria,Test,Define Routine Tests,Validation of A
3、nalytical Methods,Sample matrixCompoundsEquipment,Location,Optimize method parametersDefine performance characteristicsAcceptance criteria,Develop test casesPreliminary testsFinal tests,SOPsSystem Suitability testsAnalytical quality control,Validation Plan,Validation Report,Slide 5,Scope of the Meth
4、od,Compounds,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 CFR Part 11,ISO17025),I
5、nternational regulatory bodies and their guidelines on different aspects of MV,Examples of Methods That Require Validation Documentation,Chromatographic Methods-HPLC,GC,TLC,GC/MS,etc.Pharmaceutical Analysis-In support of CMC.Bioanalytical Analysis-In support of PK/PD/Clinical Studies.Spectrophotomet
6、ric Methods UV/VIS,IR,NIR,AA,NMR,XRD,MSCapillary Electrophoresis Methods-Zone,Isoelectric Focusing Particle Size Analysis Methods-Laser,Microscopic,Sieving,SEC,etc.Automated Analytical Methods-Robots,Automated Analysis.,7,7/8/2010,Considerations Prior to Method Validation,Suitability of Instrument S
7、tatus of Qualification and Calibration Suitability of Materials Status of Reference Standards,Reagents,Placebo Lots Suitability of Analyst Status of Training and Qualification Records Suitability of Documentation Written analytical procedure and proper approved protocol with pre-established acceptan
8、ce criteria,8,7/8/2010,Validation Step,Define the application,purpose and scope of the method.Analytes?Concentration?Sample matrices?Develop a analytical method.Develop a validation protocol.Qualification of instrument.Qualify/train operator Qualification of material.Perform pre-validation experimen
9、ts.Adjust method parameters and/or acceptance criteria if necessary.Perform full validation experiments.Develop SOP for executing the method in routine analysis.Document validation experiments and results in the validation report.,9,7/8/2010,Purpose of Method Validation,Identification of Sources and
10、 Quantitation of Potential errorsDetermination if Method is Acceptable for Intended UseEstablish Proof that a Method Can be Used for Decision MakingSatisfy Regulatory Requirements,Validation Report,type of compounds and matrixdetailed chemicals,reagents,reference standards and control sample prepara
11、tionsprocedures for quality checks of standards and chemicals usedsafety considerationsmethod parameterscritical parameters indicated from robustness testinglisting of equipment and its functional and performance requirements,e.g.cell dimensions,baseline noise,column temperature rangedetailed condit
12、ions on how the experiments were conducted,including sample preparationstatistical procedures and representative calculationsprocedures for quality control in the routine(e.g.,system suitability tests)representative plots,e.g.chromatograms,spectra and calibration curvesmethod acceptance limit perfor
13、mance datathe expected uncertainty of measurement resultscriteria for revalidationperson who developed and initially validated the methodsummary and conclusions,US FDA Validation Guidelines,FDA Guidance for Industry:Analytical Procedures and Methods Validation(DRAFT),August 2000 FDA Policy guide:Req
14、uesting Methods Validation for Abbreviated New Drug Applications(ANDAs),May 1998 FDA Guidance for Industry:Bioanalytical Method Validation,May 2001 FDA Guidance:Mass,Spectrometry for Confirmation of the Identity of Animal Drug Residues(Draft),FDA Guidance:Guideline for Submitting Samples and Analyti
15、cal Data for Methods Validation FDA Guidance:Protocol for the Conduct of Method Transfer for Type C Medicated Feed Assay Methods,May 2007,US FDA Validation Guidelines,FDA Guidance for Industry:Analytical Procedures and Methods Validation(DRAFT),August 2000 FDA Policy guide:Requesting Methods Validat
16、ion for Abbreviated New Drug Applications(ANDAs),May 1998 FDA Guidance for Industry:Bioanalytical Method Validation,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 Va
17、lidation FDA Guidance:Protocol for the Conduct of Method Transfer for Type C Medicated Feed Assay Methods,May 2007,ICH Validation Guidelines,ICH-Guidance for Industry:Q2A-Text on Validation of Analytical Procedures ICH-Guidance for Industry:Q2B-Validation of Analytical Procedures-Methodology,EU Vali
18、dation Guidelines,EURACHEM The Fitness for Purpose of Analytical Methods Probably the most detailed official document for method validation,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
19、)and Annex III(part A,Section 5)of Directive 91/414,Nov.2000,Australian Validation Guidelines,TGA Guide(Australia)-Starting Material Analytical Procedure Validation for Complimentary Medicines,March 2006NATA Technical Note#17-Guidelines for the Validation and Verification of Chemical Test Methods,Ap
20、ril 2009,US EPA Validation Guidelines,US EPA Guide to Method Flexibility and Approval of EPA Water Methods 40 CFR Part 136 Guidelines Establishing Test Procedures for the Analysis of Pollutants;Analytical Methods for Biological Pollutants in Ambient Water;Final Rule,Jan.31,200340 CFR Parts 136 and 5
21、03 Guidelines Establishing Test Procedures for the Analysis of Pollutants;Analytical Methods for Biological Pollutants in Wastewater and Sewage Sludge:March 26,2007 US EPA,Guidance for methods development and methods validation for the Resource Conservation and Recovery Act(RCRA)Program,Washington,1
22、995,Validation Guidelines,IUPAC Technical Report:Harmonized Guidelines for Single Laboratory Validation of Methods of Analysis Pure Appl.Chem.,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 500,2007U
23、nited States Pharmacopeia,Validation of Compendial Methods,e.g.,XXVI,Rockville,MD,2002 2149/2152(Chapter 1225),1999,Regulatory and Compliance Requirements Review,FDA regulations such as GMP,GLP and GCP and quality standards such as ISO17025 require analytical methods to be validated before and durin
24、g routine use.There are no specific regulations on method validations but the FDA,other agencies and industry task forces have developed guidelines for method validation.,Validation Requirements&Parameters,ICH/USP Validation Requirements&Parameters,SpecificityLinearityRangeAccuracyPrecision Repeatab
25、ilityIntermediate PrecisionReproducibilityLimit of DetectionLimit of Quantitation,ICH,SpecificityLinearity and RangeAccuracyPrecision Limit of DetectionLimit of QuantitationRuggednessRobustness,USP,USP Categories,Category 1:Quantitation of major components or active ingredientsCategory 2:Determinati
26、on of impurities or degradation productsCategory 3:Determination of performance characteristics,USP Data Elements Required For Assay Validation,*May be required,depending on the nature of the specific test.,ICH Validation Characteristics vs.Type of Analytical Procedure,AOAC Categories of Chemical Me
27、thods,Category 1:Confirmation of IdentityCategory 2:Quantifying an analyte at a low concentration Category 3:Determining if an analyte is 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
28、at a high concentrationCategory 5:Determining if an analyte is present above or below a specified,high concentration(often called a Limit Test).The specified concentration is substantially above the LOQ.Category 6:Qualitative test.,AOAC Validation Characteristics vs.Type of Analytical Procedure,AOAC
29、 Validation Characteristics-Analyte concentration versus precision within orbetween days,AOAC Validation Characteristics-Analyte recovery at different concentrations,How do we Know the expectations of the FDA?,FDA Form 483FDA Warning LettersPersonal Experiences,483 Observations,There was inadequate
30、method validation specificity data to demonstrate that each method was capable of distinguishing the active ingredient from its impurities and degradation products.Specificity studies did not include the minimum stress conditions of acid and base hydrolysis,oxidation,thermal degradation and photolys
31、is,degradation schematic for the active ingredient that identifies the major degradation products was not included for each product.,30,2009,FDA Waning Letter,On addition to the example of modifying both compendial methods and customer supplied methods,we also observed the use of unvalidated in-hous
32、e methods as well as unvalidated modifications to in-house methods.A statement indicating that the method has not been validated 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),31,2009,FDA Systems Based Inspection:Laboratory System,32,Feb July 2002:212 Inspections(US),*Reference:Albinus D Sa,FDA,CDER Office of Compliance,from AAPS,Nov.2002 presentation.,2009,Related Site,
