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 detection Limi
2、t of quantitation Precision (Intermediate precision) Accuracy Linearity/Range Selectivity/Specificity Ruggedness Robustness,Actual validation effort depends on the analysis problem,Proof suitability for intended use,Definition Method Scope,Define Validation Criteria,Test,Define Routine Tests,Validat
3、ion of Analytical Methods,Sample matrix Compounds Equipment, Location,Optimize method parameters Define performance characteristics Acceptance criteria,Develop test cases Preliminary tests Final tests,SOPs System Suitability tests Analytical quality control,Validation Plan,Validation Report,Slide 5,
4、Scope of the Method,Compounds, Sample matrix Qualitative/quantitative information Operating range (concentration) Performance characteristics Instrument (specific brand, product e.g., Agilent 1200 Series) Location (specific lab, specific site, global) Specific regulatory/standards requirements (e.g.
5、, part 21 CFR Part 11, ISO17025),International 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 sup
6、port of PK/PD/Clinical Studies. Spectrophotometric Methods UV/VIS, IR, NIR, AA, NMR, XRD,MS Capillary Electrophoresis Methods - Zone, Isoelectric Focusing Particle Size Analysis Methods - Laser, Microscopic, Sieving, SEC, etc. Automated Analytical Methods - Robots, Automated Analysis.,7,7/8/2010,Con
7、siderations Prior to Method Validation,Suitability of Instrument Status 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
8、procedure and proper approved protocol with pre-established acceptance 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/tr
9、ain operatorQualification of material.Perform pre-validation experiments.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.
10、,9,7/8/2010,Purpose of Method Validation,Identification of Sources and Quantitation of Potential errors Determination if Method is Acceptable for Intended Use Establish Proof that a Method Can be Used for Decision Making Satisfy Regulatory Requirements,Validation Report,type of compounds and matrix
11、detailed chemicals, reagents, reference standards and control sample preparations procedures for quality checks of standards and chemicals used safety considerations method parameters critical parameters indicated from robustness testing listing of equipment and its functional and performance requir
12、ements, e.g. cell dimensions, baseline noise, column temperature range detailed conditions on how the experiments were conducted, including sample preparation statistical procedures and representative calculations procedures for quality control in the routine (e.g., system suitability tests) represe
13、ntative plots, e.g. chromatograms, spectra and calibration curves method acceptance limit performance data the expected uncertainty of measurement results criteria for revalidation person who developed and initially validated the method summary and conclusions,US FDA Validation Guidelines,FDA Guidan
14、ce for Industry: Analytical Procedures and Methods Validation (DRAFT), August 2000 FDA Policy guide: Requesting Methods Validation for Abbreviated New Drug Applications (ANDAs), May 1998FDA Guidance for Industry: Bioanalytical Method Validation, May 2001 FDA Guidance: Mass, Spectrometry for Confirma
15、tion of the Identity of Animal Drug Residues (Draft), FDA Guidance: Guideline for Submitting Samples and Analytical Data for Methods ValidationFDA Guidance: Protocol for the Conduct of Method Transfer for Type C Medicated Feed Assay Methods, May 2007,US FDA Validation Guidelines,FDA Guidance for Ind
16、ustry: Analytical Procedures and Methods Validation (DRAFT), August 2000 FDA Policy guide: Requesting Methods Validation for Abbreviated New Drug Applications (ANDAs), May 1998FDA Guidance for Industry: Bioanalytical Method Validation, May 2001 FDA Guidance: Mass, Spectrometry for Confirmation of th
17、e Identity of Animal Drug Residues (Draft), FDA Guidance: Guideline for Submitting Samples and Analytical Data for Methods ValidationFDA 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
18、- Text on Validation of Analytical Procedures ICH - Guidance for Industry: Q2B - Validation of Analytical Procedures - Methodology,EU Validation Guidelines,EURACHEM The Fitness for Purpose of Analytical Methods Probably the most detailed official document for method validation, 1998EMEA Guide Residu
19、es: 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. 2000,Australian Validation Guidelines,TGA Guide (Australia)-Starting Material Analytical Procedu
20、re Validation for Complimentary Medicines,March 2006NATA Technical Note #17 - Guidelines for the Validation and Verification of Chemical Test Methods, April 2009,US EPA Validation Guidelines,US EPA Guide to Method Flexibility and Approval of EPA Water Methods 40 CFR Part 136 Guidelines Establishing
21、Test Procedures for the Analysis of Pollutants; Analytical Methods for Biological Pollutants in Ambient Water; Final Rule, Jan. 31,2003 40 CFR Parts 136 and 503 Guidelines Establishing Test Procedures for the Analysis of Pollutants; Analytical Methods for Biological Pollutants in Wastewater and Sewa
22、ge Sludge:March 26, 2007 US EPA, Guidance for methods development and methods validation for the Resource Conservation and Recovery Act (RCRA) Program, Washington, 1995,Validation Guidelines,IUPAC Technical Report: Harmonized Guidelines for Single Laboratory Validation of Methods of Analysis Pure Ap
23、pl. 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, 2007United States Pharmacopeia, Validation of Compendial Methods, e.g., XXVI, Rockville, MD, 2002 2149/2152 (Chapter 1225) ,1
24、999,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 during routine use. There are no specific regulations on method validations but the FDA, other agencies and industry
25、 task forces have developed guidelines for method validation.,Validation Requirements & Parameters,ICH/USP Validation Requirements & Parameters,Specificity Linearity Range Accuracy Precision Repeatability Intermediate Precision Reproducibility Limit of Detection Limit of Quantitation,ICH,Specificity
26、 Linearity and Range Accuracy Precision Limit of Detection Limit of Quantitation Ruggedness Robustness,USP,USP Categories,Category 1: Quantitation of major components or active ingredients Category 2: Determination of impurities or degradation products Category 3: Determination of performance charac
27、teristics,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 Methods,Category 1: Confirmation of Identity Category 2: Quantifying an analyte at a
28、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 at a high concentration Category 5: Determining if an analyte is present a
29、bove 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 Validation Characteristics - Analyte concentration versus precisi
30、on within or between days,AOAC Validation Characteristics - Analyte recovery at different concentrations,How do we Know the expectations of the FDA?,FDA Form 483 FDA Warning Letters Personal Experiences,483 Observations,There was inadequate method validation specificity data to demonstrate that each
31、 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 photolysis, degradation schematic for the active ingredient that
32、 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-house methods as well as unvalidated modifications to in-h
33、ouse 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,www.fda.gov www.fda.gov/cder/ www.usp.org www.ich.org www.aoac.org ,
