ICH 分析程序的验证方法学.pdf

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1、INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICALREQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED TRIPARTITE GUIDELINE VALIDATION OF ANALYTICAL PROCEDURES:METHODOLOGYRecommended for Adoption at Step 4 of the ICH Process on 6 November 1996 by the ICHSteering Committe

2、e This Guideline has been developed by the appropriate ICH Expert Working Group and hasbeen subject to consultation by the regulatory parties,in accordance with the ICH Process.AtStep 4 of the Process the final draft is recommended for adoption to the regulatory bodies ofthe European Union,Japan and

3、 USA.VALIDATION OF ANALYTICAL PROCEDURES:METHODOLOGYICH Harmonised Tripartite Guideline Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 6November 1996,this guideline is recommended for adoption to the three regulatoryparties to ICH Noter til A301side 4.14.ICH method

4、ology TABLE OF CONTENTS INTRODUCTION4.3 1SPECIFICITY4.3 1.1Identification4.3 1.2Assay and Impurity Test(s)2LINEARITY4.4 3RANGE4.5 4ACCURACY4.5 4.1Assay4.5 4.2Impurities(Quantitation)4.6 4.3Recommended Data4.6 5PRECISION4.6 5.1Repeatability4.6 5.2Intermediate Precision4.7 5.3Reproducibility4.7 5.4Rec

5、ommended Data4.7 6DETECTION LIMIT4.7 6.1Based on Visual Evaluation4.7 6.2Based on Signal-to-Noise4.7 6.3Based on the Standard Deviation of the Response and the Slope4.7 6.4Recommended Data4.8 7QUANTITATION LIMIT4.8 7.1Based on Visual Evaluation4.8 7.1Based on Signal-to-Noise Approach4.8 7.3Based on

6、the Standard Deviation of the Response and the Slope4.8 7.4Recommended Data4.9 8ROBUSTNESS4.9 9SYSTEM SUITABILITY TESTING4.10Noter til A301side 4.24.ICH methodology VALIDATION OF ANALYTICAL PROCEDURES:METHODOLOGY INTRODUCTION This document is complementary to the parent document which presents a dis

7、cussion of thecharacteristics that should be considered during the validation of analytical procedures.Itspurpose is to provide some guidance and recommendations on how to consider the variousvalidation characteristics for each analytical procedure.In some cases (for example,demonstration of specifi

8、city),the overall capabilities of a number of analytical procedures incombination may be investigated in order to ensure the quality of the drug substance or drugproduct.In addition,the document provides an indication of the data which should bepresented in a registration application.All relevant da

9、ta collected during validation and formulae used for calculating validationcharacteristics should be submitted and discussed as appropriate.Approaches other than those set forth in this guideline may be applicable and acceptable.It isthe responsibility of the applicant to choose the validation proce

10、dure and protocol mostsuitable for their product.However it is important to remember that the main objective ofvalidation of an analytical procedure is to demonstrate that the procedure is suitable for itsintended purpose.Due to their complex nature,analytical procedures for biological andbiotechnol

11、ogical products in some cases may be approached differently than in thisdocument.Well-characterized reference materials,with documented purity,should be used throughoutthe validation study.The degree of purity necessary depends on the intended use.In accordance with the parent document,and for the s

12、ake of clarity,this document considersthe various validation characteristics in distinct sections.The arrangement of these sectionsreflects the process by which an analytical procedure may be developed and evaluated.In practice,it is usually possible to design the experimental work such that the app

13、ropriatevalidation characteristics can be considered simultaneously to provide a sound,overallknowledge of the capabilities of the analytical procedure,for instance:specificity,linearity,range,accuracy and precision.1.SPECIFICITY An investigation of specificity should be conducted during the validat

14、ion of identificationtests,the determination of impurities and the assay.The procedures used to demonstratespecificity will depend on the intended objective of the analytical procedure.It is not always possible to demonstrate that an analytical procedure is specific for aparticular analyte(complete

15、discrimination).In this case a combination of two or moreanalytical procedures is recommended to achieve the necessary level of discrimination.1.1.Identification Suitable identification tests should be able to discriminate between compounds of closelyrelated structures which are likely to be present

16、.The discrimination of a procedure may beconfirmed by obtaining positive results(perhaps by comparison with a known referencematerial)from samples containing the analyte,coupled with negative results from sampleswhich do not contain the analyte.In addition,the identification test may be applied toNo

17、ter til A301side 4.34.ICH methodology materials structurally similar to or closely related to the analyte to confirm that a positiveresponse is not obtained.The choice of such potentially interfering materials should be basedon sound scientific judgement with a consideration of the interferences tha

18、t could occur.1.2.Assay and Impurity Test(s)For chromatographic procedures,representative chromatograms should be used todemonstrate specificity and individual components should be appropriately labelled.Similarconsiderations should be given to other separation techniques.Critical separations in chr

19、omatography should be investigated at an appropriate level.Forcritical separations,specificity can be demonstrated by the resolution of the two componentswhich elute closest to each other.In cases where a non-specific assay is used,other supporting analytical procedures should beused to demonstrate

20、overall specificity.For example,where a titration is adopted to assay thedrug substance for release,the combination of the assay and a suitable test for impurities canbe used.The approach is similar for both assay and impurity tests:1.2.1 Impurities are available For the assay,this should involve de

21、monstration of the discrimination of the analyte in thepresence of impurities and/or excipients;practically,this can be done by spiking puresubstances(drug substance or drug product)with appropriate levels of impurities and/orexcipients and demonstrating that the assay result is unaffected by the pr

22、esence of thesematerials(by comparison with the assay result obtained on unspiked samples).For the impurity test,the discrimination may be established by spiking drug substance ordrug product with appropriate levels of impurities and demonstrating the separation of theseimpurities individually and/o

23、r from other components in the sample matrix.1.2.2 Impurities are not available If impurity or degradation product standards are unavailable,specificity may be demonstratedby comparing the test results of samples containing impurities or degradation products to asecond well-characterized procedure e

24、.g.:pharmacopoeial method or other validatedanalytical procedure(independent procedure).As appropriate,this should include samplesstored under relevant stress conditions:light,heat,humidity,acid/base hydrolysis andoxidation.-for the assay,the two results should be compared.-for the impurity tests,th

25、e impurity profiles should be compared.Peak purity tests may be useful to show that the analyte chromatographic peak is notattributable to more than one component(e.g.,diode array,mass spectrometry).2.LINEARITY A linear relationship should be evaluated across the range(see section 3)of the analytica

26、lprocedure.It may be demonstrated directly on the drug substance(by dilution of a standardstock solution)and/or separate weighings of synthetic mixtures of the drug productcomponents,using the proposed procedure.The latter aspect can be studied duringinvestigation of the range.Linearity should be ev

27、aluated by visual inspection of a plot of signals as a function of analyteconcentration or content.If there is a linear relationship,test results should be evaluated byappropriate statistical methods,for example,by calculation of a regression line by the methodNoter til A301side 4.44.ICH methodology

28、 of least squares.In some cases,to obtain linearity between assays and sample concentrations,the test data may need to be subjected to a mathematical transformation prior to theregression analysis.Data from the regression line itself may be helpful to providemathematical estimates of the degree of l

29、inearity.The correlation coefficient,y-intercept,slope of the regression line and residual sum ofsquares should be submitted.A plot of the data should be included.In addition,an analysis ofthe deviation of the actual data points from the regression line may also be helpful forevaluating linearity.So

30、me analytical procedures,such as immunoassays,do not demonstrate linearity after anytransformation.In this case,the analytical response should be described by an appropriatefunction of the concentration(amount)of an analyte in a sample.For the establishment of linearity,a minimum of 5 concentrations

31、 is recommended.Otherapproaches should be justified.3.RANGE The specified range is normally derived from linearity studies and depends on the intendedapplication of the procedure.It is established by confirming that the analytical procedureprovides an acceptable degree of linearity,accuracy and prec

32、ision when applied to samplescontaining amounts of analyte within or at the extremes of the specified range of theanalytical procedure.The following minimum specified ranges should be considered:-for the assay of a drug substance or a finished(drug)product:normally from 80 to 120percent of the test

33、concentration;-for content uniformity,covering a minimum of 70 to 130 percent of the test concentration,unless a wider more appropriate range,based on the nature of the dosage form(e.g.,metered dose inhalers),is justified;-for dissolution testing:+/-20%over the specified range;e.g.,if the specificat

34、ions for a controlled released product cover a region from 20%,after 1hour,up to 90%,after 24 hours,the validated range would be 0-110%of the label claim.-for the determination of an impurity:from the reporting level of an impurity to 120%of thespecification;for impurities known to be unusually pote

35、nt or to produce toxic or unexpectedpharmacological effects,the detection/quantitation limit should be commensurate withthe level at which the impurities must be controlled.Note:for validation of impurity test procedures carried out during development,it maybe necessary to consider the range around

36、a suggested(probable)limit;-if assay and purity are performed together as one test and only a 100%standard is used,linearity should cover the range from the reporting level of the impurities1 to 120%of theassay specification;4.ACCURACY Accuracy should be established across the specified range of the

37、 analytical procedure.1.4.1.Assay 1see chapters “Reporting Impurity Content of Batches”of the corresponding ICH-Guidelines:“Impurities in New Drug Substances”and“Impurities in New Drug Products”Noter til A301side 4.54.ICH methodology 2.4.1.1 Drug Substance Several methods of determining accuracy are

38、 available:a)application of an analytical procedure to an analyte of known purity(e.g.referencematerial);b)comparison of the results of the proposed analytical procedure with those of a second well-characterized procedure,the accuracy of which is stated and/or defined(independentprocedure,see 1.2.);

39、c)accuracy may be inferred once precision,linearity and specificity have been established.4.1.2 Drug Product Several methods for determining accuracy are available:a)application of the analytical procedure to synthetic mixtures of the drug productcomponents to which known quantities of the drug subs

40、tance to be analysed have beenadded;b)in cases where it is impossible to obtain samples of all drug product components,it maybe acceptable either to add known quantities of the analyte to the drug product or tocompare the results obtained from a second,well characterized procedure,the accuracyof whi

41、ch is stated and/or defined(independent procedure,see 1.2.).c)accuracy may be inferred once precision,linearity and specificity have been established.4.2.Impurities(Quantitation)Accuracy should be assessed on samples(drug substance/drug product)spiked with knownamounts of impurities.In cases where i

42、t is impossible to obtain samples of certain impurities and/or degradationproducts,it is considered acceptable to compare results obtained by an independentprocedure(see 1.2.).The response factor of the drug substance can be used.It should be clear how the individual or total impurities are to be de

43、termined e.g.,weight/weight or area percent,in all cases with respect to the major analyte.4.3.Recommended Data Accuracy should be assessed using a minimum of 9 determinations over a minimum of 3concentration levels covering the specified range(e.g.3 concentrations/3 replicates each ofthe total anal

44、ytical procedure).Accuracy should be reported as percent recovery by the assay of known added amount ofanalyte in the sample or as the difference between the mean and the accepted true valuetogether with the confidence intervals.5.PRECISION Validation of tests for assay and for quantitative determin

45、ation of impurities includes aninvestigation of precision.5.1.Repeatability Repeatability should be assessed using:Noter til A301side 4.64.ICH methodology a)a minimum of 9 determinations covering the specified range for the procedure(e.g.3 concentrations/3 replicates each)or b)a minimum of 6 determi

46、nations at 100%of thetest concentration.5.2.Intermediate Precision The extent to which intermediate precision should be established depends on thecircumstances under which the procedure is intended to be used.The applicant shouldestablish the effects of random events on the precision of the analytic

47、al procedure.Typicalvariations to be studied include days,analysts,equipment,etc.It is not considered necessaryto study these effects individually.The use of an experimental design(matrix)is encouraged.5.3.Reproducibility Reproducibility is assessed by means of an inter-laboratory trial.Reproducibil

48、ity should beconsidered in case of the standardization of an analytical procedure,for instance,forinclusion of procedures in pharmacopoeias.These data are not part of the marketingauthorization dossier.5.4.Recommended Data The standard deviation,relative standard deviation(coefficient of variation)a

49、nd confidenceinterval should be reported for each type of precision investigated.6.DETECTION LIMIT Several approaches for determining the detection limit are possible,depending on whetherthe procedure is a non-instrumental or instrumental.Approaches other than those listed belowmay be acceptable.6.1

50、.Based on Visual Evaluation Visual evaluation may be used for non-instrumental methods but may also be used withinstrumental methods.The detection limit is determined by the analysis of samples with known concentrations ofanalyte and by establishing the minimum level at which the analyte can be reli