版权说明:本文档由用户提供并上传,收益归属内容提供方,若内容存在侵权,请进行举报或认领
文档简介
1、 Guidance for IndustryQ2B Validation of AnalyticalProcedures: MethodologyNovember 1996ICHGuidance for IndustryQ2B Validation of AnalyticalProcedures: MethodologyAdditional copies are available from:the Drug Information Branch (HFD-210,Center for Drug Evaluation and Research (CDER,5600 Fishers Lane,
2、Rockville, MD 20857 (Tel 301-827-4573/cder/guidance/index.htmorOffice of Communication,Training, and Manufacturers Assistance (HFM-40Center for Biologics Evaluation and Research (CBER1401 Rockville Pike, Rockville, MD 20852-1448,/cber/guidelines.htm(Fax 888-CBERFAX
3、or 301-827-3844(Voice Information 800-835-4709 or 301-827-1800U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDERCenter for Biologics Evaluation and Research (CBERNovember 1996ICHTable of ContentsI.II. INTRODUCTION . . . . . . . . . .
4、 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1SPECIFICITY (1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2A. Identification (1.1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5、 . . . . . . . . . . . . 2B. Assay and Impurity Test(s (1.2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2LINEARITY (2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3RANGE (3. . . . . . . . . . . . . . . . . . .
6、 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4ACCURACY (4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5A. Assay (4.1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7、 . . . . . . . . . 5B. Impurities (Quantitation (4.2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6C. Recommended Data (4.3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6PRECISION (5. . . . . . . . . . . . . . . . . . . . . . . . .
8、. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6A. Repeatability (5.1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7B. Intermediate Precision (5.2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7C. Reproduci
9、bility (5.3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7D. Recommended Data (5.4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7DETECTION LIMIT (6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10、 . . . . . . . . . . . . . 7A. Based on Visual Evaluation (6.1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7B. Based on Signal-to-Noise (6.2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8C. Based on the Standard Deviation of the Response and t
11、he Slope (6.3. . . . . . . . 8D. Recommended Data (6.4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8QUANTITATION LIMIT (7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8A. Based on Visual Evaluation (7.1. . . . . . . . .
12、 . . . . . . . . . . . . . . . . . . . . . . . . . . . 9B. Based on Signal-to-Noise (7.2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9C. Based on the Standard Deviation of the Response and the Slope (7.3. . . . . . . . 9D. Recommended Data (7.4. . . . . . . . . . . . .
13、 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10ROBUSTNESS (8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10SYSTEM SUITABILITY TESTING (9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10III. IV. V. VI. VII. VI
14、II. IX. X.iGUIDANCE FOR INDUSTRY1Q2B Validation of AnalyticalProcedures: MethodologyI. INTRODUCTIONThis document is complementary to the ICH guidance entitled Text on Validation of AnalyticalProcedures (ICH Q2A, which presents a discussion of the characteristics that should beconsidered during the v
15、alidation of analytical procedures. Its purpose is to provide someguidance and recommendations on how to consider the various validation characteristics for eachanalytical procedure. In some cases (for example, demonstration of specificity, the overallcapabilities of a number of analytical procedure
16、s in combination may be investigated in order toensure the quality of the drug substance or drug product. In addition, the document provides anindication of the data that should be presented in a new drug application.All relevant data collected during validation and formulae used for calculating val
17、idationcharacteristics should be submitted and discussed as appropriate.Approaches other than those set forth in this guidance may be applicable and acceptable. It is theresponsibility of the applicant to choose the validation procedure and protocol most suitable fortheir product. However, it is imp
18、ortant to remember that the main objective of validation of ananalytical procedure is to demonstrate that the procedure is suitable for its intended purpose. Dueto their complex nature, analytical procedures for biological and biotechnological products insome cases may be approached differently than
19、 in this document.Well-characterized reference materials, with documented purity, should be used throughout thevalidation study. The degree of purity necessary depends on the intended use.In accordance with the parent document, and for the sake of clarity, this document considers thevarious validati
20、on characteristics in distinct sections. The arrangement of these sections reflectsthe process by which an analytical procedure may be developed and evaluated.This guidance was developed within the Expert Working Group (Quality of the International Conference onHarmonisation of Technical Requirement
21、s for Registration of Pharmaceuticals for Human Use (ICH and has beensubject to consultation by the regulatory parties, in accordance with the ICH process. This document has been endorsedby the ICH Steering Committee at Step 4 of the ICH process, November 1996. At Step 4 of the process, the final dr
22、aft isrecommended for adoption to the regulatory bodies of the European Union, Japan and the United States. This guidancewas published in the Federal Register on May 19, 1997 (62 FR 27464, and is applicable to drug and biologicalproducts. This guidance represents the Agencys current thinking on the
23、validation of analytical procedures. It does notcreate or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approachmay be used if such approach satisfies the requirements of the applicable statute, regulations, or both.1In practice, it is usually
24、possible to design the experimental work such that the appropriatevalidation characteristics can be considered simultaneously to provide a sound, overall knowledgeof the capabilities of the analytical procedure, for instance: Specificity, linearity, range, accuracy,and precision.II. SPECIFICITY (1An
25、 investigation of specificity should be conducted during the validation of identification tests, thedetermination of impurities, and the assay. The procedures used to demonstrate specificity willdepend on the intended objective of the analytical procedure.It is not always possible to demonstrate tha
26、t an analytical procedure is specific for a particularanalyte (complete discrimination. In this case, a combination of two or more analyticalprocedures is recommended to achieve the necessary level of discrimination.A. Identification (1.1Suitable identification tests should be able to discriminate b
27、etween compounds of closelyrelated structures which are likely to be present. The discrimination of a procedure maybe confirmed by obtaining positive results (perhaps by comparison with a known referencematerial from samples containing the analyte, coupled with negative results from sampleswhich do
28、not contain the analyte. In addition, the identification test may be applied tomaterials 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 bebased on sensible scientific judgment w
29、ith a consideration of the interferences that couldoccur.B. Assay and Impurity Test(s (1.2For chromatographic procedures, representative chromatograms should be used todemonstrate specificity, and individual components should be appropriately labeled.Similar considerations should be given to other s
30、eparation techniques.Critical separations in chromatography should be investigated at an appropriate level. Forcritical separations, specificity can be demonstrated by the resolution of the twocomponents which elute closest to each other.In cases where a nonspecific assay is used, other supporting a
31、nalytical procedures shouldbe used to demonstrate overall specificity. For example, where a titration is adopted toassay the drug substance for release, the combination of the assay and a suitable test forimpurities can be used.2The approach is similar for both assay and impurity tests:1. Impurities
32、 are available (1.2.1For the assay, this should involve demonstration of the discrimination of theanalyte in the presence of impurities and/or excipients; practically, this can be doneby spiking pure substances (drug substance or drug product with appropriatelevels of impurities and/or excipients an
33、d demonstrating that the assay result isunaffected by the presence of these materials (by comparison with the assay resultobtained on unspiked samples. For the impurity test, the discrimination may beestablished by spiking drug substance or drug product with appropriate levels ofimpurities and demon
34、strating the separation of these impurities individually and/orfrom other components in the sample matrix.2. Impurities are not available (1.2.2If impurity or degradation product standards are unavailable, specificity may bedemonstrated by comparing the test results of samples containing impurities
35、ordegradation products to a second well-characterized procedure, e.g.,pharmacopoeial method or other validated analytical procedure (independentprocedure. As appropriate, this should include samples stored under relevantstress conditions: Light, heat, humidity, acid/base hydrolysis, and oxidation. F
36、or the assay, the two results should be compared. For the impurity tests, the impurity profiles should be compared.Peak purity tests may be useful to show that the analyte chromatographic peak isnot attributable to more than one component (e.g., diode array, massspectrometry.III. LINEARITY (2A linea
37、r relationship should be evaluated across the range (see section 3 of the analyticalprocedure. It may be demonstrated directly on the drug substance (by dilution of a standard stocksolution and/or separate weighings of synthetic mixtures of the drug product components, usingthe proposed procedure. T
38、he latter aspect can be studied during investigation of the range.Linearity should be evaluated 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 examp
39、le, by calculation of a regression line by the method ofleast squares. In some cases, to obtain linearity between assays and sample concentrations, thetest data may have to be subjected to a mathematical transformation prior to the regression3analysis. Data from the regression line itself may be hel
40、pful to provide mathematical estimates ofthe degree of linearity.The correlation coefficient, y-intercept, slope of the regression line, and residual sum of squaresshould be submitted. A plot of the data should be included. In addition, an analysis of thedeviation of the actual data points from the
41、regression line may also be helpful for evaluatinglinearity.Some 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 samp
42、le.For the establishment of linearity, a minimum of five concentrations is recommended. Otherapproaches should be justified.IV. RANGE (3The specified range is normally derived from linearity studies and depends on the intendedapplication of the procedure. It is established by confirming that the ana
43、lytical procedure providesan acceptable degree of linearity, accuracy, and precision when applied to samples containingamounts of analyte within or at the extremes of the specified range of the analytical procedure.The following minimum specified ranges should be considered.For the assay of a drug s
44、ubstance or a finished (drug product: Normally from 80to 120 percent of the test concentration;For content uniformity: Covering a minimum of 70 to 130 percent of the testconcentration, unless a wider, more appropriate range, based on the nature of thedosage form (e.g., metered dose inhalers, is just
45、ified;For dissolution testing: +/-20 percent over the specified range; e.g., if thespecifications for a controlled released product cover a region from 20 percent,after 1 hour, up to 90 percent, after 24 hours, the validated range would be 0-110percent of the label claim;For the determination of an
46、impurity: From the reporting level of an impurity2 to120 percent of the specification;See sections on "Reporting Impurity Content of Batches" of the corresponding ICH Q3A guidance entitled "Impurities in New Drug Substances" (61 FR 372; January 4, 1996 and ICH Q3B draft guidance
47、"Impurities in NewDrug Products" (61 FR 11268; March 19, 1996.24For impurities known to be unusually potent or to produce toxic or unexpectedpharmacological effects, the detection/quantitation limit should be commensuratewith the level at which the impurities must be controlled.Note: For v
48、alidation of impurity test procedures carried out during development,it may be necessary to consider the range around a suggested (probable limit;If assay and purity are performed together as one test and only a 100 percentstandard is used, linearity should cover the range from the reporting level o
49、f theimpurities 3 to 120 percent of the assay specification.V. ACCURACY (4Accuracy should be established across the specified range of the analytical procedure.A. Assay (4.11. Drug substance (4.1.1Several methods of determining accuracy are available.(a Application of an analytical procedure to an a
50、nalyte of known purity (e.g.,reference material;(b Comparison of the results of the proposed analytical procedure with those of asecond well-characterized procedure, the accuracy of which is stated and/ordefined (independent procedure, see section 1.2.;(c Accuracy may be inferred once precision, lin
51、earity, and specificity have beenestablished.2. Drug product (4.1.2Several methods for determining accuracy are available.(a Application of the analytical procedure to synthetic mixtures of the drugproduct components to which known quantities of the drug substance to beanalyzed have been added;(b In
52、 cases where it is impossible to obtain samples of all drug productcomponents, it may be acceptable either to add known quantities of the analyte to3 Ibid .5the drug product or to compare the results obtained from a second, well-characterized procedure, the accuracy of which is stated and/or defined
53、(independent procedure, see section 1.2;(c Accuracy may be inferred once precision, linearity, and specificity have beenestablished.B. Impurities (Quantitation (4.2Accuracy should be assessed on samples (drug substance/drug product spiked withknown amounts of impurities.In cases where it is impossib
54、le to obtain samples of certain impurities and/or degradationproducts, it is considered acceptable to compare results obtained by an independentprocedure (see section 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 determ
55、ined, e.g.,weight/weight or area percent, in all cases with respect to the major analyte.C. Recommended Data (4.3Accuracy 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 eachof the total
56、analytical 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.VI. PRECISION (5Validation of tests for assay and for quantitative d
57、etermination of impurities includes aninvestigation of precision.A. Repeatability (5.1Repeatability should be assessed using:(1 A minimum of 9 determinations covering the specified range for the procedure(e.g., 3 concentrations/3 replicates each; or(2 A minimum of 6 determinations at 100 percent of
58、the test concentration.6B. Intermediate Precision (5.2The 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 analytical procedure. Typicalvariations to be studied include days, analysts, equipment, etc. It is not necessary to studythese effects individually. The use of an experimental design (matrix is encouraged.C. Reproducibility (5.3Reproducibility is assessed by means of an interl
温馨提示
- 1. 本站所有资源如无特殊说明,都需要本地电脑安装OFFICE2007和PDF阅读器。图纸软件为CAD,CAXA,PROE,UG,SolidWorks等.压缩文件请下载最新的WinRAR软件解压。
- 2. 本站的文档不包含任何第三方提供的附件图纸等,如果需要附件,请联系上传者。文件的所有权益归上传用户所有。
- 3. 本站RAR压缩包中若带图纸,网页内容里面会有图纸预览,若没有图纸预览就没有图纸。
- 4. 未经权益所有人同意不得将文件中的内容挪作商业或盈利用途。
- 5. 人人文库网仅提供信息存储空间,仅对用户上传内容的表现方式做保护处理,对用户上传分享的文档内容本身不做任何修改或编辑,并不能对任何下载内容负责。
- 6. 下载文件中如有侵权或不适当内容,请与我们联系,我们立即纠正。
- 7. 本站不保证下载资源的准确性、安全性和完整性, 同时也不承担用户因使用这些下载资源对自己和他人造成任何形式的伤害或损失。
最新文档
- 八年级上册信息技术教案(川教版)
- 2024年人造皮革市场规模分析:全球人造皮革市场销售额约为61.9亿美元
- 70岁生日致辞模板
- 20年后的自己500字
- 2020年食品安全宣传计划
- 2024-2025学年小学信息技术(信息科技)六年级下册川教版(2019)教学设计合集
- 2024-2025学年初中信息技术(信息科技)八年级下册粤教版(2016)教学设计合集
- 2024-2025学年高中生物学生命科学其他版本教学设计合集
- 九年级语文教学计划
- 车联网关键技术应用
- 健康中国行动知行大赛理论试题及答案
- 超星尔雅学习通《数据时代的推断陷阱》章节测试含答案
- 政治学基础课件全部终稿
- 采购项目质量保证措施方案
- 山茶油营销大赛课件
- 管理沟通--倾听技巧课件
- 公安机关理论考试题库(1000题)
- 五年级上册数学课件-8.1 用字母表示数丨苏教版 (共24张PPT)
- 弘扬中华传统文化主题班会课件
- 药剂科质量与安全管理考核表正式版
- 现场抽水台班记录表
评论
0/150
提交评论