(1.1)--药物分析分析过程和方法的确证.pdf

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1、Validation of Analytical Procedures:Text REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE 人用药品的注册要求 ICH HARMONISED TRIPARTITE GUIDELINE ICH协调的三方指导原则协调的三方指导原则 VALIDATION OF ANALYTICAL PROCEDURES:TEXT AND METHODOLOGY 分析方法验证：正文和方法学分析方法验证：正文和方法学 Q2(R1)Current Step 4 version 现行第4阶段版本 Parent

2、 Guideline dated 27 October 1994 最初指导原则起于1994年10月27日 (Complementary Guideline on Methodology dated 6 November 1996 incorporated in November 2005)（方法学补充指导原则完成于1996年11月6日，于2005年11月合并）This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by t

3、he regulatory parties,in accordance with the ICH Process.At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union,Japan and USA.此指导原则由适当的 ICH 专家工作组起草，经调整团磋商，于 ICH 过程一致。在第四阶段，最终的草案推荐给欧盟，日本和美国的监管机构采用。Validation of Analytical Procedures:Text Q2

4、(R1)Document History Q2(R1)文件历史文件历史 First Codification 初次法典化 History 历史 Date 时间 New Codification November 2005 Parent Guideline:Text on Validation of Analytical Procedures 最初的指导原则：分析方法的验证最初的指导原则：分析方法的验证 Q2 Approval by the Steering Committee under Step 2 and release for public consultation.在第2阶段经策划委员

5、会批准，作为公用的咨询 26 October 2003 2003-10 Q2 Q2A Approval by the Steering Committee under Step 4 and recommendation for adoption to the three ICH regulatory bodies.在第4阶段经侧环委员会同意并推荐给三方ICH监管机构采用 27 October 1994 1994-10-27 Q2 Guideline on Validation of Analytical Procedures:Methodology developed to complemen

6、t the Parent Guideline 分析方法验证的指导原则：扩展的方法学作为最初指导原则的补充分析方法验证的指导原则：扩展的方法学作为最初指导原则的补充 Q2B Approval by the Steering Committee under Step 2 and release for public consultation.在第2阶段经策划委员会批准，作为公用的咨询 29 November 1995 in Q2(R1)Q2B Approval by the Steering Committee under Step 4 and recommendation for adoptio

7、n to the three ICH regulatory bodies 在第4阶段经侧环委员会同意并推荐给三方ICH监管机构采用 Current Step 4 version 现行现行 Q2A and Q2B The parent guideline is now renamed Q2(R1)as the guideline Q2B on methology has been incorporated to the parent guideline.The new title is“Validation of Analytical Procedures:Text and Methodolog

8、y”.最初的指导原则现在更名为Q2(R1)因为指导原则Q2B方法学已经合并到最初的指导原则中。新标题“分析方法验证：正文和方法学”November 2005 Q2(R1)Validation of Analytical Procedures:Text PART I:TEXT ON VALIDATION OF ANALYTICAL PROCEDURES 分析方法验证文件分析方法验证文件 ICH Harmonised Tripartite Guideline ICH协调三方指导原则协调三方指导原则 Having reached Step 4 of the ICH Process at the IC

9、H Steering Committee meeting on 27 October 1994,this guideline is recommended for adoption to the three regulatory parties to ICH 1994年10月27日的ICH策划委员会会议已经进入了ICH进程的第4阶段，此指导原则推荐给ICH三个监管部门采纳 1.Introduction This document presents a discussion of the characteristics for consideration during the validatio

10、n of the analytical procedures included as part of registration applications submitted within the EC,Japan and USA.This document does not necessarily seek to cover the testing that may be required for registration in,or export to,other areas of the world.Furthermore,this text presentation serves as

11、a collection of terms,and their definitions,and is not intended to provide direction on how to accomplish validation.These terms and definitions are meant to bridge the differences that often exist between various compendia and regulators of the EC,Japan and USA.1 介绍 作为递交给欧共体，日本和美国新药注册申请资料的一部分，对分析方法

12、验证需考虑事项的特征的讨论在此文件呈现出来。没有必要在此文件寻找覆盖在世界其他地区的药品的注册或出口所要求的测试。此外，此文作为术语的收集，和他们的定义而服务的，并没有想提供怎样完成验证的指示。这些项目和定义是连接那些常存在于欧共体，日本和美国的各种药典和规定之间的差异的桥梁。The objective of validation of an analytical procedure is to demonstrate that it is suitable for its intended purpose.A tabular summation of the characteristics

13、applicable to identification,control of impurities and assay procedures is included.Other analytical procedures may be considered in future additions to this document.分析方法验证的目的是为了阐述分析方法是适用于它要分析的目的的。应用于鉴别，杂质控制和含量测定方法的特征项的综合，可能考虑会加入到今后的文件中。2.Types of Analytical Procedures to be Validated 2所要验证的分析方法的类型

14、所要验证的分析方法的类型 The discussion of the validation of analytical procedures is directed to the four most common types of analytical procedures:分析方法验证的讨论通常集中在以下分析方法的四个最通用的方面：-Identification tests;-鉴别试验；-Quantitative tests for impurities content;-杂质含量的定量测试；Validation of Analytical Procedures:Text-Limit tes

15、ts for the control of impurities;-杂质控制的限度测试；-Quantitative tests of the active moiety in samples of drug substance or drug product or other selected component(s)in the drug product.-原料药或制剂或其他药品中选择性的组分的样品的活性部分的定量测试；Although there are many other analytical procedures,such as dissolution testing for dru

16、g products or particle size determination for drug substance,these have not been addressed in the initial text on validation of analytical procedures.Validation of these additional analytical procedures is equally important to those listed herein and may be addressed in subsequent documents.虽然有许多其他的

17、分析方法，诸如药品的溶解性试验或药品微粒大小测试，在分析方法验证最初的正文中并未给出。那些额外的分析方法的验证和在这里列出来的分析方法同样重要，且有可能在后来的文件中提出。A brief description of the types of tests considered in this document is provided below.对于此文件中考虑到的测试的类型的简短描述如下：-Identification tests are intended to ensure the identity of an analyte in a sample.This is normally ac

18、hieved by comparison of a property of the sample(e.g.,spectrum,chromatographic behavior,chemical reactivity,etc)to that of a reference standard;-鉴别试验是为了鉴定样品中某个分析物存在。通常将适当的样品与参考标准品进行比较（例如，光谱，色谱行为，化学反应等）。-Testing for impurities can be either a quantitative test or a limit test for the impurity in a sa

19、mple.Either test is intended to accurately reflect the purity characteristics of the sample.Different validation characteristics are required for a quantitative test than for a limit test;-杂质测试是对样品中的杂质进行定性或定量试验。这两种试验都是为了准确的反应样品中杂质的特性。与限度试验相比，定量试验要求不同的验证试验项。-Assay procedures are intended to measure t

20、he analyte present in a given sample.In the context of this document,the assay represents a quantitative measurement of the major component(s)in the drug substance.For the drug product,similar validation characteristics also apply when assaying for the active or other selected component(s).The same

21、validation characteristics may also apply to assays associated with other analytical procedures(e.g.,dissolution).-含量测试方法是为了测定给定样品中的被测物的量。此文件的内容中，含量测试代表原料药中的主成分的定量的测试。对于药物制剂中的活性组分或其他选择性组分进行含量测定时，相似的验证特征也同样应用。同样的验证特征也可以应用到与其他分析方法相关联的含量测试中（如，溶解）。The objective of the analytical procedure should be clea

22、rly understood since this will govern the validation characteristics which need to be evaluated.Typical validation characteristics which should be considered are listed Validation of Analytical Procedures:Text below:分析方法的目的应该清晰易懂，因为它将制约需要被评价的验证特征。应考虑的典型的验证特征如下：Accuracy 准确度 Precision 精密度 Repeatabilit

23、y 重复性 Intermediate Precision 中间精密度 Specificity 特异性 Detection Limit 检测限 Quantitation Limit 定量限 Linearity 线形 Range 范围 Each of these validation characteristics is defined in the attached Glossary.The table lists those validation characteristics regarded as the most important for the validation of diffe

24、rent types of analytical procedures.This list should be considered typical for the analytical procedures cited but occasional exceptions should be dealt with on a case-by-case basis.It should be noted that robustness is not listed in the table but should be considered at an appropriate stage in the

25、development of the analytical procedure.每一个验证特征在附属的术语中有定义。此表列出了那些验证特征，它们被认为是分析方法不同类型验证的最重要的部分。Furthermore revalidation may be necessary in the following circumstances:此外，以下情况可能有必要重新验证。-changes in the synthesis of the drug substance;-原料药合成路线变更；-changes in the composition of the finished product;-成品组分

26、变更-changes in the analytical procedure.-分析方法变更 The degree of revalidation required depends on the nature of the changes.Certain other changes may require validation as well.要求重新验证的程度取决于变更的性质。某些其他变更可能也要重新验证。TABLE Type of analytical procedure 分析方法的类型 IDENTIFICATION 鉴别试验 TESTING FOR IMPURITIES 杂质测试 ASS

27、AY-dissolution(measurement only)-content/potency含量测试-溶解度（只是测量）-含量/效力 Validation of Analytical Procedures:Text characteristics 特征 quantitat.定量 limit限度 Accuracy准确度-+-+Precision精密度 Repeatability重复性 Interm.Precision中间精密度 -+(1)-+(1)Specificity(2)特异性（2）+Detection Limit检测限-(3)+-Quantitation Limit定量限-+-Line

28、arity 线性-+-+Range 范围-+-+-signifies that this characteristic is not normally evaluated -表示此项特征通常不用评价+signifies that this characteristic is normally evaluated +表示此项特征通常要评价(1)in cases where reproducibility(see glossary)has been performed,intermediate precision is not needed (1)如果重复性（见术语表）已经履行，中间精密度不做要求

29、(2)lack of specificity of one analytical procedure could be compensated by other supporting analytical procedure(s)(2)一个分析方法特异性缺乏，可以通过其他支持性的分析方法补充(3)may be needed in some cases(3)某些情况下可能需要 GLOSSARY 术语术语 1.ANALYTICAL PROCEDURE The analytical procedure refers to the way of performing the analysis.It s

30、hould describe in detail the steps necessary to perform each analytical test.This may include but is not limited to:the sample,the reference standard and the reagents preparations,use of the apparatus,generation of the calibration curve,use of the formulae for the calculation,etc.1分析方法 分析方法是指分析测试进行的

31、方式。它应该详细地描述执行每个分析试验的必要的步骤。可能包括但不限于：样品，参考标准品和试剂制备，适用的仪器，标准曲线的产生，采用的计算公式，等等。2.SPECIFICITY Specificity is the ability to assess unequivocally the analyte in the presence of components which may be expected to be present.Typically these might include impurities,degradants,matrix,etc.Lack of specificity

32、of an individual analytical procedure may be compensated by other supporting Validation of Analytical Procedures:Text analytical procedure(s).This definition has the following implications:Identification:to ensure the identity of an analyte.Purity Tests:to ensure that all the analytical procedures p

33、erformed allow an accurate statement of the content of impurities of an analyte,i.e.related substances test,heavy metals,residual solvents content,etc.Assay(content or potency):to provide an exact result which allows an accurate statement on the content or potency of the analyte in a sample.2 特异性（专属

34、性）特异性是指清晰地评价组分中认为可能存在的被测物的能力。典型的包括：杂质，降解产物，辅料等。一个单独的分析方法的专属性缺乏，可以通过其他可支持的分析方法来补充。此定义有以下含义：鉴别：确保某个分析物的身分。纯度测试：确保所执行的所有分析方法对被测物的杂质的含量有一个准确的陈述，如，有关物质测试，重金属，残留溶剂，等。含量测试（含量或效力）提供准确的结果，对样品中被测物的含量或效力有准确的陈述。3.ACCURACY The accuracy of an analytical procedure expresses the closeness of agreement between the v

35、alue which is accepted either as a conventional true value or an accepted reference value and the value found.This is sometimes termed trueness.3。准确度 分析方法的准确度表达了可接受值，包括常规真值或可接受的参考值，与测得值之间的一致性的接近程度。4.PRECISION 4精密度精密度 The precision of an analytical procedure expresses the closeness of agreement(degre

36、e of scatter)between a series of measurements obtained from multiple sampling of the same homogeneous sample under the prescribed conditions.Precision may be considered at three levels:repeatability,intermediate precision and reproducibility.分析方法的精密度表达了，在给定条件下，获得的一系列的同一均匀样品的多次取样的测量值之间的一致性的接近程度（分散度）。

37、精密度可以从三个水平考虑：重复性，中间精密度。重现性。Precision should be investigated using homogeneous,authentic samples.However,if it is not possible to obtain a homogeneous sample it may be investigated using artificially prepared samples or a sample solution.精密度应该用同一均匀，权威样品进行考察。然而，如果不能获得同一均匀样品，可以用人工制备样品或样品溶液进行考察。The prec

38、ision of an analytical procedure is usually expressed as the variance,standard deviation or coefficient of variation of a series of Validation of Analytical Procedures:Text measurements.分析方法的精密度常用一系列测量值的变异，标准偏差，或变异系数来表达。4.1.Repeatability Repeatability expresses the precision under the same operating

39、 conditions over a short interval of time.Repeatability is also termed intra-assay precision.4.1重复性 重复性表示在短期时间间隔内，同样操作条件下的精密度。重复性也叫批内分析精密度。4.2.Intermediate precision Intermediate precision expresses within-laboratories variations:different days,different analysts,different equipment,etc.4.2中间精密度 中间精

40、密度表示在同一试验室下的变异：不同天，不同试验者，不同仪器，等。4.3.Reproducibility Reproducibility expresses the precision between laboratories(collaborative studies,usually applied to standardization of methodology).4.3重现性 重现性表示试验室之间的精密度（合作性研究，通常用于分析方法学的标准化）。5.DETECTION LIMIT The detection limit of an individual analytical proce

41、dure is the lowest amount of analyte in a sample which can be detected but not necessarily quantitated as an exact value.5检测限 一个分析方法的检测限是样品中分析物能被检测到但是没必要作为精确值定量的最小量。6.QUANTITATION LIMIT The quantitation limit of an individual analytical procedure is the lowest amount of analyte in a sample which can

42、 be quantitatively determined with suitable precision and accuracy.The quantitation limit is a parameter of quantitative assays for low levels of compounds in sample matrices,and is used particularly for the determination of impurities and/or degradation products.6定量限 一个分析方法的定量限是样品中分析物能够定量测定，具有合适的精密

43、度和准确度的最低量。定量限是样品基质中最低含量的化合物的定量分析的一个参数，特别用于测定杂质和/或降解产物。7.LINEARITY The linearity of an analytical procedure is its ability(within a given range)to obtain test results which are directly proportional to the concentration(amount)of analyte in the sample.7线性 分析方法的线性是获得的测试结果与样品中被测物的浓度成直接比例的能力。8.RANGE Val

44、idation of Analytical Procedures:Text The range of an analytical procedure is the interval between the upper and lower concentration(amounts)of analyte in the sample(including these concentrations)for which it has been demonstrated that the analytical procedure has a suitable level of precision,accu

45、racy and linearity.8范围 分析方法的范围是样品中被测物的最高浓度和最低浓度之间的间隔（包括最高和最低浓度），在此区间内，已经证明分析方法有合适的精密度，准确度和线性。9.ROBUSTNESS The robustness of an analytical procedure is a measure of its capacity to remain unaffected by small,but deliberate variations in method parameters and provides an indication of its reliability

46、during normal usage.9耐用性 分析方法的耐用性是，在故意对分析方法的参数进行微小变化后，方法仍然能保持不受影响的能力的一种测试，并且提供在正常范围内使用的可靠性说明。Validation of Analytical Procedures:Text PART II:VALIDATION OF ANALYTICAL PROCEDURES:METHODOLOGY ICH Harmonised Tripartite Guideline 第第II部分部分:分析方法的验证方法学分析方法的验证方法学 ICH协调的三方指导原则协调的三方指导原则 Having reached Step 4

47、of the ICH Process at the ICH Steering Committee meeting on 6 November 1996,and incorporated into the core guideline in November 2005,this guideline is recommended for adoption to the three regulatory parties to ICH INTRODUCTION 介绍介绍 This document is complementary to the parent document which presen

48、ts a discussion of the characteristics that should be considered during the validation of analytical procedures.Its purpose is to provide some guidance and recommendations on how to consider the various validation characteristics for each analytical procedure.In some cases(for example,demonstration

49、of specificity),the overall capabilities of a number of analytical procedures in combination may be investigated in order to ensure the quality of the drug substance or drug product.In addition,the document provides an indication of the data which should be presented in a registration application.最初

50、文件给出了分析方法验证中应该考虑到的特征的讨论，此文件是最初文件的补充。它的目的是，在关于怎样考虑每个分析方法的各种验证特征方面，提供同样的指导和荐意。一些情况下，（例如，特异性的证明），为了确保原料药或制剂的质量，可以考察多个分析方法结合的全面的能力。此外，文件给出了在注册申请中要呈报的数据指示。All relevant data collected during validation and formulae used for calculating validation characteristics should be submitted and discussed as approp