ICH分析方法验证指南--方法论 - 下载本文

ICH Q2 (R1)

In some cases:在某些情况下,有时候;

The correlation coefficient, y-intercept, slope of the regression line and residual sum of squares should be submitted. A plot of the data should be included. In addition, an analysis of the deviation of the actual data points from the regression line may also be helpful for evaluating linearity.


Some analytical procedures, such as immunoassays, do not demonstrate linearity after any transformation. In this case, the analytical response should be described by an appropriate function of the concentration (amount) of an analyte in a sample.


For the establishment of linearity, a minimum of 5 concentrations is recommended. Other approaches should be justified.

为建立线性,建议至少用5个浓度。若用其他方法应证明其合理性。 3. RANGE 范围

The specified range is normally derived from linearity studies and depends on the intended application of the procedure. It is established by confirming that the analytical procedure provides an acceptable degree of linearity, accuracy and precision when applied to samples containing amounts of analyte within or at the extremes of the specified range of the analytical procedure.


The following minimum specified ranges should be considered: 以下是应考虑的最小规定范围:

- for the assay of a drug substance or a finished (drug) product: normally from 80 to 120 percent of the test concentration;

- 对原料药或成品药(制剂)的含量测定:一般应在测试浓度的80%~120%;

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ICH Q2 (R1)

- 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;

- 对含量均匀度检测:应至少在测试浓度的70%~130%之内,超出此范围,应有正当理由,主要是根据剂型的特点(如定量吸入剂);

- for dissolution testing: +/-20 % over the specified range; - 对溶出度测试,应为规定范围的+/-20%;

e.g., if the specifications for a controlled released product cover a region from 20%, after 1 hour, up to 90%, after 24 hours, the validated range would be 0-110% of the label claim. 例如:如果是控释剂,规定1小时后达到20%,24小时后达到90%,它的验证范围应为标示量的0~110%。

- for the determination of an impurity: from the reporting level of an impurity1 to 120% of the specification;

- 对杂质测定,应为杂质的报告水平至标准规定的120%;

- for impurities known to be unusually potent or to produce toxic or unexpected pharmacological effects, the detection/quantitation limit should be commensurate with the level at which the impurities must be controlled;

- 对已知有异常功效的,有毒的或者有意外药理作用的杂质,其检测限度和定量限度应与该杂质必须被控制的水平相当。

Note: for validation of impurity test procedures carried out during development, it may be necessary to consider the range around a suggested (probable) limit.

注意:在研制阶段进行杂质检测方法验证时,有必要根据建议(可能)的限度水平来考虑范围; - 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 the assay specification.


see chapters “Reporting Impurity Content of Batches” of the corresponding

ICH-Guidelines: “Impurities in New Drug Substances” and “Impurities in New Drug Products”

- 如果一个试验同时进行含量和纯度检测,且仅使用100%的标准品,线性范围应覆盖杂质的报告水平(见相应ICH指南“新原料药中的杂质”和“新制剂中的杂质”中“批杂质含

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ICH Q2 (R1)

量的报告”章节)至含量指标120%。 4. ACCURACY 准确度

Accuracy should be established across the specified range of the analytical procedure. 应在分析方法规定的范围内建立(考察方法的)准确度。 4.1. Assay 含量

4.1.1 Drug Substance 原料药

Several methods of determining accuracy are available: 以下几种方法可用于测定准确度:

a) application of an analytical procedure to an analyte of known purity (e.g. reference material);


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 (independent procedure, see 1.2.);


c) accuracy may be inferred once precision, linearity and specificity have been established.

准确度可以在精密度,线性及专属性建立之后推论得到; 4.1.2 Drug Product 制剂

Several methods for determining accuracy are available: 以下几种方法可用于测定准确度:

a) application of the analytical procedure to synthetic mixtures of the drug product components to which known quantities of the drug substance to be analysed have been added;


b) in cases where it is impossible to obtain samples of all drug product components , it may be acceptable either to add known quantities of the analyte to the drug product or to compare the results obtained from a second, well characterized procedure, the accuracy of which is stated and/or defined (independent procedure, see 1.2.);

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ICH Q2 (R1)


c) accuracy may be inferred once precision, linearity and specificity have been established.

准确度可以在精密度,线性及专属性建立之后推论得到; 4.2. Impurities (Quantitation) 杂质(定量)

Accuracy should be assessed on samples (drug substance/drug product) spiked with known amounts of impurities.


In cases where it is impossible to obtain samples of certain impurities and/or degradation products, it is considered acceptable to compare results obtained by an independent procedure (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 determined e.g., weight/weight or area percent, in all cases with respect to the major analyte.

需要说明单杂和总杂是如何测定的,如相对于主要被分析物所占的质量分数或面积百分比。 4.3. Recommended Data 可接受数据(数据要求)

Accuracy should be assessed using a minimum of 9 determinations over a minimum of 3 concentration levels covering the specified range (e.g., 3 concentrations/3 replicates each of the total analytical procedure).


Accuracy should be reported as percent recovery by the assay of known added amount of analyte in the sample or as the difference between the mean and the accepted true value together with the confidence intervals.

准确度应以向样品中加入已知量的被测物所得的百分回收率或者平均值和可接受真实值之间的差值及置信区间来报告。 5. PRECISION 精密度

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ICH Q2 (R1)

Validation of tests for assay and for quantitative determination of impurities includes an investigation of precision.

含量和杂质的定量分析需要考察方法的精密度。 5.1. Repeatability 重复性

Repeatability should be assessed using: 重复性可以通过一下方法进行考察:

a) a minimum of 9 determinations covering the specified range for the procedure (e.g., 3 concentrations/3 replicates each);

在方法的线性范围内至少检测九次(三种浓度每种浓度重复进样三次); b) or a minimum of 6 determinations at 100% of the test concentration. 以100%测试浓度至少检测六次。 5.2. Intermediate Precision 中间精密度

The extent (程度) to which intermediate precision should be established depends on the circumstances under which the procedure is intended to be used. The applicant should establish the effects of random events on the precision of the analytical procedure. Typical variations to be studied include days, analysts, equipment, etc. It is not considered necessary to study these effects individually. The use of an experimental design (matrix) is encouraged.

中间精密度的考察程度应根据分析方法的操作环境而定。申请者应确定(弄清楚)随机时间对分析方法的精密度的影响。需要研究的典型变化有:日期,分析者,仪器等。没有必要逐项考察这些因素。建议使用试验设计(矩阵法)。 5.3. Reproducibility 重现性

Reproducibility is assessed by means of (通过) an inter-laboratory trial. Reproducibility should be considered in case of the standardization of an analytical procedure, for instance, for inclusion of procedures in pharmacopoeias. These data are not part of the marketing authorization dossier.

重现性可通过实验室之间的试验进行评估。如果方法需要标准化,例如药典方法,则应考虑重现性。这些资料不是上市申请文档的一部分(申报注册不需要考察药典收录方法的重现性,这是药典委需要考虑的问题)。 5.4. Recommended Data 数据要求

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