ICH Q2A GUIDELINES PDF

Glossary 1. Analytical Procedure The analytical procedure refers to the way of performing the analysis. It should 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. 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.

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Glossary 1. Analytical Procedure The analytical procedure refers to the way of performing the analysis. It should 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.

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 of an individual analytical procedure may be compensated by other supporting 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 performed allow an accurate statement of the content of impurities of an analyte, that is i.

Accuracy The accuracy of an analytical procedure expresses the closeness of agreement between the value which is accepted either as a conventional true value or an accepted reference value and the value found. This is sometimes termed trueness. Precision The precision of an analytical procedure expresses the closeness of agreement degree 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. 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. The precision of an analytical procedure is usually expressed as the variance, standard deviation or coefficient of variation of a series of measurements.

Repeatability is also termed intra-assay precision. Detection Limit The detection limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be detected but not necessarily quantitated as an exact value. Quantitation Limit The quantitation limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be quantitatively determined with suitable precision and accuracy.

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. Range 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, accuracy and linearity.

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 during normal usage. Part Ii: Validation of Analytical Procedures: Methodology ICH Harmonised Tripartite Guideline Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 6 November , and incorporated into the core guideline in November , this guideline is recommended for adoption to the three regulatory parties to ICH Introduction This document is complementary to the parent document which presents 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 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 registrationapplication. All relevant data collected during validation and formulae usedfor calculating validation characteristics should be submitted and discussed as appropriate.

Approaches other than those set forth in this guideline may be applicable and acceptable. It is the responsibility of the applicantto choose the validation procedure and protocol most suitable for their product.

However it is important to remember that the main objective of validation of an analytical procedure is to demonstrate that the procedure is suitable for its intended purpose.

Due to their complex nature, analytical procedures for biological and biotechnological products in some cases may be approached differently than in this document.

Well-characterized reference materials, with documented purity, should be used throughout the validation 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 the various validation characteristics in distinct sections. The arrangement of these sections reflects 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 appropriate validation characteristics can be considered simultaneously to provide a sound, overall knowledge of the capabilities of the analytical procedure, for instance: specificity, linearity, range, accuracy and precision.

Specificity An investigation of specificity should be conducted during the validation of identification tests, the determination of impurities and the assay. The procedures used to demonstrate specificity will depend on the intended objective of the analytical procedure. It is not always possible to demonstrate that an analytical procedure is specific for a particular analyte complete discrimination. In this case a combination of two or more analytical procedures is recommended to achieve the necessary level of discrimination.

The discrimination of a procedure may be confirmed by obtaining positive results perhaps by comparison with a known reference material from samples containing the analyte, coupled with negative results from samples which do not contain the analyte. In addition, the identification test may be applied to materials structurally similar to or closely related to the analyte to confirm that a positive response is not obtained.

The choice of such potentially interfering materials should be based on sound scientific judgement with a consideration of the interferences that could occur. Similar considerations should be given to other separation techniques. Critical separations in chromatography should be investigated at an appropriate level.

For critical separations, specificity can be demonstrated by the resolution of the two components which elute closest to each other. In cases where a non-specific assay is used, other supporting analytical procedures should be used to demonstrate overall specificity.

For example, where a titration is adopted to assay the drug substance for release, the combination of the assay and a suitable test for impurities can be used. The approach is similar for both assay and impurity tests: 1. Peak purity tests may be useful to show that the analyte chromatographic peak is not attributable to more than one component e.

Linearity A linear relationship should be evaluated across the range see section 3 of the analytical procedure. The 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 analyte concentration or content. If there is a linear relationship, test results should be evaluated by appropriate statistical methods, for example, by calculation of a regression line by the method 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 the regression analysis. Data from the regression line itself may be helpful to provide mathematical estimates of the degree of linearity.

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.

Range 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: for the assay of a drug substance or a finished drug product: normally from 80 to percent of the test concentration; for content uniformity, covering a minimum of 70 to percent of the test concentration, unless a wider more appropriate range, based on the nature of the dosage form e.

Accuracy Accuracy should be established across the specified range of the analytical procedure. 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. 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.

Precision Validation of tests for assay and for quantitative determination of impurities includes an investigation of precision. The applicant shouldestablish 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. 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. Recommended Data The standard deviation, relative standard deviation coefficient of variation and confidence interval should be reported for each type of precision investigated.

Detection Limit Several approaches for determining the detection limit are possible, depending on whether the procedure is a non-instrumental or instrumental. Approaches other than those listed below may be acceptable. The detection limit is determined by the analysis of samples with known concentrations of analyte and by establishing the minimum level at which the analyte can be reliably detected.

Determination of the signal-to-noise ratio is performed by comparing measured signals from samples with known low concentrations of analyte with those of blank samples and establishing the minimum concentration at which the analyte can be reliably detected. A signal-to-noise ratio between 3 or is generally considered acceptable for estimating the detection limit.

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