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(5)The ICH Guidelines on Validation of Analytical Procedures

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allelipraise's version from 2018-06-06 16:43

Section 1

Question Answer
the International Conference on Harmonization a project that brings together the regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of pharmaceutical product registration
Validation of an Analytical Procedureto demonstrate that the analytical procedure is suitable for its intended purpose
Identification Testsintended to ensure the identity of an analyte in a sample
Testing of Impuritiescan be either a quantitative test or a limit test for the impurity in a sample - intended to accurately reflect the purity characteristics of the sample - different validation characteristics are required for a quantitative test than for a limit test
Assay- intended to measure the analyte present in a given sample - represents a quantitative measurement of the major component(s) in the drug substance
Specificitythe ability to assess unequivocally the analyte in the presence of components (e.g., impurities, degradants, matrix, etc.) which may be expected to be present
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Section 2

Question Answer
Performance Characteristicscriteria of instruments that can be used to decide whether a given instrumental method is suitable for attacking an analytical problem
Figures of Meritnumerical measures of performance characteristics
SpecificityThe ability to assess unequivocally the analyte in the presence of components (e.g., impurities, degradants, matrix, etc.) which may be expected to be present
Identificationto ensure the identity of an analyte (able to discriminate between compounds of closely related structures which are likely to be present)
Purity Teststo ensure that all the analytical procedures performed allow an accurate statement of the content of impurities of an analyte, i.e., related substances test, heavy metals, residual solvents, 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 (used to demonstrate specificity.)
Assay and Impurity Test(s) Impurities are availableFor the assay, this should involve demonstration of the discrimination of the analyte in the presence of impurities and/or excipients, e.g., by spiking.(the drug substance/product with appropriate levels of impurities and demonstrating the separation of these impurities in the sample matrix.)
Assay and Impurity Test(s) Impurities are not availableSpecificity may be demonstrated by comparing the test results of samples containing impurities or degradation products to a second well-characterized procedure.( For the assay, the two results should be compared; for impurity tests, the impurity profiles should be compared.)
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Section 3

Question Answer
Accuracy(Trueness)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
Assay of Drug SubstanceApplication of an analytical procedure to an analyte of known purity (e.g., reference material or standard)  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  Inferred once precision, linearity and specificity have been established
Assay for Drug Product Application of an analytical procedure to synthetic mixtures of the drug product  For complex formulations, 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- established procedure  Inferred once precision, linearity and specificity have been established
Test for ImpuritiesAccuracy should be assessed on samples (drug substance/drug product) spiked with known amounts of impurities.  If it is impossible to obtain samples of certain impurities and/or degradation product, it is acceptable to compare results obtained by an independent procedure.
Biasprovides a measure of the systematic, or determinate, error of an analytical method
Biasinvolves analyzing one or more standard reference materials whose analyte concentration is known
Determinate ErrorsInstrumental Errors/ Operative Errors/ Errors of the method
Precisionexpresses 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
Repeatability expresses precision under the same operating conditions over a short interval of time; also termed intra-assay precision
Intermediate Precisionexpresses within-laboratories variations: different days, different analysts, different equipment, etc.
Reproducibilityexpresses the precision between laboratories (collaboration studies, usually applied to standardization of methodology)
Intermediate Precisionthe extent 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.
Reproducibilityassessed by means of an interlaboratory trial  Should be considered in case of the standardization of an analytical procedure, for instance for inclusion in pharmacopoeias.
Indeterminate Errorsrevealed by small differences in successive measurements made by the same analyst under virtually identical conditions; cannot be predicted or estimated
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Section 5

Question Answer
Linearitythe ability of an analytical procedure to obtain test results (within a given range) which are directly proportional to the concentration (amount) of analyte in the sample
Rangethe 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 - for the assay of a drug substance or a finished product, normally from 80% to 120% of the test concentration
Detection Limit (Limit of Detection, LOD)the lowest amount of analyte in a sample which can be detected but not necessarily quantitated as an exact value
Based on Visual Evaluationby analysis of samples with known concentrations of analyte and by establishing the minimum level at which the analyte can be reliably detected
Based on Signal-to-Noiseby comparing measured signals from samples with known low concentrations of analyte with those of blank samples; acceptable signal-to-noise ratio is between 3 or 21
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Section 6

Question Answer
Quantitation Limit (Limit of Quantitation, LOQ)the lowest amount of analyte in a sample which can be quantitatively determined with suitable precision and accuracy
Quantitation Limit (Limit of Quantitation, LOQ)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
Based on Visual Evaluationby analysis of samples with known concentrations of analyte and by establishing the minimum level at which the analyte can be quantified with acceptable accuracy and precision
Based on Signal-to-Noise by comparing measured signals from samples with known low concentrations of analyte with those of blank samples; acceptable signal-to-noise ratio is between 101
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Section 7

Question Answer
Robustnessa measure of the capacity of an analytical procedure to remain unaffected by small, but deliberate variations in method parameters and provides an indication of its reliability during normal usage
System Suitabilitydesigned to evaluate the components of the analytical system (i.e., equipment, electronics, analytical operations and samples) in order to show that the performance of the system meets the standards required by the method
Selectivitythe degree to which the method is free from interference by other species contained in the sample matrix - selectivity coefficients are usually computed to give the relative response of the method to interfering species as compared with the species of interest - selectivity coefficients can range from zero to values a good deal greater (or less) than unity
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