The Canadian Health Protection Branch (HPB) issued a Drugs Directorate Guideline in 1992 entitled "Acceptable Methods" [9], The guideline covers basic principles for methods, validation and revalidation, methods content and documentation, reference standards and performance checks. Chromatographic, dissolution and physicochemical methods are covered. Typical parameters that should be covered in validation are similar to those already mentioned, but specific definitions and procedural guidelines are given as follows:
Precision - Two measures are required - precision of the method and of the system. The method precision should be performed a) intra-day, with six assays of one drug substance or six assays of a composite of the drug product on a single day - the relative standard deviation should be less than 1.0% for drug substance and less than 2.0% for dosage forms, and b )inter-day - duplicate or triplicate assays on five consecutive days. For system precision of chromatographic methods, five replicate injections of a standard solution should give a coefficient of variation of less than 1.0%. Precision limits for impurities/related substances are also provided.
Accuracy - The required accuracy is a bias of 2% or less for dosage forms, and 1% or less for drug substances.
Limit of detection - For instrumental methods, a signal to noise ratio of 3:1 is generally accepted.
Limit of quantitation - Defined for instrumental methods as the best estimate of the lowest concentration of an analyte that gives a relative standard deviation of approximately 10% for six replicate determinations. The method should be able to quantitate each individual impurity for which the method will be applied at or below the limit for that impurity.
Selectivity/specificity - Selectivity is determined by comparing test results from the analysis of samples containing impurities, degradation products, or placebo ingredients, with those obtained from the analysis of samples without them.
Sensitivity - This is defined as the slope of the linear regression line (see also Chapter 2).
Linearity and range - Linearity is determined by mathematical treatment of test results obtained by analysis of samples with analyte concentrations across the claimed range of the method. The range of the method is estimated from the linearity and is verified by confirming that the method provides acceptable precision and linearity when applied to samples containing analyte at the extremes of the range as well as within the range.
Ruggedness - Determined by analysis of aliquots from homogeneous lots in different laboratories, by different analysts (see also Chapter 2).
Table 3.3 shows the data required the Canadian Guidelines for different types of analysis.
Tabulation Of Validation Requirements For Various Types Of Test (ICH Guidelines)
Type of analytical Identification Testing for impurities Assay: dissolution procedure: (measurement)
Intermediate precision +1 +1
Detection limit -3 +
Note: - signifies that this parameter is not normally evaluated; + signifies that this parameter is normally evaluated; 1 in cases where reproducibility (see Glossary in ICH Guidelines) has been performed, intermediate precision is not needed; 2 lack of specificity of one analytical procedure could be compensated by other supporting analytical procedure(s); 3 may be needed in some cases
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