Drug validation methods selection

There are four basic steps in the development (excluding validation) of a dissolution method for low-dose drug products (1) selection of dissolution apparatus (2) selection of a suitable analytical technique to quantify analyte release (3) selection of dissolution medium and (4) selection of dissolution apparatus operating conditions. 

In studies of quantitative structure activity relationships (QSAR), the relative potencies of a series of drugs are subjected to analysis with the hope that biological potency will be described by a mathematical equation. QSAR is an actuarial or statistical method in which only objective data are used with no intrusion of models or mechanistic hypotheses. The equation that is obtained not only accounts for the relative potencies of the compounds, but from it are deduced predictions of the potencies of untested compounds if the equation is valid, the predictions are ineluctable. The method thus has the capacity of yielding new (structurally related) drugs with desired potency, perhaps drugs with enhanced selectivity or fewer side effects. 

The validation process begun in Phase I is extended during Phase II. In this phase, selectivity is investigated using various batches of drugs, available impurities, excipients, and samples from stability studies. Accuracy should be determined using at least three levels of concentration, and the intermediate precision and the quantitation limit should be tested. For quality assurance evaluation of the analysis results, control charts can be used, such as the Shewart-charts, the R-charts, or the Cusum-charts. In this phase, the analytical method is refined for routine use. 

The CE method was validated in terms of accuracy, precision, linearity, range, limit of detection, limit of quantitation, specificity, system suitability, and robustness. Improved reproducibility of the CZE method was obtained using area normalization to determine the purity and levels of potential impurities and degradation products of IB-367 drug substance. The internal standard compensated mainly for injection variability. Through the use of the internal standard, selected for its close mobility to IB-367, the method achieved reproducibility in relative migration time of 0.13% relative standard deviation (RSD), and relative peak area of 2.75% RSD. 

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