Drug development calibration standard matrix

It can be assumed that with the development and study of new methods, the ability to determine M (S), the method bias component of uncertainty, cannot be done given that it can be evaluated only relative to a true measure of analyte concentration. This can be achieved by analysis of a certified reference material, which is usually uncommon, or by comparison to a well-characterized/accepted method, which is unlikely to exist for veterinary drug residues of recent interest. Given that method bias is typically corrected using matrix-matched calibration standards, internal standard or recovery spikes, it is considered that the use of these approaches provides correction for the systematic component of method bias. The random error would be considered part of the interlaboratory derived components of uncertainty. 

In general, it is easier (and faster) to develop an HPLC-ESI-MS/MS method for multiple analytes with the matrix effects identified and under control as compared to IA (see below). Furthermore, selectivity and interference from matrix components and/or metabolites is less of a problem with an LC-MS/MS method compared to IA. With an appropriate internal standard (IS), LC-MS/MS methods are more precise than IA. Moreover, the LC-MS/MS calibration range is broader and can accommodate disproportionate concentration ranges of the drug compound and its metabolites. In contrast, most IA are geared to quantify only one analyte at a time because the method development of multiplex IA is complicated and often cannot be optimized for all analytes of interest. 

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