Content Uniformity: Separation and quantitation of sources of dose variation

Abstract A propagation of error formula is presented which describes a mathematical relationship between uniformity of dosage units (dose variation) and the individual sources of variability. Using this propagation of error formula and a minor modification of the USP Content Uniformity test procedure, one can assign dose variation to weight variation, blend heterogeneity and assay imprecision without compromising the information required by the USP XXII. This formula separates and quantitates the sources of dose variation and defines the manner in which weight variation, blend heterogeneity and assay imprecision are propagated. By knowing how the dose variation is propagated, specific measures can be taken to improve the uniformity of dosage units. The propagation of error formula can also be used to calculate a priori estimates of dose variation by choosing reasonable or expected variances for weight variation, blend heterogeneity and assay imprecision. Such calculations can save hours of fruitless effort which attempt to improve the content uniformity without considering how dose variation is propagated and to what extent the expected dose variation can be improved.