Multiple-time-point dissolution specifications for a sampling acceptance plan.

ABSTRACT

In dissolution testing, multiple dissolution measurements at specific time points are used to obtain the dissolution characteristics for most extended-release and some immediate-release drug products. This paper presents a general procedure for defining specifications by a multivariate confidence region or by simultaneous confidence limits on the dissolution values of individual time points. The confidence regions and simultaneous confidence limits were estimated using two approaches the first approach assumed a multivariate normal distribution on the multiple dissolution values and the second approach used the bootstrap resampling method. The multivariate confidence region was constructed using the Hotelling's T2 statistic (equivalently, Mahalanobis distance D2), and the simultaneous confidence limits were based on the Mahalanobis statistic as well as on the Bonterroni adjustment. The Mahalanobis simultaneous confidence limits specification criteria have the overall false out-of-specification rate too low in both parametric and bootstrap approaches.