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

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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 T 2 statistic (equivalently, Mahalanobis distance D 2), and the simultaneous confidence limits were based on the Mahalanobis statistic as well as on the Bonferroni adjustment. The Mahalanobis simultaneous confidence limits specification criteria have the overall false out-of-specification rate too low in both parametric and bootstrap approaches.

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