A Simple Approach for Comparing the In Vitro Dissolution Profiles of Highly Variable Drug Products: a Proposal.

When in vitro dissolution profile variability prohibits the use of the F2 metric, there currently is no satisfactory alternative available. Published reports evaluating alternative approaches such as Multivariate Statistical Distance and use of a bootstrap F2 identify sources of bias that can limit the utility of these alternatives. Within veterinary medicine, an additional complication is the potential magnitude of interlot variability associated with dosage forms containing "natural" ingredients. In situations when both interlot and intralot variability need to be factored in the test and reference profile comparison, we designed a method that integrates such concepts as F2, USP S1 and S2 criteria and statistical tolerance limits. Unlike F2, this alternative approach integrates a statistical confidence into the determination through the use of tolerance limits about the reference product profile. Moreover, while differences in product variability, along with differences in mean profiles, will influence the comparability assessment, this method does not impose the need to confirm homogeneity of variances: there is not direct statistical comparison of test versus reference dissolution data. For more typical situations when interlot variability is not a concern, the F2 component can be omitted from the profile comparison. Lastly, by being a model-independent approach, we avoid the potential for introducing error into the comparability determination due either to model misspecification or problems associated with a lack of collinearity. This manuscript details this alternative approach and the results of performance characterization efforts to illustrate its behavior under a range of potential situations.