Dissolution Edge Charts for Immediate Release Products and Their Applications: a Simulation Study to Aid the Setting of Specifications.

One of the most commonly used methods to establish the clinical relevance of dissolution is to align the dissolution specifications with pivotal clinical batches. The objective of the study was to create edge charts for the dissolution of immediate release (IR) drug products to quantitatively establish the bases for setting clinically relevant and discriminating dissolution specifications and to clarify which stage in the US Pharmacopoeia (USP) <711> acceptance tables should be targeted. The simulations of dissolution data were performed on a batch of IR products with 1,000,000 units. The desired acceptance criterion was Q = 80% of the label claim at 30 min. A total of 110 scenarios for IR data were generated, which included various combinations of two determinants: the batch mean and SD (standard deviation). For each scenario, the dissolution data were tested based on USP three-stage procedures to determine the pass/fail at each stage. This process was repeated 10,000 times. The failure rate at each stage for each scenario was calculated as the percentage of failed replicates across 10,000 trials. Contour plots, named edge charts, were created to demonstrate the relationship between the dissolution failure rates and the two determinants (mean and SD). The edge lines represent the failure rates for the given combinations of the mean and SD. The edge charts can provide a quantitative estimate based on the observed dissolution data and provide fundamental support for recommendations on using USP stage 2 as a target for setting the acceptance limit(s).