The F2 metric has been successfully applied for comparing product in vitro dissolution profiles. Comparisons are based upon an allowable magnitude of profile differences (without considering a probability about that assessment). The F2 metric can only be applied when the within-product variability at the first timepoint does not exceed a 20% coefficient of variation (%CV) or 10% at all other timepoints (FDA 1997 Dissolution Guidance). This constraint raises an unresolved need to identify methods for comparing in vitro dissolution profiles when products fail to meet these variability constraints. Despite efforts to define multivariate approaches, the appropriateness of proposed alternatives remain debated (e.g., Mangas-Sanjuan et al., 2016, Paixão et al., 2017; Cardot et al., 2017).
Within the FDA CVM, highly variable in vitro dissolution data are typically encountered with products formulated as Type A medicated articles (i.e., drugs delivered in food). Thus, we sought to develop an approach for comparing the in vitro profiles for these products. Unlike existing multivariate approaches, our proposed method does not provide a statistical comparison of the test and reference formulations but rather uses the reference product to define the bounds within which the individual test product observations must be constrained. Based upon USP allowable deviations about some quality control specifications (USP <711>), these bounds are defined by an allowable distance from the 99% tolerance limits about the reference dissolution data (estimated with 95% confidence) and confirmation of sameness of the average dissolution profiles using the F2algorithm. Using simulated data, the proposed method succeeded in identifying formulations with different profile shapes or similar shapes but differences in variability at some or all sampling times. Therefore, we believe that our proposed method provides a simple approach for handling dissolution data that do not conform to the criteria for applying F2.
References:
Dissolution Testing of Immediate Release Solid Oral Dosage Forms. Center for Drug Evaluation and Research, US FDA. Published online: 08/1997. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070237.pdf
Mangas-Sanjuan V, Colon-Useche S, Gonzalez-Alvarez I, Bermejo M, Garcia-Arieta A. Assessment of the Regulatory Methods for the Comparison of Highly Variable Dissolution Profiles. AAPS J. 2016 Nov;18(6):1550-1561.