aQbD as a platform for IVRT method development - A regulatory oriented approach.

The EMA draft guideline on quality and equivalence of topical products and the FDA non-binding product specific guidances release has encouraged the establishment of a regulatory background for in vitro release testing (IVRT). Herein, a novel framework applicable to the development of a discriminatory IVRT method is described, according to analytical quality by design (aQbD) principles. A commercially available diclofenac emulgel formulation was used as model product. Through the definition of IVRT analytical target profile, a risk assessment analysis was carried out, in which the critical analytical attributes (in vitro release rate, cumulative amount released at an initial/final point and dose depletion) and critical method variables (medium, membrane and dosage regimen) were identified. Based on this information, a 3 × 2 × 3 full factorial design was performed. Statistical modeling and system desirability assessment enabled the selection of the most suitable IVRT parameters, which were fully validated according with new EMA requirements. These consisted of PBS:Ethanol (80:20, pH = 7.4), Tuffryn membranes and 300 mg of applied product. aQbD provided a comprehensive framework for developing a reliable and effective IVRT method. A thorough analysis of the new EMA draft guideline requirements revealed that some of the established criteria may be challenging to attain.