A Predictive Modeling Approach to Support the Overfill Volume Definition of Liquid-in-Vial Drug Products.

Liquid-in-vial drug products are typically overfilled to meet the label claim volume specification while taking into account losses in the container-closure system and withdrawal device. Any overfill volume setting requires justification. The aim of this study was to estimate the overfill volume required for a liquid drug product in a vial using a prediction model. Glass vials sized from 2R to 20R capacity were filled with sorbitol-based aqueous solutions having a viscosity at 20°C ranging from 1 to 40 mPa·s. Viscosity and vial neck diameter were shown to be the main contributors to the hold-up volume of sorbitol-based aqueous solutions in vial and withdrawal syringe. The hold-up volume of various molecules of therapeutic interest was successfully estimated using a model built from sorbitol-based aqueous solutions data. A total variability approach is proposed for estimating the overfill volume of liquid-in-vial drug products, taking into account the product hold-up volume in vial and withdrawal syringe, the filling variability, and the extractable volume test variability. This prediction model could provide a first guess of the fill volume range to be tested to support overfill volume definition.