The effects of tray side and drying chamber wall temperature on the performance of freeze-drying of pharmaceuticals in vials arranged in clusters of hexagonal arrays on trays are studied, and the results of this work indicate that it would be beneficial to operate the lyophilization process by (i) employing freeze-dryers whose trays have no tray sides, (ii) using heat input control that runs the freeze-drying process close to the melting and scorch temperature constraints during the primary and secondary drying stages, respectively, and (iii) keeping the drying chamber wall temperature slightly higher than the melting temperature constraint during the primary drying stage, while during the secondary drying stage the drying chamber wall temperature should not be significantly lower than the scorch temperature constraint. The modeling and system formulation approach presented here provide a quantitative method that can be used in the analysis, optimization and control of the lyophilization process, as well as in the design of freeze-dryers.