Freeze-drying from mixtures of water and organic solvents has been demonstrated to be beneficial to both product quality and process duration. The aim of this study was to develop a new model-based technology (referred to as valveless monitoring system) that makes it possible to monitor noninvasively the sublimation step in the case of lyophilization from both aqueous solutions and organic/water cosolvent systems. This technology can directly measure the rate of sublimation and infer key quality variables, which cannot be measured online, from process variables (i.e., pressure inside the drying chamber and condenser) that are commonly measured during a freeze-drying cycle. These estimations are useful not only to monitor the process but also to design the cycle. In fact, the proposed monitoring system can also estimate either the heat transfer coefficient or the mass transfer resistance through two separate experiments. This study also shows how these two parameters (coupled with a mathematical model of the process) can be used to identify the values of the process conditions that allow maintenance of key quality variables within specified limits. Examples of application of this system to a tert-butanol/water cosolvent-based formulation are presented and discussed to demonstrate the effectiveness of the proposed approach.