A new method using vacuum-induced nucleation to control the freezing process as a means of reducing the freeze-drying cycle and promoting batch homogeneity is proposed. Emphasis was also given to the primary drying stage performed by using in-line monitoring and control. Some modifications to the original control method during freezing were applied with success. For example, in this study the drying chamber is isolated (from the condenser) during the depressurization phase; this modification was found to give a great contribution to the elimination of the aesthetic defects (i.e., blow-up and flake formation), improving the quality of the final product. A detailed investigation of the operating conditions of the new method was performed using a mannitol 5% solution; some parameters were varied during the freeze-drying process and by adding an annealing step. The mass-transfer resistance values obtained from each cycle were used to calculate the design space and simulate the process. The cycle simulation highlighted both the reduction of the cycle duration with the new method when compared with an uncontrolled (stochastic) cycle and the influence of the operating conditions of the method on freeze-drying cycle optimization. Finally, the performance of the new method was also evaluated using solutions of lactose (5% w/w) and mannitol with a higher solid content (10% w/w).