Computer programs in FORTRAN were developed to rapidly determine the optimal shelf temperature, T_f, and chamber pressure, P_c, to achieve the shortest primary drying time. The constraint for the optimization is to ensure that the product temperature profile, T_b, is below the target temperature, T_target. Five percent mannitol was chosen as the model formulation. After obtaining the optimal sets of T_f and P_c, each cycle was assigned with a cycle rank number in terms of the length of drying time. Further optimization was achieved by dividing the drying time into a series of ramping steps for T_f, in a cascading manner (termed the cascading T_f cycle), to further shorten the cycle time. For the purpose of demonstrating the validity of the optimized T_f and P_c, four cycles with different predicted lengths of drying time, along with the cascading T_f cycle, were chosen for experimental cycle runs. Tunable diode laser absorption spectroscopy (TDLAS) was used to continuously measure the sublimation rate. As predicted, maximum product temperatures were controlled slightly below the target temperature of −25°C, and the cascading T_f-ramping cycle is the most efficient cycle design. In addition, the experimental cycle rank order closely matches with that determined by modeling. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3469–3482, 2009