A novel and scalable method has been developed to enable control of the ice nucleation step for the freezing process during lyophilization. This method manipulates the chamber pressure of the freeze dryer to simultaneously induce nucleation in all product vials at a desired temperature. The effects of controlled nucleation on the drying rate of various formulations including 5% (w/w) mannitol, 5% (w/w) sucrose, and a mixture of 3% (w/w) mannitol and 2% (w/w) sucrose were studied. For a 5% (w/w) mannitol, uncontrolled ice nucleation occurred randomly at product temperatures between −8.0°C and −15.9°C as the vials were cooled to −40°C. Controlled ice nucleation was achieved at product temperatures between −2.3°C and −3.7°C. The effect of nucleation control on the effective pore radius (re) of the cake was determined from the product temperature profiles using a pore diffusion model in combination with a nonlinear parameter estimation approach reported earlier. Results show that the value of re for 5% (w/w) mannitol was enlarged from 13 to 27 μm by uniformly inducing nucleation at higher temperatures. Applying the resistance parameters obtained from the pore diffusion model for 5% (w/w) mannitol, optimized cycles were theoretically generated and experimentally tested, resulting in a 41% reduction in primary drying time. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3453–3470, 2011