This article presents our efforts toward the development and scale-up of a fluidized bed process for co-granulation of two highly water-soluble active pharmaceutical ingredients (APIs) with a polymeric binder. The granulations were produced at three scales using Glatt GPCG3 (small), GPCG15 (pilot), and GPCG120 (commercial) fluid bed columns. The effects of binder concentration, atomization air pressure, and inlet air temperature were first investigated at the small scale. Based on the process knowledge generated at the small scale, various granulations were produced at the pilot scale to determine the effects of solution spray rate. We have demonstrated that, for a given binder solution, the droplet size distribution can be maintained similar by adjusting the atomization pressure when different spray rates were used upon scale-up. Superficial air velocity and moisture level in the powder bed appear to be the other key response parameters, which are, in turn, governed by various process and design parameters as well as formulation properties. This article demonstrates that the process and product quality remains invariant when the aforementioned key response variables are maintained during scale-up through some simple scale-up rules.