The solvent freeze out (SFO) technology for protein crystallization involves a solid-layer melt crystallization to freeze out the solvent and therefore to supersaturate the protein solution where protein crystals are formed. Herewith, the optimization strategy for the SFO in terms of yield, activity and quality of the protein crystals is presented. It is based on technical concepts of melt and solution crystallizations, design of experiments (DOE) and previous results on lysozyme crystallization. The motivation has been the necessity of an efficient crystallization process which preserves a good quality of the protein crystals, has a retention time of only few hours, involves low costs and is on top of it environmentally friendly. (C) 2012 Elsevier B.V. All rights reserved.