The scale-up of the Knoevenagel-condensation between vanillin and barbituric acid carried out in planetary ball mills is investigated from an engineering perspective. Generally, the reaction proceeded in the solid state without intermediate melting and afforded selectively only one product. The reaction has been used as a model to analyze the influence and relationship of different parameters related to operation in planetary ball mills. From the viewpoint of technological parameters the milling ball diameter, dMB, the filling degree with respect to the milling balls' packing, ΦMB,packing, and the filling degree of the substrates with respect to the void volume of the milling balls' packing, ΦGS, have been investigated at different reaction scales. It was found that milling balls with small dMB lead to higher yields within shorter reaction time, treaction, or lower rotation frequency, rpm. Thus, the lower limit is set considering the technology which is available for the separation of the milling balls from the product after the reaction. Regarding ΦMB,packing, results indicate that the optimal value is roughly 50% of the total milling beakers' volume, VB,total, independent of the reaction scale or reaction conditions. Thus, 30% of VB,total are taken by the milling balls. Increase of the initial batch sizes changes ΦGS significantly. However, within the investigated parameter range no negative influence on the yield was observed. Up to 50% of VB,total can be taken over by the substrates in addition to 30% for the total milling ball volume. Scale-up factors of 15 and 11 were realized considering the amount of substrates and the reactor volume, respectively. Beside technological parameters, variables which influence the process itself, treaction and rpm, were investigated also. Variation of those allowed to fine-tune the reaction conditions in order to maximize the yield and minimize the energy intensity.