Utilizing a model based approach, a multivariate design space was identified for the reaction and distillative crystallization unit operations of an API synthetic step. Initially, a kinetic model for the conversion of the final intermediate to API was developed from laboratory data as a function of concentration, temperature, and equivalents of reagent. In addition, a process model was also developed for the kinetics of API degradation in the subsequent distillative crystallization. The kinetic degradation model was coupled to a vapor-liquid-equilibrium model to evaluate process performance under different pressures and distillation times. The multidimensional process design space was then mapped by visualizing the results of the models as surface plots. When combined with quantitative API isolation information, these surface plots provided the foundation for a quality gate on the level of residual intermediate. This not only provided control of a critical quality attribute (CQA) but also compressed the reaction design space into a single output parameter. Model performance was verified in a late stage pilot plant campaign and the process models described here will be further utilized as a key portion of future Quality by Design efforts for this project.