A systematic retrofitting methodology supported by real data implementation was developed to facilitate the optimization of pharmaceutical drug purification processes. The methodology consists of five tasks: (I) understand the plant through measurements, (II) create a process model, (III) adapt the model for optimization, (IV) optimize the process model, and (V) interpret the outcome of the task. A novelty of this methodology is the use of path-flow decomposition as a tool to provide a visual representation of the process, thus facilitating its understanding and the creation of the process model. Furthermore, a decision-tree diagram furnishes detailed and specific support during the creation of the process model, in particular for a dissolution-filtration-crystallization process. Identification of constraints and optimization variables ensure the applicability of the methodology to pharmaceutics. Incorporation of measured process data improves the reliability of the methodology, making it applicable in real case studies. The methodology was applied to an industrial case study. (C) 2015 Elsevier Ltd. All rights reserved.