This paper presents challenges of using discrete event simulation when supporting decision in early stages of production system design, when significant changes are introduced. It was based on three real-time case studies performed at one manufacturing company during 2014–2016. Challenges in the cases were mapped to previous literature, pointing out discrepancies and highlighting three additional challenges, specifically related to issues in the early stages of the production system design process. The significant change introduced to the assembly system, and the early phases of evaluation put significant challenges to the use of discrete event simulation and the study points out further efforts needed to support manufacturing companies under change, with an established industrial structure and legacy systems to consider.