The makeup of mixed-manifest freight trains is often determined through rigid operating rules designed based on steady-state in-train forces under nominal vehicle and track conditions. Despite compliance with these rules, excessive forces experienced during exceptional situations still hold significant potential to result in derailments. This paper presents a case study involving a mixed train derailment in a sharp curve following an undesired brake release. The operating conditions and sequence of events are modelled using a novel multiscale simulation approach to combine industry-established longitudinal and multi-body dynamics simulation packages. The root cause of the derailment in this case study is assessed, along with the effectiveness of subsequent rule changes in mitigating the corresponding risk. The case study and results are further discussed in the broader context of a research initiative to utilize near real-time data collection from wayside and vehicle-mounted measurement systems, together with robust multiscale simulation approaches, to improve the area of mixed train marshalling.