The effects of pump failures in nine zone and pump configurations for the size-exclusion simulated moving bed purification of insulin are analyzed. Simulations based on verified intrinsic parameters are used to understand the dynamic wave phenomena. This understanding helps determine the best zone and pump configuration, determine the time window to recover from the degraded state, and formulate contingency responses to failures. The results show the open-loop three-zone simulated moving bed is the best. It is more reliable and has higher productivity and reduced residence time of the high molecular weight impurities. A disadvantage of the three-zone is the higher solvent consumption. In the recommended configuration: desorbent pump failure is critical and dual redundant pumps are recommended; feed pump failure is marginal and results in diluted product; and zone II pump failure is critical—the time window for corrective action is half a step-time. Zone pumps are recommended instead of outlet pumps because they do not result in stationary phase collapse from high pressure drop and allow higher productivity in pressure-limited systems.