Membrane chromatography (MC) systems are finding increasing use in downstream processing trains for therapeutic proteins due to the unique mass-transfer characteristics they provide. As a result, there is increased need for model-based methods to scale-up MC units using data collected on a scaled-down unit. Here, a strategy is presented for MC unit scale-up using the zonal rate model (ZRM). The ZRM partitions an MC unit into virtual flow zones to account for deviations from ideal plug-flow behavior. To permit scale-up, it is first configured for the specific device geometry and flow profiles within the scaled-down unit so as to achieve decoupling of flow and binding related non-idealities. The ZRM is then configured for the preparative-scale unit, which typically utilizes markedly different flow manifolds and membrane architecture. Breakthrough is first analyzed in both units under nonbinding conditions using an inexpensive tracer to independently determine unit geometry related parameters of the ZRM. Binding related parameters are then determined from breakthrough data on the scaled-down MC capsule to minimize sample requirements. Model-based scale-up may then be performed to predict band broadening and breakthrough curves on the preparative-scale unit. Here, the approach is shown to be valid when the Pall XT140 and XT5 capsules serve as the preparative and scaled-down units, respectively. In this case, scale-up is facilitated by our finding that the distribution of linear velocities through the membrane in the XT140 capsule is independent of the feed flow rate and the type of protein transmitted. Introduction of this finding into the ZRM permits quantitative predictions of breakthrough over a range of industrially relevant operating conditions. (C) 2014 The Authors Biotechnology and Bioengineering Published by Wiley Periodicals, Inc.