Recent studies have shown that by combining orthogonal, non-affinity chromatography steps, it is possible to rapidly develop efficient purification processes for molecules of interest. Here, we build upon previous work to develop a flexible framework for identifying resins that remove optimally orthogonal sets of impurities for a wide variety of products. Our approach involves screening a library of proteins with diverse properties (pI ranging from 5.0-11.4 and varying hydrophobicity measured by retention in a HIC gradient) on a library of resins and quantifying each resin's ability to separate every protein pair in the library. Orthogonality is then defined as the degree to which two resins separate mutually exclusive sets of protein pairs. We applied this approach to a library of model proteins and a series of strong, salt tolerant, and multimodal ion exchangers and evaluated which resin combinations performed well and which performed poorly. In particular, we found that strong cation and strong anion exchangers were orthogonal, while strong and salt tolerant anion exchangers were not orthogonal. Interestingly, salt tolerant and multimodal cation exchangers were found to be orthogonal and the best resin combination included a multimodal cation exchange resin and a tentacular anion exchange resin. This approach for quantifying orthogonality is valuable in that it can be used both as a criteria for resin design as well as process design. We envision that, using this framework, it will be possible to design a set of next generation chromatography ligands that are explicitly engineered to optimize separability and orthogonality. Copyright © 2020. Published by Elsevier B.V.