Binding free energy calculations predict the potency of compounds to protein binding sites in a physically rigorous manner and see broad application in prioritizing the synthesis of novel drug candidates. Relative binding free energy calculations (RBFE) have emerged as an industry standard approach to achieve highly accurate rank-order predictions of the potency of related compounds; however, this approach requires that the ligands share a common scaffold and a common binding mode, restricting the methods' domain of applicability. This is a critical limitation, since complex modifications to the ligands, especially core hopping, are very common in drug design. Absolute Binding Free Energy calculations (ABFE) are an alternate method, which can be used for ligands that are not congeneric. However, ABFE suffer from a known problem of long convergence times, due to the need to sample additional degrees of freedom within each system, such as sampling rearrangements necessary to open and close the binding site. Here, we report on an alternative method for RBFE, called Separated Topologies (SepTop), which overcomes the issues in both of the aforementioned methods, by enabling large scaffold changes between ligands with a convergence time comparable to traditional RBFE. Instead of only mutating atoms that vary between two ligands, this approach performs two absolute free energy calculations at the same time in opposite directions, one for each ligand. Defining the two ligands independently allows the comparison of binding of diverse ligands without the artificial constraints of identical poses or a suitable atom-atom mapping. This approach also avoids the need to sample the unbound state of the protein, making it more efficient than absolute binding free energy calculations. Here, we introduce an implementation of SepTop. We developed a general and efficient protocol for running SepTop, and we demonstrated the method on four diverse, pharmaceutically relevant systems. Here we report the performance of the method, as well as our practical insights into strengths, weaknesses, and challenges of applying this method in an industrial drug design setting. We find that the accuracy of the approach is sufficiently high to rank order ligands with an accuracy comparable to traditional RBFE calculations, while maintaining the additional flexibility of SepTop.