Opportunities for process intensification and increased productivity have made the field of Continuous Biomanufacturing an area of high interest and active research. Within the purification train of producing biologics, Tangential Flow Filtration (TFF) is typically employed after chromatographic separations, to increase drug substance concentration, making the process more economical and further meeting dosage specifications. In a batch operation, concentration occurs via recirculation of the feed material where desired output concentration is attained through multiple pump-passes over the TFF membrane, while steadily excluding the buffer. Single-Pass Tangential Flow Filtration (SPTFF) enables continuity of this process by achieving similar concentration factors through a single – pass over these membranes while operating at low feed flow rates. Our work elucidates the development of a mechanistic process model to predict SPTFF performance across a relatively wide design space using a first principles approach. The developed model is found to be accurate for a range of high feed flow rates but is inaccurate at flow rates below 25 L/m2/hr. At very low flow rates, small differences in the mass transfer coefficient have been observed to significantly alter the prediction of the retentate concentration. We thus describe the challenges in predictive process modeling of SPTFF in antibody biomanufacturing.