Flat-sheet membrane discs represent the current standard format used for experimental prediction of the scale-up of normal flow filtration processes. Use of this format is problematic, however, since the scale-down results typically show a 40–55% difference in performance compared to large-scale cartridges depending upon the feedstock used. In this work, novel pleated scale-down devices (Am = 1.51–15.1 × 10−3 m2) have been designed and fabricated. It is shown that these can more accurately predict the performance of industrial scale single-use pleated membrane cartridges (Am = 1.06 m2) commonly used within biopharmaceutical manufacture. The single-use scale-down cartridges retain the same pleat characteristics of the larger cartridges, but require a reduced feed volume by virtue of a substantially diminished number of active membrane pleats. In this study, a 1,000-fold reduction in feed volume requirement for the scale-down cartridge with the smallest membrane area was achieved. The scale-down cartridges were tested both with clean water and a pepsin protein solution, showing flux-time relationships within 10% of the large-scale cartridge in both cases. Protein transmission levels were also in close agreement between the different scale cartridges. The similarity in performance of the scale-down and the large-scale cartridges, coupled with the low feed requirement, make such devices an excellent method by which rapid scale-up can be achieved during early stage process development for biopharmaceutical products. This new approach is a significant improvement over using flat-sheet discs as the quantitative similarity in performance with the large-scale leads to reliable scale-up predictions while requiring especially small volumes of feed material. Biotechnol. Bioeng. 2011; 108:830–838. © 2010 Wiley Periodicals, Inc.