Development of oral solid dosage forms containing biologics has attracted intense interests recently due to the high patient convenience and the commercial potential of related products. The aim of this study was to understand how the difference in the particle properties prepared using two different drying principles, i.e. freeze-drying and spray-drying, may influence the compaction behavior of particulate protein systems. Here, trypsin was used as a model protein drug and lactose as a filler. The raw freeze-dried (FD) powder composed mostly of trypsin and lactose was dissolved in Milli-Q water and processed by spray-drying to produce spray-dried (SD) powder. Meanwhile, the raw FD powder was micronized by a ball mill into fine ball-milled (BM) powder with a comparable particle size to that of SD powder. Next, the FD, BM and SD powders were characterized with regard to morphology, residual moisture content (RMC), solid form, and surface chemistry using scanning electron microscope (SEM), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD), and X-ray photoelectron spectroscopy (XPS), respectively. Subsequently, a compaction simulator was employed to prepare tablets within the compaction pressure range of 25 to 400 MPa. The results showed that FD and BM powders could be compressed into tablets within the investigated compaction pressure range. In contrast, tablets compacted from SD powder displayed capping/lamination tendency under high compaction pressures and thus had poor tabletability. XPS analyses revealed that there were more surface enrichments of trypsin in the SD powder compared to that of FD powder. It implies that there would be more hydrophobic inter-particulate trypsin-trypsin interactions and less hydrophilic lactose-lactose interactions during the compression of SD powder compared to the compaction of FD powder. The weak hydrophobic inter-particulate trypsin-trypsin interactions may not be maintained during the decompression phase especially when compacted at high compaction pressure ranges, resulting in capping/lamination of the SD tablets. This study demonstrates that the two drying principles, i.e. freeze-drying and spray-drying, can result in different particle properties of biologics, which can in turn influence the tabletability of the resulting solid materials.