The production of purified virus particles with high quality and quantity for vaccine preparation requires scalable purification procedure in downstream step. A purification scheme based on combined strong anion-exchange and size exclusion chromatography (2D -AEC×SEC) is developed for production non-structural protein (NSP) free foot and mouth diseases (FMD) vaccine and the whole procedure is accomplished with 78 % recovery, 85 % virus yield and more than 90 % of residual DNA (rDNA) is removed from the purified vaccine. Due to use AEC as the first column, the injection volume increases four times compare to previous report. Alternatively, a mathematical modeling and simulation approach based on plate model chromatography are developed and matched with the experimental chromatography data to obtain better perception in predicting retention behavior and saving time in downstream scale-up method development. The analysis of purified virus particles by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), dynamic light scattering (DLS) high performance size exclusion chromatography (HP-SEC), matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), transmission electron microscopy (TEM) and biological test provide to the best quality of purified FMD virus.