Interest in producing large amounts of plasmid DNA (pDNA) has increased in the last decade as a result of the advances made in gene therapy and DNA vaccines. The last stage of the manufacturing process involves a purification scheme guaranteeing a safe and stable product, considering the authorities' recommendations. This work studies the first step of the purification scheme, i.e., a group separation step based on size exclusion chromatography and using the simulated moving bed technology (SMB). The cleaning in place, crucial for the process validation, is implemented into the SMB in the so-called CIP-SMB configuration. Experiments were designed using the simple approach of triangle theory. The feed consisted of a clarified cleared lysate. The results indicate that total recovery of pDNA is possible and that the productivity can be tuned considering the trade-off with purity. Detailed simulations were used to validate these results after a cleared lysate model was established.