The upstream production process is designed to yield the intended biopharmaceutical active ingredient, but it also carries with it a complex impurity profile that needs to be separated away from the desired biopharmaceutical drug substance—the many product-related impurities and process-related impurities. The downstream purification process must be adequately and appropriately designed for this hand-off from the upstream process to effectively accomplish the needed purification. Downstream purification requires adherence to cGMPs and tight control over the process parameters to end up with a regulatory-compliant acceptable level for each of the residual impurities—which is no mean feat to accomplish. The focus of this chapter is on the downstream purification process for both the protein-based biopharmaceuticals (recombinant proteins and monoclonal antibodies) and the gene-based biopharmaceuticals (viral vectors, non-viral vectors, and genetically modified patient cells). Regulatory authorities have high expectations, as well as major requirements for the downstream manufacturing process of the biopharmaceutical drug substance, which will be examined in this chapter. Application, where appropriate, for the minimum CMC regulatory compliance continuum risk-based approach will be discussed.