All biopharmaceuticals, whether protein-based biopharmaceuticals (recombinant proteins and monoclonal antibodies) or gene-based biopharmaceuticals (viral vectors, non-viral vectors, genetically modified patient cells), have a highly complex process-related impurity safety profile due to the biological manufacturing processes employed. Patient safety risk from these process-related impurities needs to be assessed. In this chapter, the risk-based control strategy for prioritizing the concerns associated with the numerous process-related impurities produced by the different biopharmaceutical manufacturing processes, will be discussed. Application of the minimum CMC regulatory compliance continuum risk-based approach will be examined. In addition, four specific process-related impurities impacting all biopharmaceutical manufacturing processes will be discussed in detailed—residual DNA, residual host cell proteins (HCPs), residual endotoxin, and extractables/leachables.