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, seemingly endless, product-related structural variant profile due to both the biological manufacturing processes employed and the nature of the product produced. These biomolecular structural variants will range in functional biological activity, patient safety, and clinical efficacy. Therefore, knowing both the biomolecular structural variants that could be formed and how the manufacturing process contributes to their presence is most important. In this chapter, the risk-based control strategy for prioritizing the concerns associated with the numerous product-related structural variants produced by the different biopharmaceutical manufacturing processes will be examined. Application of the minimum CMC regulatory compliance continuum risk-based approach will be discussed.