Manufacturers need the freedom to make changes to improve their biopharmaceutical processes, not only during clinical development, but also for continuous process improvement once in the marketplace. Along with this freedom to make manufacturing process changes comes the responsibility of carefully assessing the potential safety and efficacy impact on the biopharmaceutical due to those changes. Demonstrating comparability (i.e., meeting the standard of “highly similar”) for a biopharmaceutical after a manufacturing process change is no easy task, whether it be for a recombinant protein, monoclonal antibody, viral vector, non-viral vector, or genetically modified patient cells. In this chapter, the three risk-based elements that need to be addressed by an effective comparability study will be examined: (1) the stage of clinical development when the change is planned, (2) the nature (type, extent, process location) of the change that is planned, and (3) the residual uncertainty remaining after the analytical/functional testing has been evaluated. Also, a firmer understanding of how to obtain a post-approval change management plan (PACMP) with a regulatory authority will be discussed.