Process intensification is necessary to create economical processes. Cleavage reaction is one of the critical unit operations in peptide manufacturing processes as it involves cutting of concatemer expressed to obtain monomer. In this paper, solubilization and cleavage reaction have been merged into a single unit operation so as to allow for simultaneous solubilization and cleavage. Critical variables such as urea concentration, calcium chloride concentration, pH, and enzyme loading were optimized using quality by design (QbD) principles. The subsequent RP-HPLC unit operation was also intensified with respect to elution gradient and product stability in elution buffer so as to facilitate direct freeze-drying and storage. The proposed three-step process was analysed for its economics and compared with the previous generation process, showing significant improvements including a 21% reduction in batch time, 27% increase in productivity, and 30% reduction in manufacturing cost. The work illustrates the effectiveness of applying QbD principles and process intensification for creation of a more efficient manufacturing bioprocess.