The goal of consistently achieving critical quality attributes (CQAs) for synthetic peptide active pharmaceutical ingredients (APIs) may be challenging owing to the complexity of the manufacturing process and the large number of potential sources of variability. This chapter outlines the principles of process design and the development of a comprehensive control strategy for manufacturing peptide APIs of consistent quality. A approach is described that involves process design utilizing a practical application of quality target product profile (QTPP), quality-by-design (QbD), identification and mitigation of risks and process characterization. The parallel development of supporting analytical tools requires the development of a testing strategy that encompasses all stages of manufacturing from starting materials, in-process testing through drug substance release testing and stability testing. Phase-appropriate approaches to synthetic, hybrid and semisynthetic technologies used for manufacturing peptides are discussed.