Adopting the Quality by Design (QbD) approach in the drug development process has transformed from 'nice-to-do' into a crucial and required part of the development, ensuring the quality of pharmaceutical products throughout their whole life cycle. This review is discussing the implementation of the QbD thinking into the production of long-acting PLGA/PLA-based injectable microspheres for the therapeutic peptide and protein delivery. Various key elements of the QbD approaches are initially elaborated using Bydureon®, a commercial product of long-acting PLGA/PLA-based injectable microspheres, as a classical example. Subsequently, the factors influencing the release patterns and the stability of the peptide and protein drugs are discussed. This is followed by a summary of the state-of-the-art of manufacturing long-acting PLGA/PLA-based injectable microspheres and the related process parameters. Finally, a landscape of generic product development of long-acting injectable (LAI) PLGA/PLA-based microspheres is reviewed including some major challenges in the field.