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The clinical and commercial development of polymeric sub-micron size formulations based on poly(lactic-co-glycolic acid) (PLGA) particles is hampered by the challenges related to their good manufacturing practice (GMP)-compliant, scale-up production without affecting the formulation specifications. Continuous process technologies enable large-scale production without changing the process or formulation parameters by increasing the operation time. Here, we explore three well-established process technologies regarding continuity for the large-scale production of sub-micron size PLGA particles developed at the lab scale using a batch method. We demonstrate optimization of critical process and formulation parameters for high-shear mixing, high-pressure homogenization and microfluidics technologies to obtain PLGA particles with a mean diameter of 150–250 nm and a small polydispersity index (PDI, ≤0.2). The most influential parameters on the particle size distribution are discussed for each technique with a critical evaluation of their suitability for GMP production. Although each technique can provide particles in the desired size range, high-shear mixing is found to be particularly promising due to the availability of GMP-ready equipment and large throughput of production. Overall, our results will be of great guidance for establishing continuous process technologies for the GMP-compliant, large-scale production of sub-micron size PLGA particles, facilitating their commercial and clinical development.

Contains fulltext : 244666.pdf (Publisher’s version ) (Open Access) Nanomedicines based on poly(lactic-co-glycolic acid) (PLGA) carriers offer tremendous opportunities for biomedical research. Although several PLGA-based systems have already been approved by both the Food and Drug Administration (FDA) and the European Medicine Agency (EMA), and are widely used in the clinics for the treatment or diagnosis of diseases, no PLGA nanomedicine formulation is currently available on the global market. One of the most impeding barriers is the development of a manufacturing technique that allows for the transfer of nanomedicine production from the laboratory to an industrial scale with proper characterization and quality control methods. This review provides a comprehensive overview of the technologies currently available for the manufacturing and analysis of polymeric nanomedicines based on PLGA nanoparticles, the scale-up challenges that hinder their industrial applicability, and the issues associated with their successful translation into clinical practice.