Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen and Oncode Institute, The Netherlands; Evonik Nutrition & Care GmbH, Health Care, 64293 Darmstadt, Germany.
Evonik Nutrition & Care GmbH, Health Care, 64293 Darmstadt, Germany.
Int J Pharm. 2018 Oct 25;550(1-2):140-148. doi: 10.1016/j.ijpharm.2018.08.044. Epub 2018 Aug 23.
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.
基于聚（乳酸-共-乙醇酸）（PLGA）颗粒的聚合物亚微米尺寸制剂的临床和商业开发受到与其良好生产规范（GMP）相符的、在不影响制剂规格的情况下进行规模化生产的挑战的阻碍。连续工艺技术通过增加操作时间而无需改变工艺或制剂参数即可实现大规模生产。在这里，我们探索了三种成熟的连续工艺技术，用于使用分批法在实验室规模上开发的亚微米尺寸 PLGA 颗粒的大规模生产。我们展示了对高剪切混合、高压匀浆和微流控技术的关键工艺和制剂参数的优化，以获得平均直径为 150-250nm 且小多分散指数（PDI，≤0.2）的 PLGA 颗粒。我们讨论了每种技术中对粒径分布影响最大的参数，并对它们在 GMP 生产中的适用性进行了严格评估。尽管每种技术都可以提供所需粒径范围内的颗粒，但由于可获得 GMP 级别的设备和较大的生产吞吐量，高剪切混合被发现特别有前途。总之，我们的研究结果将为建立 GMP 合规的、亚微米尺寸 PLGA 颗粒的大规模连续工艺技术提供重要指导，促进其商业和临床开发。
