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Int J Pharm. 2018 Oct 25;550(1-2):140-148. doi: 10.1016/j.ijpharm.2018.08.044. Epub 2018 Aug 23.

A comparative assessment of continuous production techniques to generate sub-micron size PLGA particles.

Author information

1
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.
2
Evonik Nutrition & Care GmbH, Health Care, 64293 Darmstadt, Germany.
3
Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen and Oncode Institute, The Netherlands.
4
Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen and Oncode Institute, The Netherlands. Electronic address: carl.figdor@radboudumc.nl.
5
Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen and Oncode Institute, The Netherlands. Electronic address: oya.tagit@radboudumc.nl.

Abstract

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.

KEYWORDS:

Continuous process technology; Homogenization; Microfluidics; Poly(lactic-co-glycolic acid); Scale-up production; Sub-micron particles

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