(408d) First Steps Toward Large-Scale Production of PLGA Nanoparticles

Owing to its excellent biocompatibility, adjustable degradation and release characteristics, low immunogenicity, and high versatility, poly(lactic-co-glycolic acid) (PLGA) is one of the most widely employed polymers in the biomedical field. Consequently, more than 60 PLGA-based formulations with different properties have received US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approvals, respectively. However, despite intensive research, no nanopharmaceutical based on PLGA has been granted a marketing authorization yet [1]. This can be attributed to the fact that a nanoproduct launch involves a complex and expensive pathway from formulation development on a laboratory-scale to scale-up manufacturing and clinical trials. Thereby, scale-up is particularly challenging, since nanoparticle characteristics including their efficacy and safety, are directly related to their physicochemical properties and may change during conversion from laboratory-scale to large-scale production [2], [3]. In addition, laboratory-scale manufacturing of PLGA nanoparticles is mainly conducted by bottom-up methods such as nanoprecipitation, dialysis and ultrasonication, which involve a variety of different processing steps and are not transferable to industry [1]. Hence, there is a need to convert PLGA nanoparticle preparation toward scalable manufacturing technologies.

This study aims at comprehensively investigating the manufacturing performance of PLGA nanoparticles prepared by high shear mixing (HSM) followed by high pressure homogenization (HPH) or microfluidization (MF). After a standardized pre-emulsification step, a formulation and process optimization were conducted with both devices by means of Design of Experiments (DoE). This involved investigating the effect of input parameters such as stabilizer concentration, proportion of organic solvent, pressure and number of cycles on the resulting particle size and particle size distribution (i.e., polydispersity index (PdI)). The optimized formulations were further characterized regarding surface charge, stability and shape using cryo-scanning electron microscopy.

By means of DoE, it was found that for both HPH and MF the stabilizer concentration, the pressure, and the number of cycles exerted the most significant influence on particle size and PdI. Compared to HPH, manufacturing via MF resulted in smaller particle sizes and a narrower particle size distribution. These results can be attributed to lower pressure fluctuations due to the electronically controlled pressure pumps of the MF device in contrast to the manually controlled valve of the HPH device. Formulation and process optimization revealed particle sizes in the range of approximately 140 (MF) to 150 (HPH) nm with a narrow particle size distribution (PdI values below 0.1). Moreover, they exhibited a high physical stability, a negative surface charge and an almost spherical shape. This highlights that both technologies are suitable for the large-scale manufacturing of PLGA nanoparticles, whereby a more reliable performance can be expected with MF.

REFERENCES

[1] M. C. Operti, A. Bernhardt, S. Grimm, A. Engel, C. G. Figdor, and O. Tagit, “PLGA-based nanomedicines manufacturing: Technologies overview and challenges in industrial scale-up,” Int. J. Pharm., vol. 605, p. 120807, Aug. 2021, doi: 10.1016/J.IJPHARM.2021.120807.

[2] H. Havel et al., “Nanomedicines: From Bench to Bedside and Beyond,” AAPS J., vol. 18, no. 6, pp. 1373–1378, Nov. 2016, doi: 10.1208/S12248-016-9961-7/TABLES/1.

[3] J. M. Metselaar and T. Lammers, “Challenges in nanomedicine clinical translation,” Drug Deliv. Transl. Res., vol. 10, no. 3, p. 721, Jun. 2020, doi: 10.1007/S13346-020-00740-5.