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Manufacturing and Analytical Characterization - Chemical

(W1130-02-10) Defining a Robust, Discovery-Scale Process to Manufacture PLGA Microsphere Prototypes

Wednesday, November 12, 2025
11:30 AM - 12:30 PM CT
Purpose: Long acting injectables (LAIs) offer significant clinical benefits by extending therapy duration, stabilizing drug levels, and enhancing patient adherence. Biodegradable polymeric microspheres, particularly those based on poly(lactic-co-glycolic acid) (PLGA), are a widely used platform for achieving sustained drug release. However, the complex formulation and manufacturing variables of PLGA microspheres pose significant challenges for consistent drug release and generic development. Therefore, robust process control and reproducibility at the small-scale production stage are critical to enable reliable early-stage in vitro and in vivo evaluation. This presentation details key parameters for lab-scale emulsification and downstream processing of PLGA microspheres, designed to minimize API usage while ensuring quality and facilitating a streamlined transition to clinical development. 

Methods: A membrane emulsification method using commercially available AXF-mini equipment (Micropore Technologies, UK) was selected for microsphere production due to its higher throughput compared to microfluidics and improved particle size control over rotor-stator homogenization. Membrane pore sizes (50–100 µm) and dispersed phase flow rates (2–6 mL/min) were varied against a continuous phase flow of 40 mL/min. Solvent removal was achieved via vacuum evaporation. Downstream processing involved conventional isolation and hardening techniques, including dilution and stirring at varied rates, followed by freezing the bulk suspension in deionized water at –20 ºC without excipients. PLGA polymers with consistent lactic-to-glycolic ratios but varying molecular weights were evaluated. Particles were characterized by laser diffraction (Horiba LA-950), polarized light microscopy, and scanning electron microscopy (SEM). Particle size and morphology data guided selection of the optimal process, which was then applied to test multiple PLGA grades with different molecular weights. Subsequent studies with active formulations explored drug loading and PLGA grade variations using risperidone as a model API, given its extensive prior development in PLGA microspheres. 

Results: Variations in carrier-to-dispersed phase flow rates and membrane pore size had minimal effect on particle size distribution. Dilution during the hardening step was critical for achieving reproducible, monomodal particle populations. Lower hardening temperatures maintained consistent particle sizes before and after hardening. Slow stirring improved yield and uniformity by reducing particle agglomeration, while flash freezing significantly minimized settling and aggregation compared to slow freezing. Different PLGA molecular weights showed limited influence on particle size. The optimized process produced uniform risperidone-loaded PLGA microparticles with monomodal particle size distribution for in vitro release testing.

Conclusion: This streamlined procedure enabled rapid, resource-efficient evaluation of PLGA microsphere formulations suitable for early discovery. It produced uniform particles with acceptable yield. Ongoing work will focus on characterizing drug-loaded microspheres to evaluate encapsulation efficiency, particle size, and in vitro release profiles across varying API loadings.

References: Park K, Otte A, Sharifi F, Garner J, Skidmore S, Park H, Jhon YK, Qin B, Wang Y. Formulation composition, manufacturing process, and characterization of poly (lactide-co-glycolide) microparticles. Journal of controlled release. 2021 Jan 10;329:1150-61.
Piacentini E, Dragosavac M, Giorno L. Pharmaceutical particles design by membrane emulsification: preparation methods and applications in drug delivery. Current pharmaceutical design. 2017 Jan 1;23(2):302-18.
Garner J, Skidmore S, Park H, Park K, Choi S, Wang Y. Beyond Q1/Q2: the impact of manufacturing conditions and test methods on drug release from PLGA-based microparticle depot formulations. Journal of pharmaceutical sciences. 2018 Jan 1;107(1):353-61.

Acknowledgements: All authors were employed by Merck & Co., Inc., Rahway, NJ, USA at the time the research described herein was conducted. The main author of this research was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program under Award No. (W81XWH-15-1-0718). Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense.

Figure 1: Particle size distribution of PLGA 7502E microspheres fabricated by emulsification using different pore sized membranes and with different flow rates.

Figure 2: Impact of dilution level and freezing technique on particle size of PLGA 7502E microspheres.

Figure 3: Particle size distribution of A) risperidone-loaded (37%) PLGA 7505E microspheres and B) risperidone-loaded (37%) PLGA 7509E microspheres through the optimized emulsion and isolation process.