A short term quality control tool for biodegradable microspheres

Abstract

Accelerated in vitro release testing methodology has been developed as an indicator of product performance to be used as a discriminatory quality control (QC) technique for the release of clinical and commercial batches of biodegradable microspheres. While product performance of biodegradable microspheres can be verified by in vivo and/or in vitro experiments, such evaluation can be particularly challenging because of slow polymer degradation, resulting in extended study times, labor, and expense. Three batches of Leuprolide poly(lactic-co-glycolic acid) (PLGA) microspheres having varying morphology (process variants having different particle size and specific surface area) were manufactured by the solvent extraction/evaporation technique. Tests involving in vitro release, polymer degradation and hydration of the microspheres were performed on the three batches at 55°C. In vitro peptide release at 55°C was analyzed using a previously derived modification of the Weibull function termed the modified Weibull equation (MWE). Experimental observations and data analysis confirm excellent reproducibility studies within and between batches of the microsphere formulations demonstrating the predictability of the accelerated experiments at 55°C. The accelerated test method was also successfully able to distinguish the in vitro product performance between the three batches having varying morphology (process variants), indicating that it is a suitable QC tool to discriminate product or process variants in clinical or commercial batches of microspheres. Additionally, data analysis utilized the MWE to further quantify the differences obtained from the accelerated in vitro product performance test between process variants, thereby enhancing the discriminatory power of the accelerated methodology at 55°C.

Fig. 1

Scanning electron micrographs for formulations a, b, and c at two magnifications

Fig. 2

Correlation of accelerated release with real-time release (formulation A) (from (34))

Fig. 3

Reproducibility of accelerated release (within a lot) for formulation A

Fig. 4

Reproducibility of accelerated release (between lots) for formulation A

Fig. 5

Accelerated release at 55°C in 0.1 M PBS, pH 7.4, for formulations A, B, and C (particle sizes: 25, 106–125 ,and > 300 μm, respectively)

Fig. 6

Results of model fit for formulation A with two intended commercial formulations using the modified Weibull equation (MWE)

Fig. 7

Model fit using the MWE for formulations A, B, and C (process variants) at 55°C in 0.1 M PBS, pH 7.4 (particle sizes: 25, 106–125, and >300 μm, respectively)

Fig. 8

Hydration of formulations A, B, and C at 55°C in 0.1 M PBS, pH 7.4 (particle sizes: 25, 106–125, and >300 μm, respectively)

Fig. 9

Change in molecular weight for formulations A, B, and C at 55°C in 0.1 M PBS, pH 7.4 (Particle sizes: 25, 106–125, and >300 μm, respectively