Non-Destructive Analysis of Subvisible Particles with Mie-Scattering-Based Light Sheet Technology: System Development.

The characteristics of subvisible particles (SbVPs) are critical quality attributes of injectable and ophthalmic solutions in pharmaceutical manufacturing. However, current compendial SbVP testing methods, namely the light obstruction method and the microscopic particle count method, are destructive and wasteful of target samples. In this study, we present the development of a non-destructive SbVP analyzer aiming to analyze SbVPs directly in drug product (DP) containers while keeping the samples intact. Custom sample housings are developed and incorporated into the analyzer to reduce optical aberrations introduced by the curvature of typical pharmaceutical DP sample containers. The analyzer integrates a light-sheet microscope structure and models the side scattering event from a particle with Mie scattering theory with refractive indices as prior information. Equivalent spherical particle size under assigned refractive index values is estimated, and the particle concentration is determined based on the number of scattering events and the volume sampled by the light sheet. The resulting analyzer's capability and performance to non-destructively analyze SbVPs in DP containers were evaluated using a series of polystyrene bead suspensions in ISO 2R and 6R vials. Our results and analysis show the particle analyzer is capable of directly detecting SbVPs from intact DP containers, sorting SbVPs into commonly used size bins (e.g. ≥ 2 µm, ≥ 5 µm, ≥ 10 µm, and ≥ 25 µm), and reliably quantifying SbVPs in the concentration range of 4.6e2 to 5.0e5 particle/mL with a margin of ± 15 % error based on a 90 % confidence interval.