Abstract：
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.
摘要：
亚可见颗粒（SbVP）的特征是药物制造中可注射和眼用溶液的关键质量属性。然而,当前的药典SbVP测试方法，即光阻法和微观粒子计数法，对目标样品具有破坏性和浪费性。在这项研究中,我们介绍了一种非破坏性SbVP分析仪的开发，旨在直接分析药品（DP）容器中的SbVP，同时保持样品完整。开发定制样品外壳并将其结合到分析仪中,以减少由典型的药物DP样品容器的曲率引入的光学像差。分析仪集成了光片显微镜结构，并使用Mie散射理论对粒子的侧向散射事件进行建模，并以折射率作为先验信息。估计在指定的折射率值下的等效球形粒径，并且基于散射事件的数量和由光片采样的体积来确定颗粒浓度。使用ISO2R和6R小瓶中的一系列聚苯乙烯珠悬浮液评估所得分析仪在DP容器中的非侵入性分析SbVP的能力和性能。我们的结果和分析表明，颗粒分析仪能够直接检测完整DP容器中的SbVP，将SbVPs分类到常用的尺寸箱中(例如≥2µm，≥5µm,≥10µm,且≥25µm)，并可靠地定量4.6e2至5.0e5颗粒/mL浓度范围内的SbVPs，基于90%置信区间，误差幅度为±15%。
