California Institute of Technology, Electrical Engineering, Pasadena, CA 91125, USA.
Amgen Process Development, Thousand Oaks, CA 91320, USA.
J Pharm Sci. 2024 Sep;113(9):2817-2825. doi: 10.1016/j.xphs.2024.07.015. Epub 2024 Jul 18.
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.
亚可见颗粒（Subvisible Particles，SbVPs）的特性是制药领域中注射剂和眼用制剂的关键质量属性。然而，现行的药典 SbVP 检测方法，即光阻法和显微粒子计数法，具有破坏性且对目标样品浪费较大。本研究介绍了一种非破坏性 SbVP 分析仪的开发，旨在保持样品完整的情况下，直接对药品容器中的 SbVPs 进行分析。本研究开发了定制的样品外壳并将其纳入到分析仪中，以减少由典型制药 DP 样品容器的曲率引起的光学像差。该分析仪集成了光片显微镜结构，并利用 Mie 散射理论和折射率作为先验信息，对粒子的侧向散射事件进行建模。根据指定折射率值的等效球形粒子尺寸进行估计，并基于散射事件的数量和光片采样的体积确定粒子浓度。使用一系列聚苯乙烯珠悬浮液在 ISO 2R 和 6R 小瓶中对所得分析仪在 DP 容器中对 SbVPs 进行非破坏性分析的能力和性能进行了评估。我们的结果和分析表明，该粒子分析仪能够直接从完整的 DP 容器中检测 SbVPs，将 SbVPs 分类到常用的尺寸箱中（例如≥2μm、≥5μm、≥10μm 和≥25μm），并可靠地在 4.6e2 到 5.0e5 粒子/mL 的浓度范围内定量 SbVPs，置信区间为 90%时，误差幅度为±15%。
