Late Stage Pharmaceutical and Processing Development, Pharmaceutical Development & Supplies, Pharma Technical Development Biologics EU, F. Hoffmann-La Roche Ltd., Basel 4070, Switzerland; Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, Basel 4056, Switzerland.
Late Stage Pharmaceutical and Processing Development, Pharmaceutical Development & Supplies, Pharma Technical Development Biologics EU, F. Hoffmann-La Roche Ltd., Basel 4070, Switzerland.
J Pharm Sci. 2018 Nov;107(11):2810-2822. doi: 10.1016/j.xphs.2018.06.025. Epub 2018 Jul 10.
Pharmaceutically elegant lyophilisates are highly desirable implying a stable and robust freeze-drying process. To ensure homogenous and intact cake appearance after process scale-up and transfer, characterization of lyophilisates during formulation and cycle development is required. The present study investigates different imaging techniques to characterize lyophilisates on different levels. Cake appearance of freeze-dried bovine serum albumin formulations with different dextran/sucrose ratios was studied by visual inspection, three-dimensional laser scanning, polydimethylsiloxane embedding, scanning electron microscopy, and microcomputed tomography (μ-CT). The set of techniques allowed a holistic evaluation of external cake appearance and internal structure providing complementary information at macroscopic and microscopic scale. In comparison to state of the art technologies like visual inspection or scanning electron microscopy, three-dimensional laser scanning and μ-CT provided quantitative information allowing comparison of visual cake appearance. In particular μ-CT enables a global, qualitative, and quantitative characterization of external and internal cake structure with a single measurement detecting heterogeneities of lyophilisates. We even demonstrated the use of noninvasive μ-CT for qualitative imaging of internal cake structure through the glass vial. Providing meaningful characterization of the entire lyophilisate, μ-CT can serve as a powerful tool during development of freeze-drying cycles, process scale-up, and transfer.
药用优美的冻干产品是非常理想的，这意味着稳定且强大的冷冻干燥工艺。为了确保在工艺放大和转移后获得均匀和完整的饼状物外观，需要在配方和循环开发过程中对冻干产品进行特性描述。本研究探讨了不同的成像技术，以在不同层面上对冻干产品进行特性描述。通过目视检查、三维激光扫描、聚二甲基硅氧烷嵌入、扫描电子显微镜和微计算机断层扫描（μ-CT）研究了不同右旋糖酐/蔗糖比的冷冻干燥牛血清白蛋白制剂的饼状物外观。这组技术允许对外部饼状物外观和内部结构进行整体评估，提供宏观和微观尺度的互补信息。与视觉检查或扫描电子显微镜等现有技术相比，三维激光扫描和 μ-CT 提供了定量信息，允许对视觉饼状物外观进行比较。特别是，μ-CT 能够对外部和内部饼状物结构进行全局、定性和定量的特征描述，单次测量即可检测冻干产品的不均匀性。我们甚至展示了使用非侵入性 μ-CT 通过玻璃小瓶对内部饼状物结构进行定性成像。μ-CT 可以为整个冻干产品提供有意义的特性描述，因此可作为冷冻干燥周期、工艺放大和转移开发过程中的有力工具。
