Optical Coherence Tomography Based Freeze Drying Microscopy

描述（由申请人提供）：Physical Sciences Inc. (PSI)与康涅狄格大学（UConn）合作，提出开发第二代先进的3D冷冻干燥显微镜（FDM）系统，以促进对冷冻干燥的理解，并开发高效的商业冷冻干燥工艺。 在I期项目期间，PSI展示了光学相干断层扫描（OCT）在商业相关药品包装系统（小瓶）冷冻干燥期间对产品配方的3D结构成像的应用。OCT-FDM系统使得能够在小瓶中进行产品结构成像和塌陷温度Tc）测定，克服了询问薄膜产品样品的当前光透射（LT）FDM系统的限制。OCT-FDM系统消除了Tc测定中的错误，这将缩短处理时间并降低生产和药物成本。 生物药物通常需要冻干以产生储存在小瓶中并重构以供患者使用的稳定产品。最关键的工艺设计参数是产品进行初步干燥的温度。在产品Tc以上干燥导致粘性流动、产品结构和美观性的损失、残余水分含量增加、储存稳定性差以及重构时间长和/或重构差。LT-FDM是目前用于估计Tc的一种方法，使用1 - 2 μ L冷冻在显微镜载玻片之间的液体产品样品，导致冷冻产品厚度为50 - 100 μ m。这些样品不能代表在厚度为5 - 50 mm的小瓶中干燥的样品。与小瓶冷冻干燥相比，薄膜具有不同的冰成核速率、溶质结晶趋势、冷冻产品结构和干燥速率。因此，LT-FDM不能准确估计具有实际意义的容器中冷冻干燥的Tc。[Our创新OCT-FDM技术克服了所有这些缺点。I期项目证明，使用OCT-FDM可显著更准确地测定Tc，尤其是蛋白制剂。这是一个重要的结果，因为蛋白质药物疗法是制药行业增长最快的部分。 与基于LT-FDM的工艺相比，基于Tc的OCT-FDM测定的蛋白质制剂的实验室冷冻干燥导致初级干燥时间减少80%。] 在第二阶段计划中，PSI将开发第二代OCT-FDM系统，该系统具有改进的成像性能、仪器控制、数据采集和图像处理软件。OCT-FDM将用于：研究冷冻过程中的冰形成，监测初级干燥过程中的3D结构变化，测量不同固体含量的多组分制剂中的Tc，以及监测升华前沿的进展。该研发的目标是开发和应用一种实验室工具，该工具能够准确测定产品的热性能，并开发最佳的商业冷冻干燥工艺[用于经济的药物生产]。

DESCRIPTION (provided by applicant): Physical Sciences Inc. (PSI), in collaboration with the University of Connecticut (UConn), proposes to develop the 2nd generation of an advanced 3D freeze-drying microscopy (FDM) system to advance the understanding of freeze-drying and to enable the development of efficient commercial freeze drying processes. During the Phase I program PSI demonstrated the application of Optical Coherence Tomography (OCT) for imaging the 3D structure of product formulations during freeze drying in commercially relevant pharmaceutical packaging systems, vials. The OCT-FDM system enabled product structure imaging and collapse temperature Tc) determination in a vial, overcoming the limitation of current light transmission (LT) FDM systems which interrogate thin film product samples. The OCT-FDM system eliminates errors in Tc determinations which will lead to shorter processing times and reduced production and drug costs. Biological drugs often require lyophilization to produce stable products that are stored in vials and reconstituted for patient use. The most critical process design parameter is the temperature at which the product undergoes primary drying. Drying above the product Tc results in viscous flow, loss of product structure and elegance, increased residual moisture content, poor storage stability, and long and/or poor reconstitution. LT- FDM, one method currently applied to estimate Tc, uses 1 - 2 ¿L liquid product samples frozen between microscope slides, resulting in a frozen product thickness of 50 - 100 ¿m. These samples are not representative of samples dried in vials which may have thicknesses of 5 - 50 mm. Thin films have different ice nucleation rates, crystallization tendencies for solutes, frozen product structures and drying rates as compared to vial freeze drying. Thus, LT-FDM does not accurately estimate Tc for freeze drying in a container of practical significance. [Our innovative OCT-FDM technique overcomes all of these shortcomings. The Phase I program demonstrated significantly more accurate determination of Tc using OCT-FDM, especially for a protein formulation. This is an important result as protein drug therapies are the fastest growing segment of the pharmaceutical industry. Laboratory freeze drying of the protein formulation based on the OCT-FDM determination of Tc resulted in an 80% reduction in primary drying time compared to an LT-FDM based process.] During the Phase II program PSI will develop a 2nd generation OCT-FDM system with improved imaging performance, instrument control, data acquisition and image processing software. The OCT-FDM will be used to: investigate ice formation during freezing, monitor 3D structural changes during primary drying, measure Tc in multi-component formulations of varying solid content, and monitor the advancement of the sublimation front. The goal of this R&D is the development and application of a laboratory tool which enables accurate determination of product thermal properties and development of optimal commercial freeze drying processes [for economical drug production].