Optical Coherence Tomography Based Freeze Drying Microscopy

描述（由申请人提供）：物理科学公司（PSI）与康涅狄格大学药学院（UConn）合作，提议开发一种先进的冷冻干燥显微镜（FDM）系统，用于确定药物配方的崩溃温度。在第一阶段项目中，PSI将展示光学相干断层扫描（OCT）在标准产品小瓶中冷冻干燥产品配方3D结构成像中的应用。OCT-FDM系统将使相关药品包装系统内的产品崩溃成像和崩溃温度测定成为可能，克服了当前询问薄膜产品样品的FDM系统的限制。这将消除崩溃温度测定中的错误，这些错误会导致更长的处理时间，浪费资源以及增加生产和药物成本。生物药物的开发通常要求产品配方必须经过冻干，以产生稳定的产品，储存在小瓶中，并可以重新配制供患者使用。最关键的工艺设计参数是产品在初次干燥过程中发生结构坍塌的温度，即“坍塌温度”Tc。低温冷冻干燥是必要的，以确保美观，低残留含水量，因此良好的储存稳定性和重构特性。FDM是目前用于估计Tc的一种方法，它使用1 - 2 uL液体产品样品在显微镜载玻片之间冷冻，导致冷冻产品厚度为50 - 100 um。这些样品不代表在小瓶中干燥的样品，小瓶的厚度可能为5 - 50毫米。与小瓶冷冻干燥相比，薄膜具有不同的冰核速率、溶质结晶倾向、冷冻产物结构和干燥速率。因此，目前的FDM可能无法准确估计具有实际意义的容器中冷冻干燥的Tc。文献研究表明，当前FDM和小瓶干燥之间的Tc差异通常是几度，导致产品加工温度每降低20℃，干燥时间增加25%。新的OCT-FDM技术将产生更准确的坍塌温度测定，代表生产规模干燥过程中观察到的情况。实验室规模的多瓶实验将使用基于使用新系统确定的产品Tc开发的干燥工艺进行。将比较不同干燥工艺的产品质量（外观、残留水分和表面积），验证OCT-FDM测量技术的使用。该研发计划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药物制剂的热特性，以开发有效的商业冷冻干燥工艺。

DESCRIPTION (provided by applicant): Physical Sciences Inc. (PSI) in collaboration with the University of Connecticut, School of Pharmacy (UConn), proposes to develop an advanced freeze-drying microscopy (FDM) system for determining drug formulation collapse temperature. During the Phase I program PSI will demonstrate the application of Optical Coherence Tomography (OCT) for imaging the 3D structure of product formulations freeze dried in standard product vials. The OCT-FDM system will enable product collapse imaging and collapse temperature determination within relevant pharmaceutical packaging systems, overcoming the limitation of current FDM systems which interrogate thin film product samples. This will eliminate errors in collapse temperature determinations which lead to longer processing times, wasted resources and increased production and drug costs. The development of biological drugs often requires product formulations that must be lyophilized to produce stable products that are stored in vials and can be reconstituted for patient use. The most critical process design parameter is the temperature at which the product undergoes structural collapse during primary drying, the "collapse temperature" Tc. Freeze drying below Tc is necessary to insure elegant appearance, low residual water content and therefore good storage stability, and reconstitution characteristics. FDM is one method currently applied to estimate Tc and it uses 1 - 2 uL liquid product samples frozen between microscope slides resulting in a frozen product thickness of 50 - 100 um. 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 than in vial freeze drying. Thus, current FDM may not accurately estimate Tc for freeze drying in a container of practical significance. Literature studies suggest that the differences in Tc between current FDM and vial drying are typically several degrees resulting in a 25% increase in drying time for every 20 degree C decrease in product processing temperature. The new OCT-FDM technique will result in more accurate collapse temperature determinations representative of what is observed during production scale drying. Laboratory scale, multi-vial experiments will be performed using drying processes developed based on the product Tc determined using the new system. Product quality (appearance, residual moisture and surface area) will be compared for the different drying processes, validating the use of the OCT-FDM measurement technique. The goal of this R&D program is the development and application of a laboratory tool which enables accurate determination of drug product formulation thermal properties for the development of efficient commercial freeze drying processes. PUBLIC HEALTH RELEVANCE: The purpose of this research is to assess the feasibility of developing a laboratory tool that can provide 3D product structural information during freeze drying and product collapse temperature data in a product/container format that is the same as typically used during laboratory and manufacturing scale freeze drying.