Late-stage Preclinical Development and cGMP Production of a First-in-Class Cornea Cryopreservation Kit Based on FDA Feedback

摘要 之前NIH SBIR和库尔特基金会奖的支持使CryoCrate团队开发了一种新的 角膜冷冻保存技术，商标为IcyEye®，受国际专利保护。IcyEye®是一款 包括高效冷冻保存介质C80EZ®的套件，可防止存储过程中的冰重结晶 大约。-80oC和一种新的机械设备，它物理地将细胞破坏的冰晶与组织分开 在冰冻期间。结合这两种行动机制，这套工具独特地实现了长期(至少6个月) 解冻后内皮细胞活性的常规-80°C冷冻箱中冷冻保存角膜 组织质量史无前例地达到并超过临床移植标准。血凝素在临床上的应用 这项新技术不仅将提高移植组织的质量和眼库的效率 手术一般，但也将允许眼库在任何未来的医疗保健期间保持正常操作 类似于当前新冠肺炎大流行的危机。 最近，与FDA就可能的提交举行了一次510(K)计划前的会议。根据FDA对 IcyEye®技术以获得相关许可，在此项目中，我们组织了与我们的 监管顾问(红衣主教健康)、代工组织(Bryllan和Plas-tech)、合同 研究组织(Catalent)，学术联合发明人(密苏里大学-堪萨斯州城市愿景研究 中心)和三个当地眼科银行合作伙伴，以实现以下里程碑： IcyEye®试剂盒的生产符合510(K)提交所要求的GMP资格； 生物相容性评价表明符合FDA指南以及体外和体内试验 使用标准动物模型进行的安全性和有效性评估演示了IcyEye®技术 等同于现有的制冷协议；以及 III.使用人类角膜进行的安全性和有效性的体外评估展示了IcyEye®技术 等同于现有的制冷协议。 在这些资格的基础上，我们将完成510(K)的提交和生产线的最终确定 关于FDA在项目期结束前的进一步反馈。我们期待IcyEye®广泛的临床应用 在FDA获得批准后的三年内，为该行业提供改善的供体组织质量和 在国内和国际上都有更高的运行效率。

SUMMARY Previous support from NIH SBIR and Coulter Foundation awards allowed the CryoCrate team to develop a novel corneal cryopreservation technology, trademarked as IcyEye®, with international patent protection. IcyEye® is a kit that includes an efficient cryopreservation medium, C80EZ®, that prevents ice recrystallization during storage at approx. -80oC and a novel mechanical device that physically separates cell damaging ice crystals from tissues during freezing. Combining both mechanisms of action, this kit uniquely enables long-term (at least 6 months) storage of corneas through cryopreservation in regular -80°C freezers with post-thaw endothelial cell viability and tissue quality unprecedently meeting and exceeding clinical criteria for transplantation. The clinical use of this novel technology will not only improve tissue quality for transplantation and the efficiency of eye bank operations in general, but will also allow eye banks to maintain normal operations during any future health care crises similar to the current COVID-19 pandemic. A pre-510(k) meeting with the FDA for the potential submission took place recently. Based on FDA feedback for the IcyEye® technology to gain the associated clearances, in this project we organized the collaboration with our regulatory consultant (Cardinal Health), contract manufacturing organizations (Bryllan and Plas-tech), contract research organization (Catalent), academic co-inventor (University of Missouri – Kansas City Vision Research Center), and three local eye bank partners, to achieve the following milestones: I. The production of IcyEye® kits meets GMP qualifications required for 510(k) submission; II. The biocompatibility assessment shows compliance with FDA guidance and the in vitro and in vivo evaluation of safety and efficacy using a standard animal model demonstrates IcyEye® technology to be equivalent to existing refrigeration protocols; and III. The in vitro evaluation of safety and efficacy using human corneas demonstrates IcyEye® technology to be equivalent to existing refrigeration protocols. Based on those qualifications, we will complete the 510(k) submission and finalize of the production line based on further FDA feedback before the end of the project period. We expect extensive clinical use of the IcyEye® technology within three years after FDA clearance, providing the industry with improved donor tissue quality and higher operational efficacy for both domestic and international use.