Microfluidic technology platform as a continuous end-line process to inactivate pharmaceuticals

项目摘要 为了达到FDA要求的用于人体的无菌保证水平，药品必须 进行最终灭菌或无菌生产。这可以通过物理或化学方法来实现。 对于简单的药物制剂，可以使用诸如加热或甲醛的方法;然而，对于 具有更复杂的药物配方或含有对下游重要的生物活性材料 应用（含细胞治疗剂、疫苗等），γ辐射是优选的方法， 灭菌伽马射线照射破坏核酸以消灭病原体或使任何细胞复制 但结构成分如蛋白质保持完整。依赖伽马射线的后勤挑战 然而，用于最终灭菌辐照是重要的。伽马辐射需要高剂量的辐射， 需要重大的监管限制和专门的基础设施，推高成本和处理 时间来制造成品药物。因此，很少有生物医学研究和生产设施能够 在内部采用伽马辐照工艺，以加快制造时间表， 集中屏蔽设施。低能电子辐照（LEEI）是一种实用而廉价的 然而，低穿透深度限制了其对于液体悬浮液的实用性。到 为了克服这些障碍，Heat Biologics与格鲁吉亚理工学院和德克萨斯A&M大学合作， 大学开发一种微流体启用的在线连续过程，用于高通量LEEI灭菌， 大药厂该策略使用微流体歧管将连续流动的产品带入微流体系统。 在足够的体积流率下LEEI束的工作深度，以允许缩放到商业容量。 由于产品通过该过程进行最终灭菌，因此可以实现端到端控制， 在屏蔽设施进行集中消毒。在初步研究中，快速原型设计导致了一个 可消耗芯片歧管。微流控芯片的计算建模和实验验证 设计证明了流动均匀性和良好的电子束穿透通道， 生物材料。在第一阶段的STTR项目中，这个跨学科的团队将完成微流体设计， 并在两种药物细胞治疗产品中测试原型系统以确认灭活效率， 辐照后活性剂的生物利用度。将建造一个消耗性商业装置，以达到30 L/小时 处理以确保系统可以适当地缩放以适应商业规模生产。 这些目标的完成将验证一个高通量微流体装置，当与e- 光束辐照将为标准的生物研究和生产实验室提供生产能力， 并在生产现场辐照生物活性药物产品。

PROJECT SUMMARY To achieve the FDA’s required Sterility Assurance Level for use in humans, pharmaceutical products must undergo terminal sterilization or aseptic manufacturing. This can be accomplished using physical or chemical methods such as heat or formaldehyde for simple drug formulations; however, for pharmaceutical products that have more complex drug formulations or that contain biologically active material important for downstream applications (cell-containing therapeutics, vaccines, etc.), gamma irradiation is the preferred method of sterilization. Gamma irradiation destroys nucleic acids to inactivate pathogens or render any cells replication incompetent but leaves structural components like proteins intact. The logistical challenges of reliance on gamma irradiation for terminal sterilization are, however, significant. Gamma irradiation requires high doses of radiation, necessitating significant regulatory restrictions and specialized infrastructure, driving up costs and processing times to manufacture a finished drug. As such, few biomedical research and production facilities are able to adopt gamma-irradiation processes in-house to expedite manufacturing timelines, and they remain reliant on centralized shielded facilities. Low energy electron irradiation (LEEI) represents a practical and inexpensive alternative to gamma irradiation; however, a low penetration depth limits its utility for liquid suspensions. To overcome these obstacles, Heat Biologics has partnered with Georgia Institute of Technology and Texas A&M University to develop a microfluidics-enabled in-line continuous process for high-throughput LEEI sterilization of pharmaceuticals. This strategy uses microfluidic manifolds to bring a continuously flowing product into the working depth of an LEEI beam at a sufficient volumetric flow rate to allow for scaling to commercial capacity. Since the product is terminally sterilized by this process, it enables end-to-end control as an alternative to centralized sterilization at a shielded facility. In preliminary studies, rapid prototyping resulted in the design of a consumable chip manifold. Computational modeling followed by experimental validation of the microfluidic chip design demonstrated flow uniformity and good e-beam penetration through the channels without compromising biological material. In this Phase I STTR project, this interdisciplinary team will finalize the microfluidics design and test the prototype system in two pharmaceutical cell therapy products to confirm inactivation efficiency and active agent bioavailability following irradiation. A consumable commercial set will be built to achieve 30L/hour processing to ensure that the system can be appropriately scaled to accommodate commercial scale production. Completion of these objectives will validate a high-throughput microfluidics device that when combined with e- beam irradiation will provide standard biological research and production laboratories with the ability to produce and irradiate biologically active pharmaceutical products at the site of manufacture.