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

项目总结 为了达到FDA要求的用于人类的无菌保证水平，药品必须 进行终端灭菌或无菌制造。这可以使用物理或化学方法来完成 对于简单的药物配方，如加热或甲醛；然而，对于 有更复杂的药物配方或含有对下游重要的生物活性物质 应用(细胞疗法、疫苗等)，伽马照射是治疗的首选方法 绝育手术。伽马射线破坏核酸以灭活病原体或使任何细胞复制 不起作用，但保持结构成分，如蛋白质完好无损。依赖伽马带来的后勤挑战 然而，用于终端灭菌的辐射是重要的。伽马辐射需要高剂量的辐射， 需要严格的监管限制和专门的基础设施，从而推高了成本和加工 制造一种成品药物的时间。因此，很少有生物医学研究和生产设施能够 采用内部伽马辐照工艺来加快制造时间表，它们仍然依赖于 集中式屏蔽设施。低能电子辐照(LEEI)代表了一种实用和廉价的 可替代伽马辐照；然而，较低的穿透深度限制了其在液体悬浮液中的应用。至 克服这些障碍，热生物公司与佐治亚理工学院和德克萨斯A&M公司建立了合作伙伴关系 大学将开发一种启用微流控的在线连续工艺，用于高通量LEEI灭菌 制药公司。该策略使用微流控歧管将连续流动的产品带入 LEEI梁在足够的体积流量下的工作深度，以允许按比例扩展到商业容量。 由于该产品通过该过程进行终端灭菌，因此它能够实现端到端控制，作为替代 在屏蔽设施中进行集中消毒。在初步研究中，快速成型导致了一种 可消耗芯片歧管。微流控芯片的计算建模和实验验证 设计证明了流动的均匀性和良好的电子束穿透通道而不会影响 生物材料。在这个第一阶段的STTR项目中，这个跨学科的团队将最终完成微流体设计 并在两种药物细胞治疗产品中测试原型系统，以确认失活效率和 活性物质在照射后的生物利用度。将建造一台耗材商用机组，实现30L/小时 加工，以确保系统可以适当扩展，以适应商业规模的生产。 完成这些目标将验证一种高通量微流控设备，当与e- 束流辐照将为标准的生物研究和生产实验室提供 并在制造现场照射具有生物活性的药品。

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.