To achieve the FDA's required Sterility Assurance Level for use in humans, pharmaceutical products mustundergo terminal sterilization or aseptic manufacturing. This can be accomplished using physical or chemicalmethods such as heat or formaldehyde for simple drug formulations; however, for pharmaceutical products thathave more complex drug formulations or that contain biologically active material important for downstreamapplications (cell-containing therapeutics, vaccines, etc.), gamma irradiation is the preferred method ofsterilization. Gamma irradiation destroys nucleic acids to inactivate pathogens or render any cells replicationincompetent but leaves structural components like proteins intact. The logistical challenges of reliance on gammairradiation for terminal sterilization are, however, significant. Gamma irradiation requires high doses of radiation,necessitating significant regulatory restrictions and specialized infrastructure, driving up costs and processingtimes to manufacture a finished drug. As such, few biomedical research and production facilities are able toadopt gamma-irradiation processes in-house to expedite manufacturing timelines, and they remain reliant oncentralized shielded facilities. Low energy electron irradiation (LEEI) represents a practical and inexpensivealternative to gamma irradiation; however, a low penetration depth limits its utility for liquid suspensions. Toovercome these obstacles, Heat Biologics has partnered with Georgia Institute of Technology and Texas A&MUniversity to develop a microfluidics-enabled in-line continuous process for high-throughput LEEI sterilization ofpharmaceuticals. This strategy uses microfluidic manifolds to bring a continuously flowing product into theworking 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 tocentralized sterilization at a shielded facility. In preliminary studies, rapid prototyping resulted in the design of aconsumable chip manifold. Computational modeling followed by experimental validation of the microfluidic chipdesign demonstrated flow uniformity and good e-beam penetration through the channels without compromisingbiological material. In this Phase I STTR project, this interdisciplinary team will finalize the microfluidics designand test the prototype system in two pharmaceutical cell therapy products to confirm inactivation efficiency andactive agent bioavailability following irradiation. A consumable commercial set will be built to achieve 30L/hourprocessing 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 produceand irradiate biologically active pharmaceutical products at the site of manufacture.
Public Health Relevance Statement: PROJECT NARRATIVE
Drug product regulatory standards require that pharmaceuticals undergo sterilization to inactivate pathogens
and render any living cells incapable of replicating. For complex drug formulations containing active biological
materials, such as vaccines, this necessitates sterilization by gamma irradiation, which is accompanied by
substantial logistical and financial challenges. To expedite drug manufacturing and provide standard biological
research and production facilities with the ability to irradiate pharmaceutical products at the site of manufacture,
Heat Biologics, Inc. is developing a microfluidics-enabled inactivation system that leverages low energy electron
irradiation to support high-throughput sterilization of pharmaceuticals at a fraction of the cost and with no need
for specialized infrastructure.
Project Terms: <µfluidic technology><γ-irradiation><γ-Radiation><γ-Ray>| <µfluidic>
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