Thesis (M.S.)--Virginia Polytechnic Institute, 1942. / Includes bibliographical references (leaves 129-132). Also available via the Internet.

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Thesis (Ph. D.)--University of Wisconsin--Madison, 1954. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 253-257).

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A major challenge facing the global health community is the production of thermally stable vaccines that eliminate the need for unfavorable cold-chain storage protocols, which often require temperatures as low as -80°C. Spray drying is a promising technique to produce thermally stable vaccine powders that retain their efficacy when stored at ambient conditions. Spray drying is gaining popularity in the pharmaceutical community due to its scalability, low cost and high throughput. Processing by spray drying can rapidly immobilize the active vaccine ingredient, such as a viral vector, in an amorphous glassy matrix of a stabilizing excipient tailored to the biologic being stabilized. This encapsulation and reduction in mobility keeps the biologic isolated from mechanical, thermal or chemical stresses that cause damage and inactivation. However, choosing the best excipient, or excipient blend, and optimizing the formulation are costly and time-consuming processes and furthermore, the effects of spray drying on viral vector activity are not fully understood. This thesis focuses on modelling the processing environment for preparing such vaccine powders, by both experimental and numerical means, to understand the relevance of mechanical, thermal and chemical stresses on viral vector activity. Specifically, the viral vector studied here was human type 5 adenovirus (AdHu5), with intended use in tuberculosis vaccines. Mechanical stresses associated with the shear inside the nozzle of a spray dryer were experimentally studied. Viral activity losses associated with shear stresses in an atomizing nozzle were attributed to aggregation; aggregation was created by damaging the virus at very high mechanical stresses but most aggregation was attributed to dispersing the virus in the excipient solution. It was concluded that overall, mechanical stresses in the nozzle caused a minimal amount of viral activity loss compared to other processing factors during spray drying, and in fact, could have a positive influence at moderate shear rates since it actually caused the break-up of AdHu5 aggregates. To investigate thermo-chemical stresses, it was necessary to demonstrate that acoustic levitation of a single drying droplet was an effective screening method to select promising excipients for spray dried vaccines, and could be used to experimentally validate a numerical model of droplet drying. For several different sets of binary carbohydrate blends, levitated particles were found to match property and activity trends seen in spray dried powders when the surrounding temperature of the levitator matched the outlet temperature of the spray dryer. The numerical droplet drying model could predict drying time, particle size, and component distribution within a final dried particle; the component distribution was used to aid in spatially locating the viral vector which was shown to be related to vaccine thermal stability. The model predictions associated with virus location in a dried particle were confirmed experimentally using coated silica nanoparticles as virus analogues, and several different molecular weight dextrans in the mannitol/dextran blend in order to change the location of the virus. Overall, this work provides a deeper understanding of how spray drying can be used to produce thermally stable vaccine powders, and the arising guidance can be applied to improve formulation development based on the end targets and applications. Shear stress was found to be a negligible source of viral vector activity loss, and the application of heat to the acoustic levitator was found to create drying conditions that allowed the levitator to create materials that mimicked the properties of spray dried powders. Finally, a numerical model was validated experimentally, with both modelled predictions and confocal laser scanning microscopy confirming that an increase in dextran molecular weight in formulations caused a decrease in viral vector and silica nanoparticles at the air-solid interface. The knowledge gained by using screening methods and mathematical models of the spray drying process can reduce the time and cost inputs of vaccine development by identifying promising excipients with minimal experimentation. / Thesis / Doctor of Philosophy (PhD) / To retain their effectiveness, most mass-market vaccines must be stored in refrigerated or frozen conditions but the specialized equipment associated with such storage limits the success of administration programs. Creating dry powder vaccines that can be stored at room temperature is an efficient method to limit liquid vaccine wastage caused by exposure to warmer temperatures. This is achieved by combining the active ingredient with protective stabilizing materials and drying the solution into a powder using spray drying. However, identifying and developing effective dry powder products is costly and time-consuming. This research aims to reduce the costs associated with vaccine development by using other drying methods to identify potential protective sugars without the need for large-scale experiments, as well as by using mathematical models to predict the outcomes of the drying process. The effect of various stresses during the drying process on the active vaccine ingredient are evaluated to improve the effectiveness of the final dry product. Overall, the ability to produce stable dry powder vaccines will allow for more wide-spread vaccination programs and stockpiling of vaccines to better prepare for global pandemics.

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Ph.D.

Thesis (M.S.)--University of Wyoming, 2007. / Title from PDF title page (viewed on June 17, 2008). Includes bibliographical references (p. 206-215).