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Inhalation June 2024 13 for impact on biologic/vaccine viability. Generally, higher solids concentration in feedstock will lead to more rapid particle formation, larger particles and lower proportions of material exposed to degrad- ing forces of the air-interface [7]. Two fluid nozzles can be used at lower atomization pressures to pro- duce larger particles suitable for nasal deposition; however, it should be noted that the generation of larger droplets can affect the ultimate dryness of the resulting powder and may require secondary dry- ing after collection, particularly when smaller-scale spray dryers are used. When selecting a nozzle for the production of a nasal powder, a two-fluid nozzle can be beneficial due to the smaller particle size requirements of an aerosol- ized powder. Understanding and control over atomi- zation/liquid feed rates, as well as cyclone collection, are key to capturing a powder suitable for nasal delivery. A powder must be suitably small and non- cohesive so it can be readily taken up in an airstream and exit the device orifice without clogging. Another common nozzle type, pressure nozzles, (typically used for oral spray drying), have the benefit of nar- row particle size distribution (PSD) and scalability, and can produce powders with particle size as small as 30 µm [15]. Pressure nozzles, however, are difficult to use at laboratory scales and tend to produce dense powders not suitable for aerosolization. [23] While spray drying and conventional micronization continue to remain the mainstays for manufacturing respirable powders, alternative technologies are also being investigated. in-film freeze drying (TFFD) is a recently developed platform technology that can be applied to engineer aerosolizable nasal dry pow- ders. Data from recent studies demonstrated the fea- sibility of applying TFFD to prepare dry powders of vaccines and monoclonal antibodies (mAbs) for intranasal delivery [24]. TFFD is a two-step, bottom- up method to prepare aerosolizable dry powders. Briefly, a liquid solution or dispersion, containing the APIs of interest and other excipients, is dropped onto a cryogenically cooled surface; the droplets, upon impact, spread and are rapidly frozen (100 - 1000 K/s) into thin films. Water and/or other solvents are then sublimed from the frozen films to produce dried thin films or discs. Powders prepared using the TFFD process are often highly porous, brittle and low in density, suitable for aerosolization with no or minimal additional processing. Case study: Vaccine and mAb powder for nasal delivery using TFFD e feasibility of applying TFFD technology to pre- pare dry powders of a vaccine or mAbs for intranasal delivery was recently investigated [25, 26]. Results demonstrated the successful application of TFFD in converting a complex model vaccine candidate into a mucoadhesive dry powder. e vaccine formulation, ability to hydrogen bond and vitrify large molecules, preventing alpha/beta relaxation and denaturation. e use of mannitol has been shown to replace water and reduce the local (beta) mobility of proteins, while trehalose, by forming a glassy matrix, has been demonstrated to impact global (alpha) mobility [7]. Sugars can be used independently; however, they can be used in combination due to the differing stabiliz- ing effects they impart [21]. Residual water, which acts as a plasticizer of these spray-dried powders, will greatly affect their stability, the magnitude of which can be calculated using the Gordon-Taylor equation. Strict control over moisture levels during manufac- ture, packaging and shelf storage is key in ensur- ing the stability of engineered dry powders that are intended to be aerosolized. Powder manufacture: Spray drying and new technologies In the production of nasal powder, various process- ing methods are used [4, 22]. One such method is lyophilization, which involves freezing the liquid solution and then removing the ice by sublimation under reduced pressure. Another technique, spray freeze drying, uses a combination of atomization and quick freezing in liquid nitrogen before lyophiliza- tion. Micronized powders and micronized agglom- erates have also been used to produce aerosolizable powders for nasal delivery. More commonly, nasal powders in development uti- lize spray drying, which involves atomizing a liquid feedstock into a heated chamber, resulting in rapid drying of the droplets into powder. Because spray drying has become a commonly used pharmaceu- tical operation for oral and pulmonary powders, many have applied its use to engineer powders for nasal administration. Spray drying is particularly well suited to engineer particles for nasal powder, where a d 50 of 25-50 µm is desired and an amorphous API or biologic can be sta- bilized. e upper limit of particle size for nasal pow- ders is not a function of deposition as in pulmonary powders (where > 5 µm is considered non- respirable), but rather limited by what size will effectively aerosol- ize and escape the nozzle of the selected nasal device. Conversely, the quantity of particles with a diame- ter of less than 10 µm should be well controlled and limited as much as possible since particles in this size range would be capable of navigating through the nasal passages and depositing in the lungs. For stress-sensitive biologics and vaccines, careful control of outlet and collection temperatures to reduce thermal degradation is necessary. Utilization of excipients such as leucine that will compete for the air-liquid interface of the drying droplets will also reduce process stress. Further, atomization noz- zles and accompanying pressures should be screened