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34 Pharmaceutical Technology ® Trends in Formulation 2022 eBook PharmTech.com Biologics sublimate the solvent until a powder is formed (3). A disadvantage of shelf FD is that the powder must be further processed by milling to improve particle size and surface area. Unfortunately, for proteins, this causes mechanical stress, re- sulting in degradation, uneven par ticle size distribution, and low yield of the expensive biologic (3). Despite this challenge, shelf FD is almost exclusively used for products that are temperature sensitive, but the process can take days, creating inconvenience for manufactur- ing and distribution (12). • Spray freeze-drying (SFD) combines the ad- v a nt a ges of f re ez e-d r y i ng a nd t r a d it ion a l spray dr ying to produce highly porous parti- cles, which is an advantage for inhalation (2). The SFD process involves spraying an aqueous solution through a high-pressure nozzle into a cold gas vapor above liquid nitrogen. The result- ing powder has a high surface area, and droplet shape and size can be customized with various atomization nozzles and spray rates (13). Some limitations are the large phase-liquid interface and shear stress, which results in challenges in formulating proteins (2). Also, atomization of the liquid through the high-pressure nozzle causes degradation of surface-active proteins and loss of activity (14). • Spray freezing into liquid (SFL) involves spray- ing the liquid formulation directly into a liquid cryogen, a substance used to produce very low temperatures. This has a slower freezing rate than SFD, which results in a lower surface area, improving stability by lowering the risk of water adsorption (3). SFL produces protein powders with better properties than SFD, including less adsorption, aggregation, and denaturation, and higher enzymatic activity (15). Notably, SFD, SFL, and shelf FD all avoid the use of heat, which can denature proteins (13). Despite the advantages these technologies offer, properties of powders produced by SFD, SFL, and shelf FD may not be ideal for inhalation, especially in the context of bi- ologics, as these techniques can cause aggregation— abnormal association of proteins into larger aggregate structures—leading to loss of activity (15). Thin-film freezing and improving the delivery of biologics Thin-film freezing (TFF) is an advanced formulation process that can produce stable protein particles of submicron size and is potentially ideal for overcoming some of the challenges described above. The process is described in the following steps: • A drug, with or without inactive ingredients (ex- cipients), is dissolved in a solvent system. • The product is applied to a cryogenically cooled surface, typically of a stainless-steel drum (13,16). This flash freezing results in a frozen thin film. • The frozen solvent system is removed by subli- mation, and the collection of the powder pro- duces a high yield—almost 100% compared to 80% with SFD (15). • The powder is processed to create drugs for tar- geted administration via inhalation, intranasal delivery, reconstitution for injection, or topically to the skin or eye. TFF technolog y was originally developed to im- prove drugs with poor water solubility and shows advantages over other cryogenic techniques used for preparing biologics, creating unique particle charac- teristics that are advantageous for inhalation (17,18). The powder is porous with a large surface area and low density that can be aerosolized to facilitate de- livery to the lungs, nose, and eyes. TFF has a similar cooling rate to SFL but can form high surface area particles, which is advantageous for inhaled thera- pies. Additionally, the cooling rate can be more easily controlled (1). TFF has also been shown to maintain protein stability and bioactivity and to cause less de- naturation compared to other techniques (14,18,19). TFF is especially convenient for the development of vaccine formulations. Repeated freezing and thawing of a dry powder vaccine containing aluminum salts formulated using TFF did not show aggregation fol- lowing reconstitution (8). TFF can also maintain drug activity after high-temperature storage. The immu- nogenicity of a TFF dry powder vaccine was preserved after storage temperatures as high as 40 ˚C for up to three months, which is a major advantage for cold chain logistics (20). TFF technology is being applied to multiple ther- apies, including biologics, currently in preclinical and clinical development and holds relevance for deliver y of respirator y treatments, as it allows for targeted delivery of therapy to the lungs with a faster onset of action and reduced systemic side effects. One application where TFF technology can provide a sig- nificant advantage is the use of dr y powder mAbs for COVID-19. TFF has been shown to produce better aerosol properties of mAbs compared to shelf FD, and a dry powder version of a mAb tested in vivo success- fully neutralized SARS-CoV-2 infection and reduced vira l load (21,22). Deliver y of the TFF dr y powder COVID-19 antibody to infected hamsters resulted in a dose-dependent reduction of viral load when the administration was initiated 24 hours after infection with SARS-CoV-2 (21). TFF is also being applied to im- prove the delivery of non-biologic antiviral therapies for COVID-19, including remdesivir and niclosamide, and could offer a promising alternative for outpatient COVID-19 treatment (23).