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32 Pharmaceutical Technology ® Trends in Formulation 2022 eBook PharmTech.com Biologics the final product must be considered during formu- lation to fit the route of administration. This article explores technological innovations that could overcome challenges in formulation and the delivery of biologics—especially for respiratory diseases where inhaled drug delivery offers a signif- icant advantage—to address the need for scale-up of biologics to benefit a broad range of patients. Overcoming the challenges of oral delivery of biologics A major issue for respirator y and lung conditions treated via oral therapies is that a lower amount of drug reaches the lung with a higher amount delivered systemically, which can reduce effectiveness and lead to potentially life-threatening toxicities. Vaccines are one example of a biologic that when delivered directly to the respiratory system, rather than through systemic injections, can offer significant advantages and side- step challenges of oral delivery. The lungs have a large surface area and thin peripheral epithelium, so the administration of vaccines directly to this area allows for faster onset of action (4). Additionally, vaccines ad- ministered by inhalation directly into the respiratory system can stimulate the mucosal membrane surface, an advantage for immunity as it triggers the memory T-cell immune response at the site of infection, which can allow for quicker neutralization of the virus and serve as a prevention strategy for infectious diseases (5). While delivery of respiratory drugs, including vac- cines, is a potential route to overcoming the challenges of oral delivery, vaccine formulation has its own chal- lenges and requires appropriate development, man- ufacturing, distribution, and storage considerations. While vaccines are commonly refrigerated between 2–8 ˚C, they should ideally be stored at ambient tem- peratures with a long shelf life to reduce cost for both storage and distribution (6). Sensitive vaccines, such as mRNA vaccines, require even colder temperatures to preserve activity. However, vaccines in liquid form cannot be frozen, as this process induces stress to the mixture and can cause irreversible changes to protein shape and therefore function (6). Common vaccine ad- juvants, such as aluminum salts, also cannot be frozen and require expensive cold chain storage for distribu- tion (7,8). Excipients and other stabilizers can improve the stability of liquid vaccines, but reformulation via dry powders offers a more elegant solution. Dry powder formulations can improve thermosta- bility, avoiding or minimizing requirements of cold chain storage; improve aerosol properties for direct- to-lung or nose delivery; and offer greater f lexibility for convenient routes of administration, all at a lower dose—thereby improving safety and efficacy. Nebuliz- ers and metered-dose inhalers deliver drugs in liquid form, which can expose biologics to harsh conditions and inconvenience patients with a longer administra- tion time, while dry powder formulations can be de- livered using a standard inhaler, intranasally, and/or reconstituted for injection (3,9). However, formulating biologics into dry powders is no easy task. To maintain activity and potency, biolog- ics must retain their physical and chemical structure, which introduces challenging formulation questions. There is an unmet need for a formulation and delivery technology that can create biologics with aerosoliza- tion properties that also maintain structural integrity and stability to improve drug delivery of biologics. Ad- dressing this need could transform the pharmaceutical space and improve the treatment process for millions of patients being treated with biologics. Current techniques in dry powder development Research has revealed properties of dry powders that are favorable for aerodynamic delivery to the lungs and other areas, including a highly porous surface area and small, submicron, and micron-sized parti- cles (10). However, depending on the modality of the drug, physical and chemical degradation can occur during the drying process, and the choice of technique must be carefully considered. Techniques to produce inhalable pharmaceutical powders include: • Spray drying (SD), or spraying solutions into d r ied hot a i r. T h i s ca n be u sed to produce products for inhalation but is mostly limited to small molecules and proteins that are not ther- mally sensitive (2). • Nano-milling is one of the most common pro- cesses to improve the bioavailability of poorly water-soluble drugs. The process involves wet milling, or dispersion of particles through im- pact, to mechanically decrease particle size and increase surface area and has ideal properties for oral, injectable, and inhalable administra- tion (11). Increasing surface area increases dis- solution rate and, therefore, increases bioavail- ability, but conditions can be harsh. • Shelf freeze-drying (shelf FD)/lyophilization is a common process for producing stable pro- tein par ticles and dr y powder vaccines. The process involves using a freeze dr yer known a s a lyoph i l i zer to f reeze l iqu id d r ugs a nd [F]ormulating biologics into dry powders is no easy task.