There are many complex molecular and physicochemical factors driving the design of biologic drug products that impact the biophysical and biochemical stability of protein drugs, as shown in Figure . These include protein concentration (up to 100 mg/ml and 200 mg/ml and beyond for high and ultrahigh concentrations, respectively, for subcutaneous delivery), a broad range of temperatures, and the engineering processes that accommodate various administration routes and final drug product forms, from sterile liquid to solid state. Thermal, chemical, and mechanical stresses are present throughout the entire development and manufacturing processes. Specifically, as shown in Figure , a broad range of temperature stresses, from low-temperature storage and freezing stress from lyophilization to thermal stress from the spray drying process, can significantly affect protein aggregation behavior. These stresses alter the thermodynamic and energy state of proteins, resulting in increased aggregation, fibrillization, degradation, oxidation, and other processes that can compromise stability, quality, and bioavailability. Among several formulation strategies, solid biologics via drying processes have shown advantages in preserving protein stability. However, changes in protein structure and protein-sugar interactions, acidity shifts, and excipient crystallization can occur during the freezing step of lyophilization, subsequently compromising protein stability in the solids. Therefore, the rational selection of appropriate drying processes, excipients and stabilizers, and storage conditions plays a critical role in crafting stable biologic products, which will be further discussed in this review. Drying of peptide and protein drugs utilizes a few engineering processes with the goal of the removal of water and stabilizing protein in solid-state. This section will briefly discuss both traditional and emerging drying techniques for producing protein solids. A schematic illustration of drying methods is presented in Figure . The advantages and limitations of each drying method as well as the stresses that protein may encounter during freezing and drying are summarized in Table . The choice of drying technique is a decision made with many considerations including drying efficiency and product storage stability. Comprehensive reviews of these techniques can be found in recent articles. We would like to briefly introduce their crucial process and our perspective on the advantages and disadvantages of their mechanistic impacts on protein stability discussed in the following section. 13-16, 28-31 Table . Drying techniques for solid-state biologics formulation and manufacturing processes. Lyophilization, known as freeze-drying and illustrated in Figure , is a process that involves water freezing followed by sublimation for water removal and is widely used for the stabilization of biologics. The lyophilized biologics formulations provide better physical and chemical stability and long-term storage stability. Rational design of freeze-drying process and formulation composition is critical to enable stable lyophilized protein formulation. Freeze drying is a batch process and is time-consuming and energy-intensive. If the process is not well optimized, it can result in not only a longer drying time but also compromised product stability. Protein unfolding can also occur due to the stress of freezing and drying, and therefore efficient formulation is needed to inhibit unfolding at each step. Aside from process development, the formulation excipient selection, such as sugar excipient, pH and buffer, is also crucial in maintaining the stability of protein during the freeze-drying process, storage, and extended shelflife. Compared to traditional lyophilization technology which is a batch process and time-consuming with very low energy usage efficiency, the spray-drying (SD) process involving solution rapidly atomization and evaporation has raised growing interest in manufacturing biologic solids due to its continuous process with a high output rate. It also provides the opportunity for designing inhalation biologic products with suitable powder flowability by controlling the particles' properties through the spray drying process. Exubera as an inhalable insulin product and Raplixa as a mixture of thrombin and fibrinogen are recent approved examples of biological products using SD techniques. However, there is a concern about the stability of spray-dried protein solids because spray drying may result in the displacement of protein on the surface of the droplet due to the extraction of moisture. The removal of water from the center of the droplet to the surface can result in the diffusion of proteins to the edge of the dried particles, exposing them to air-liquid interfacial stresses that induce protein unfolding and loss of functionality. Therefore, understanding the impact of formulation conditions on the distribution of protein and its structure can aid in designing drying conditions to create more homogeneous drug products with robust stability. Considering for nature of SD process, it has its own distinct unique caveats. The product yield depends on the work scale and formulation composition, where yield is typically low. Furthermore, SD proteins are typically administrated through parenteral delivery which needs a sterile product. Ensuring the sterility of protein products during the spray drying process poses a significant challenge in maintaining an aseptic operation. Moreover, achieving extremely low residual water content in the final product may necessitate the use of additional drying methods, which could potentially diminish the time and energy advantages associated with spray drying when contrasted with lyophilization. Spray freeze drying (SFD) refers to the process of atomized liquid stream into a frozen medium followed by sublimation of the frozen droplet. Such a process provides the potential advantage of minimizing the possibility of phase separation between drug and excipient and therefore results in a more homogeneous distributed drug product. During the SFD process, the formation of porous spherical particles leads to an increase in surface area and subsequently contributes to a reduction in the time needed for sublimation and secondary drying. In addition, the spherical shape of these SFD particles contributes to reasonably acceptable flowability and aerosol performance. However, due to the diversity and complexity of SFD processes, SFD is still highly experimental and only scaled for laboratory purposes in the pharmaceutical applications, which is mostly used in the food idustry. Electrostatic spray drying (ESD) recently has been developed as an emerging drying method to the traditional spray drying process. ESD utilizes an atomizing nozzle where a charge is applied to the feedstock during the atomization. The use of electrostatic technology can overcome the disadvantage of uncontrolled distribution of drugs inside or on the surface of dried particles. The solvent has the highest ability to polarize and will pick up the most electrons by the applied charge. The carrier, being less conductive than the solvent, will pick up fewer electrons, and the active being least conductive pick up the fewest electrons. As such, the formation of a solvent-rich and a solute-rich core within the droplet can improve the microencapsulation efficiency and facilitate drying at a lower temperature. Application of the ESD has been evaluated in nanoparticles, nanosuspensions, microsphere encapsulations, and also food. Though most ESD applications were experimented with the lab scale, nowadays ESD technologies are commercially available ranging from small lab scale to commercial manufacturing. Supercritical fluid (SCF) drying is another alternative drying method for protein stabilization. There are two proposed concepts of the SCF process for solid protein products. The first concept is to use supercritical fluid as an anti-solvent for water extraction, which leads to the precipitation of concentrated protein and is followed by additional water extraction through freezing and drying before obtaining final dried particles. The second concept is to use supercritical fluid as a propellant or effervescent agent where the SCF is dissolved at high pressure. SCF has been carried out on only a few food products. Some studies have demonstrated that SCF is capable formulating solid protein particles with good stability and acceptable flow properties. One major challenge during the SCF process is the loss of other polar soluble compounds along with water. Lyospheres are defined as round, discrete, and freeze-dried beads composed of a pharmaceutical active ingredient and excipients. The lyospheres provide the advantage of continuous manufacturing and individual beads can be dried in bulk which can be converted into the final product container with flexibility in dose and potency targeting. Such technology enables dose titration, superior combination products, space-saving bulk storage, and flexible drug product packaging, and overcomes the limitations associated with traditional vial images. In addition, lyospheres technology has the potential to improve the stability and aid custom medicines and vaccines including alternative delivery, and novel adjuvants for patients could be made using this technology. The functionally coated lyospheres using a coating that targets release in the colon can also be used for targeted therapies for oral delivery. Despite the mentioned benefits, lyospheres have been recognized as a vulnerable and delicate product, which can pose significant difficulties in terms of handling, transportation, and packaging. Microwave vacuum drying (MVD) is a proprietary form of applying a microwave under a vacuum to achieve dehydration at lower temperatures. Drying is faster than lyophilization as heat transfer occurs by radiation (microwaves) instead of conduction. The processing time can be reduced to 6-12 hrs compared to days in lyophilization. This provides an alternative fast-drying technology that enables semi-continuous manufacturing and flexible on-demand manufacturing as well as high-volume products. Härdter et al. studied stability of 6 monoclonal antibodies following MVD and lyophilization. The microwave assisted drying showed similar storage stability profile as lyophilization but shorten process. Furthermore, they demonstrated application of MVD would be particularly beneficial for antibody formulations with low concentrations. However, the application of MVD in the pharmaceutical industry is limited due to a lack of understanding of uniform sublimation and interaction between microwave and biologics and excipients in the formulation.