Most biologics are formulated as parenteral drugs for intravenous and subcutaneous administration. 307 Subcutaneous injection, especially when combined with pre-filled syringes or auto-injectors, is gaining attention as it improves patient compliance and reduces medical costs, particularly for patients with chronic diseases who require frequent and chronic administration. However, to avoid pain at the injection site, the injection volume for subcutaneous administration is typically limited to 1-1.5 ml. This necessitates highconcentration protein formulations, which create an enhanced molecular crowding environment, presenting challenges such as high viscosity, protein aggregation, particle formation, and degradation. 309 Figure proposes formulation strategies to achieve high and ultrahigh protein concentrations while mitigating the risk of high viscosity. Briefly, high protein concentration is often achieved via ultrafiltration in an aqueous setup. However, solution formulations can exhibit an exponential increase in viscosity as concentration rises. To push protein concentrations further, dried protein particles, such as those obtained via spray drying, can be suspended in non-aqueous media, potentially presenting lower viscosity with minimized protein-protein contacts. 312 Additionally, using crystalline or amorphous suspension formulations may offer the advantage of lower viscosity compared to solution formulations of similar concentrations. 310 For instance, crystalline suspensions of monoclonal antibodies (mAbs) like Infliximab at a concentration of 150 mg/ml exhibit an acceptable viscosity of 26 cP, whereas a solution formulation at a comparable concentration increases viscosity approximately tenfold. Moreover, the use of protein crystals in pharmaceutical applications offers advantages in terms of enhancing protein stability and improving the pharmacokinetics of drug delivery. Figure . A schematic illustration of formulation strategies to achieve high (≥100 mg/ml) and ultrahigh (≥200 mg/ml) protein concentrations, specifically by utilizing dry protein powder in non-aqueous suspensions and crystalline or amorphous protein particles in aqueous suspensions. Using a crystalline or amorphous suspension formulation may offer the advantage of lower viscosity compared to solution formulations of similar concentration. 310 In addition, the utilization of protein crystals in pharmaceutical applications offers advantages in terms of enhancing protein stability and improving the pharmacokinetics of drug delivery. Reichert et al. studied the crystallization processes for the purification, drug delivery, and storage of Pembrolizumab (Keytruda®). The production of uniform crystalline suspensions, ranging from 1 to 5 μm in size, has been achieved using rotational mixers to minimize sedimentation and temperature gradients to induce and regulate crystallization. Through these techniques, it has been possible to obtain crystalline suspensions with desirable properties such as acceptable viscosity (less than 10 cP), suitable rheological characteristics, and syringeability, enabling the preparation of injectable formulations. An important hurdle in drug development is the limited availability of high-resolution characterization methods to assess the crystallinity and stability of microcrystals of monoclonal antibodies (mAbs) in their native formulations. Traditional analytical techniques face difficulties in evaluating the structural properties of mAb microcrystals within suspension due to factors such as the presence of visible particles, small crystal size, high protein concentration, and the complex composition of liquid formulations. Li et al. recently developed the first high-resolution characterization of mAb microcrystalline suspension using MAS NMR spectroscopy using pembrolizumab crystalline suspension as a model system, as shown in Figure -D. The remarkably narrow linewidth of approximately 29 Hz observed in the C spectral analysis indicates a high level of crystallinity and conformational uniformity in pembrolizumab crystals. The evaluation focuses on assessing the effects of thermal stress and dehydration on the structure, dynamics, and stability of these monoclonal antibody (mAb) crystals within the formulation environment. Though a decrease in structural homogeneity was found when stress at 55 °C, pembrolizumab did not experience severe structural perturbations or thermal unfolding as the position of major peaks remained the same. In addition, the technique of isotopic labeling combined with heteronuclear 13 C and N spectroscopies has been employed to detect and study the interaction between caffeine and pembrolizumab in the crystal lattice. The intermolecular interactions are suggested by the chemical shift changes of caffeine and good agreement with the structure elucidated by single-crystal X-ray diffraction. This approach offers valuable molecular insights into the co-crystallization process of the protein and ligand. Moreover, the polymorphs of the pembrolizumab-caffeine co-crystals (Form I and II) have been detected and differentiated by both SAXS and ssNMR, as shown in Figure and