Glycine as a context-dependent excipient in protein-based biopharmaceutical formulations

Glycine is widely used as an excipient in protein-based biopharmaceutical formulations, yet its functions are often described too broadly, particularly in terms of stabilization. This review critically examines the physicochemical basis and formulation behavior of glycine across liquid, frozen, and freeze-dried systems, with emphasis on how its effects are governed by formulation composition, physical state, and processing history. Available evidence shows that glycine can contribute to several formulation functions, but its performance is highly product- and condition-dependent. In particular, crystallization represents a central feature of glycine-containing systems because it can support physical robustness and process performance while also creating risks associated with phase separation and loss of local stabilization. This benefit-risk balance depends on the extent of crystallization, the composition of the residual amorphous phase, and the surrounding formulation environment. These outcomes are further modified by interactions with sugars, buffers, surfactants, salts, and other excipients. Evidence from marketed protein-based biopharmaceutical products is also considered to place these mechanistic observations in a practical context. The review also identifies important evidence gaps, particularly in high-concentration protein formulations and in understanding how glycine physical state interacts with other formulation components. Overall, glycine is a multifunctional, physical-state- and process-dependent excipient, and its use should be supported by direct characterization of physical state and product-specific stability.