Characterization of Excipient Effects on Reversible Self-Association, Backbone Flexibility, and Solution Properties of an IgG1 Monoclonal Antibody at High Concentrations: Part 2

Ongoing Challenges to Develop High Concentration Monoclonal Antibody-based Formulations for Subcutaneous Administration: Quo Vadis?

“…The rational approach includes elucidation of the sites of PPIs and the nature of such interactions followed by selection of excipients that will disrupt such undesired interactions at high concentrations. 30,31 The empirical approach includes screening different classes of additives from a list of excipients already found in approved parenteral drug products. 26 Often, the former approach is scientifically satisfying yet time-consuming and lacks certainty of success, while the latter approach is labor intensive and difficult to justify in terms of why such additives work.…”

“…another example, using the same HX-MS approach described above, the ability of series of charged excipients for one mAb, and a series of hydrophobic excipients with a second mAb, were demonstrated to interact with specific sites within the mAbs to disrupt specific PPI molecular interactions (i.e., charge-charge and hydrophobic attractions, respectively) and lower solution viscosity at high protein concentrations 30,31. Although viscosity reduction of aqueous HCAF solutions by excipient addition can often be achieved by changing the ionic strength, through pH optimization/buffer selection, or the use of specific additives, e.g., amino acids such as arginine,15 a second key challenge is then to ensure adequate long-term storage stability of the mAb under these same HCAF conditions.…”

Strategies for high‐concentration drug substance manufacturing to facilitate subcutaneous administration: A review

“…As discussed above, excipients can be added to the formulation to provide stabilizing effects (Chang et al, 1996; Kerwin, 2008; Mahler et al, 2005; Randolph & Jones, 2002). These include detergents, protein‐stabilizing agents, and other additives that can reduce protein–protein interactions to enable high protein concentration formulations with good stability profiles (Hu, Arora et al, 2019; Hu, Toth et al, 2019). Polysorbates are often added to stabilize proteins against interface‐induced aggregation and to minimize surface adsorption of proteins (Bam et al, 1998; Carpenter, Kendrick, Chang, Manning, & Randolph, 1999).…”

Product-Specific Impact of Viscosity Modulating Formulation Excipients During Ultra-High Concentration Biotherapeutics Drug Product Development

“…11,27,28 In addition to evaluating the effect of pH and salt addition, Whitaker et al 12 studied the addition of various amino acids for their viscosity-reducing and stabilization effects across ultra-high protein concentration. Furthermore, Hu et al 29 characterized effects of similar excipients on reversible protein selfassociation, specifically how these excipients alter regions of the mAb with a high propensity for PPIs. Although many excipients are widely known to modulate viscosity and stability, these excipient effects can sometimes be protein specific.…”