Studying Excipient Modulated Physical Stability and Viscosity of Monoclonal Antibody Formulations Using Small-Angle...

Area of Science:

• Biopharmaceutical Formulation
• Protein Chemistry
• Physical Chemistry

Background:

• Excipients are crucial for therapeutic product stability and manufacturability.
• Concentrated protein formulations (>50 mg/mL) can suffer from undesirable protein-protein interactions (PPI), leading to self-association and high viscosity.
• Understanding excipient effects on PPI is vital for efficient formulation development.

Purpose of the Study:

• To investigate the influence of various excipients on the physical stability and viscosity of concentrated monoclonal antibody formulations.
• To characterize excipient-modulated PPI and bulk solution viscosities using multiple analytical techniques.

Main Methods:

• Utilized NIST monoclonal antibody (NISTmAb) as a model protein.
• Employed Small Angle X-ray Scattering (SAXS), Differential Scanning Calorimetry (DSC), Dynamic Light Scattering (DLS), and viscosity measurements.
• Varied pH, salt composition, and included cosolutes like amino acids, sugars, and nonionic surfactants.

Main Results:

• SAXS and DLS/SLS showed good correlation, validating DLS/SLS for predicting colloidal stability.
• Ionic excipients (pH, salts) induced short-range attraction, while nonionic excipients (sugars, amino acids, surfactants) promoted repulsive PPI.
• No protein denaturation or aggregation was observed; however, excipients influenced solution viscosity at high protein concentrations.

Conclusions:

• Excipients significantly modulate protein-protein interactions and viscosity in concentrated antibody formulations.
• The effective structure factor S(q)eff and the second virial coefficient B22 show promise as predictors of solution viscosity.
• Further research is needed to identify factors beyond PPI influencing the rheological properties of concentrated protein solutions.