Succinate Buffer in Biologics Products: Real-world Formulation Considerations, Processing Risks and Mitigation...

Area of Science:

• Pharmaceutical Sciences
• Biophysical Chemistry
• Drug Formulation

Background:

• Succinic acid/succinate buffers offer excellent buffering capacity for biologics.
• Limited use in drug products due to freezing-induced crystallization and pH shifts.
• Previous studies often lacked pharmaceutically relevant conditions.

Purpose of the Study:

• Characterize succinate buffer behavior under pharmaceutical processing conditions.
• Investigate pH shifts and crystallization mechanisms during freezing.
• Evaluate the impact of sucrose as a cryoprotectant and its effect on monoclonal antibody (mAb) stability.

Main Methods:

• Physicochemical characterization of succinate formulations under freezing conditions.
• X-ray diffractometry to identify crystalline species.
• Formulation of three mAbs with succinate and sucrose, followed by freeze-thaw, frozen storage, and lyophilization.
• Assessment of mAb quality attributes (HMW, turbidity, concentration, particles).

Main Results:

• A pH increase of ~1.2 units observed in succinate buffers during freezing.
• Selective crystallization of monosodium succinate identified as the cause of pH shift.
• Sucrose (2% w/v) effectively mitigated salt crystallization and pH shift.
• No detrimental impact on mAb quality attributes observed for mAbs formulated with succinate and sucrose.
• Lyophilized formulations with succinate and sucrose showed acceptable accelerated stability.

Conclusions:

• Succinate buffers can be effectively stabilized against freezing-induced pH shifts by incorporating sucrose.
• Sucrose addition prevents monosodium succinate crystallization, maintaining buffer performance.
• Succinate/sucrose formulations are suitable for mAb drug products, including those subjected to lyophilization.
• This study supports the broader application of succinate buffers in biopharmaceutical formulations.