Freeze-Dried Biopharmaceutical Formulations are Surprisingly Less Stable than Liquid Formulations during Dropping

Area of Science:

• Pharmaceutical Sciences
• Biotechnology
• Materials Science

Background:

• Optimized freeze-dried (FD) biopharmaceutical formulations are typically stable.
• Liquid formulations are generally considered less susceptible to physical degradation.
• Dropping stress is a relevant physical stressor during biopharmaceutical handling and transport.

Purpose of the Study:

• To investigate the phenomenon of increased degradation in FD biopharmaceuticals compared to liquid formulations under dropping stress.
• To identify the underlying causes of this observed degradation.
• To propose recommendations for biopharmaceutical formulation screening.

Main Methods:

• Utilized two monoclonal antibodies (mAbs) and a fusion protein (FP) as model biopharmaceuticals.
• Assessed stability after dropping stress using ultraviolet-visible (UV-Vis) spectroscopy, size exclusion high-performance liquid chromatography (SE-HPLC), micro-flow imaging (MFI), and dynamic light scattering (DLS).

Main Results:

• FD formulations exhibited significantly higher levels of sub-visible particles (SbVPs) post-dropping stress compared to liquid formulations.
• Micro-flow imaging (MFI) and dynamic light scattering (DLS) were key in detecting particle formation.
• Traditional methods like UV-Vis and SE-HPLC were less sensitive to the observed degradation.

Conclusions:

• Elevated temperatures resulting from dropping stress on FD powders are a probable cause for increased particle formation.
• Dropping stress should be incorporated into early-stage screening for selecting between liquid and FD biopharmaceutical formulations.
• This study highlights the importance of considering physical stress factors in biopharmaceutical stability assessment.