A streamlined workflow for early phase formulation development of monoclonal antibodies comprising multi-attribute...

Area of Science:

• Biopharmaceutical Development
• Analytical Chemistry
• Protein Chemistry

Background:

• Early-phase formulation development for monoclonal antibodies (mAbs) is complex and costly.
• Existing methods often require significant amounts of valuable early-stage material.
• There is a need for efficient workflows that ensure quality and patient safety.

Purpose of the Study:

• To develop and validate a streamlined workflow for early-phase mAb formulation.
• To integrate liquid chromatography-mass spectrometry multi-attribute method (LC-MS MAM) with surface plasmon resonance (SPR) for comprehensive analysis.
• To reduce costs and timelines in mAb development without compromising quality.

Main Methods:

• Combined LC-MS MAM and SPR for structure/function correlation of mAbs.
• Incorporated high-throughput methods for high molecular weight material (HMWM), conformational, and colloidal stability.
• Utilized forced degradation studies, pH optimization, and design of experiments (DoE) for excipient screening.

Main Results:

• The workflow successfully identified critical quality attributes (CQAs), such as Met105 oxidation in pembrolizumab.
• DoE confirmed that methionine effectively inhibited oxidation and stabilized protein binding.
• An optimized formulation (20 mM histidine, 25 mM methionine, 0.02% PS80, 300 mM sucrose, pH 5.5) was developed.

Conclusions:

• The integrated workflow provides a comprehensive understanding of mAb CQAs and stability.
• This streamlined process significantly reduces the need for early development material.
• The workflow has the potential to decrease costs and shorten development timelines for mAbs.