Premium
Amino Acid‐Based Advanced Liquid Formulation Development for Highly Concentrated Therapeutic Antibodies Balances Physical and Chemical Stability and Low Viscosity
Author(s) -
Kemter Kristina,
Altrichter Jens,
Derwand Roland,
Kriehuber Thomas,
Reinauer Eva,
Scholz Martin
Publication year - 2018
Publication title -
biotechnology journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.144
H-Index - 84
eISSN - 1860-7314
pISSN - 1860-6768
DOI - 10.1002/biot.201700523
Subject(s) - chemistry , chromatography , high performance liquid chromatography , viscosity , chemical stability , amino acid , excipient , biochemistry , organic chemistry , materials science , composite material
To develop highly concentrated therapeutic antibodies enabling convenient subcutaneous application, well stabilizing pharmaceutical formulations with low viscosities are considered to be key. The purpose of this study is to select specific amino acid combinations that reduce and balance aggregation, fragmentation and chemical degradation, and also lower viscosity of highly concentrated liquid antibodies. As a model, the therapeutically well‐established antibody trastuzumab (25–>200 mg mL −1 ) in liquid formulation is used. Pre‐testing of formulations based on a stabilizing and protecting solutions (SPS®) platform is conducted in a thermal unfolding model using differential scanning fluorimetry (DSF) and accelerated aging at 37 and 45 °C. Pre‐selected amino acid combinations are further iteratively adjusted to obtain stable highly concentrated antibody formulations with low viscosity. Size exclusion chromatography (SE‐HPLC) reveals significantly lower aggregation and fragmentation at specific amino acid:sugar and protein:excipient ratios. Dynamic viscosities <20 mPa * s of highly concentrated trastuzumab (≥200 mg mL −1 ) are measured by falling ball viscosimetry. Moreover, less chemical degradation is found by cationic exchange chromatography (CEX‐HPLC) even after 6 months liquid storage at 25 °C. In conclusion, specifically tailored and advanced amino acid‐based liquid formulations avoid aggregation and enable the development of stable and low viscous highly concentrated biopharmaceuticals.