Journal
JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 103, Issue 3, Pages 862-869Publisher
WILEY
DOI: 10.1002/jps.23861
Keywords
monoclonal antibody; protein aggregation; stability; surfactants; cyclodextrins; processing
Funding
- MedImmune
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This study investigates the mechanism of protein particle formation during ultrafiltration/diafiltration (UF/DF), finding that agitation drives particle formation by promoting protein-interface adsorption and desorption. Low conductivity and the presence of surfactant reduced the level of particle formation in small-scale stirring studies, and the same trends were observed in pumping and UF/DF. Polysorbate 80 (PS80) and hydroxypropyl--cyclodextrin (HPCD) reduced particle formation in UF/DF by factors of 15 and 4, respectively. Measurements of conformational stability, colloidal stability, and surface tension demonstrated that PS80 protects against particle formation by preventing protein-interface adsorption, low conductivity improves the colloidal stability of the protein, and the mechanism of action of HPCD remains unclear. This work demonstrates that interfacial adsorption-desorption of the protein during UF/DF is the principal cause of particle formation, that the level of surfactant-free particle formation depends on the colloidal stability of the protein, and that the inclusion of surfactant greatly reduces in-process particle formation during UF/DF. (c) 2014 The Authors. Journal of Pharmaceutical Sciences published by Wiley Periodicals, Inc.
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