title: Investigating high-concentration monoclonal antibody powder suspension in nonaqueous suspension vehicles for subcutaneous injection.
abstract: Developing high-concentration monoclonal antibody (mAb) liquid formulations for subcutaneous (s.c.) administration is challenging because increased viscosity makes injection difficult. To overcome this obstacle, we investigated a nonaqueous powder suspension approach. Three IgG1 mAbs were spray dried and suspended at different concentrations in Miglyol® 840, benzyl benzoate, or ethyl lactate. Suspensions were characterized for viscosity, particle size, and syringeability; physical stability was visually inspected. Suspensions generally outperformed liquid solutions for injectability despite higher viscosity at the same mAb concentrations. Powder formulations and properties had little effect on viscosity or injectability. Ethyl lactate suspensions had lowest viscosity (<20 cP) and lowest syringe injection glide force (<15 N) at mAb concentrations as high as 333 mg/mL (500 mg powder/mL). Inverse gas chromatography analysis indicated that the vehicle was the most important factor impacting suspension performance. Ethyl lactate rendered greater heat of sorption (suggesting strong particle-suspension vehicle interaction may reduce particle-particle self-association, leading to low suspension viscosity and glide force) but lacked the physical suspension stability exhibited by the other vehicles. Specific mixtures of ethyl lactate and Miglyol® 840 improved overall performance in high mAb concentration suspensions. This study demonstrated the viability of high mAb concentration (>300 mg/mL) in suspension formulations for s.c. administration.
authors.affiliation: Pharmaceutical Processing and Technology Development, Genentech, A Member of the Roche Group, South San Francisco, California 94080, USA.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Bowen
authors.forename: Nick
authors.initials: N
authors.lastname: Armstrong
authors.forename: Yuh-Fun
authors.initials: YF
authors.lastname: Maa
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000737:chemistry*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000737:chemistry*; D001565:Benzoates / Q000737:chemistry*; D000068258:Bevacizumab; D002460:Cell Line; D006224:Cricetinae; D003890:Desiccation; D004075:Diglycerides / Q000737:chemistry*; D006801:Humans; D007279:Injections, Subcutaneous; D007773:Lactates / Q000737:chemistry*; D010316:Particle Size; D014677:Pharmaceutical Vehicles / Q000737:chemistry; D011208:Powders; D055550:Protein Stability; D000069283:Rituximab; D000068878:Trastuzumab; D014199:Trehalose / Q000737:chemistry; D014783:Viscosity
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D001565:Benzoates; D004075:Diglycerides; D007773:Lactates; D014677:Pharmaceutical Vehicles; D011208:Powders; D000068258:Bevacizumab; D000069283:Rituximab; C079597:miglyol 840; D014199:Trehalose; C015866:ethyl lactate; C006723:benzyl benzoate; D000068878:Trastuzumab