title: Self-buffering antibody formulations.
abstract: Monoclonal antibodies (mAbs) often require the development of high-concentration formulations. In such cases, and when it is desirable to formulate a mAb around pH 5.0, we explored a novel approach of controlling the formulation pH by harnessing the ability of mAbs to "self-buffer." Buffer capacities of four representative IgG(2) molecules (designated mAb1 through mAb4) were measured in the pH 4-6 range. The buffer capacity results indicated that the mAbs possessed a significant amount of buffer capacity, which increased linearly with concentration. By 60-80 mg/mL, the mAb buffer capacities surpassed that of 10 mM acetate, which is commonly employed in formulations for buffering in the pH 4-6 range. Accelerated high temperature stability studies (50 degrees C over 3 weeks) conducted with a representative antibody in a self-buffered formulation (50 mg/mL mAb1 in 5.25% sorbitol, pH 5.0) and with solutions formulated using conventional buffers (50 mg/mL mAb1 in 5.25% sorbitol, 25 or 50 mM acetate, glutamate or succinate, also at pH 5.0) indicated that mAb1 was most resistant to the formation of soluble aggregates in the self-buffered formulation. Increased soluble aggregate levels were observed in all the conventionally buffered (acetate, glutamate, and succinate) formulations, which further increased with increasing buffer strength. The long-term stability of the self-buffered liquid mAb1 formulation (60 mg/mL in 5% sorbitol, 0.01% polysorbate 20, pH 5.2) was comparable to the conventionally buffered (60 mg/mL in 10 mM acetate or glutamate, 5.25% sorbitol, 0.01% polysorbate 20, pH 5.2) formulations. No significant change in pH was observed after 12 months of storage at 37 and 4 degrees C for the self-buffered formulation. The 60 mg/mL self-buffered formulation of mAb1 was also observed to be stable to freeze-thaw cycling (five cycles, -20 degrees C --> room temperature). Self-buffered formulations may be a better alternative for the development of high-concentration antibody and protein dosage forms.
authors.affiliation: Department of Pharmaceutics, Amgen Inc., Thousand Oaks, California 91320, USA. ygokarn@amgen.com
authors.forename: Yatin R
authors.initials: YR
authors.lastname: Gokarn
authors.forename: Eva
authors.initials: E
authors.lastname: Kras
authors.forename: Carrie
authors.initials: C
authors.lastname: Nodgaard
authors.forename: Vasumathi
authors.initials: V
authors.lastname: Dharmavaram
authors.forename: R Matthew
authors.initials: RM
authors.lastname: Fesinmeyer
authors.forename: Heather
authors.initials: H
authors.lastname: Hultgen
authors.forename: Stephen
authors.initials: S
authors.lastname: Brych
authors.forename: Richard L
authors.initials: RL
authors.lastname: Remmele
authors.forename: David N
authors.initials: DN
authors.lastname: Brems
authors.forename: Susan
authors.initials: S
authors.lastname: Hershenson
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry; D002021:Buffers; D002626:Chemistry, Pharmaceutical; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D006358:Hot Temperature; D006863:Hydrogen-Ion Concentration
chemical_list: D000911:Antibodies, Monoclonal; D002021:Buffers