RESEARCH PAPER Quantitative Correlation between Viscosity of Concentrated MAb Solutions and Particle Size Parameters Obtained from Small-Angle X-ray Scattering Masakazu Fukuda 1 & Chifumi Moriyama 1 & Tadao Yamazaki 1 & Yoshimi Imaeda 1 & Akiko Koga 1 Received: 22 February 2015 /Accepted: 9 June 2015 # Springer Science+Business Media New York 2015 ABSTRACT Purpose To investigate the relationship between viscosity of concentrated MAb solutions and particle size parameters obtained from small-angle X-ray scattering (SAXS). Methods The viscosity of three MAb solutions (MAb1, MAb2, and MAb3; 40–200 mg/mL) was measured by elec- tromagnetically spinning viscometer. The protein interactions of MAb solutions (at 60 mg/mL) was evaluated by SAXS. The phase behavior of 60 mg/mL MAb solutions in a low-salt buffer was observed after 1 week storage at 25°C. Results The MAb1 solutions exhibited the highest viscosity among the three MAbs in the buffer containing 50 mM NaCl. Viscosity of MAb1 solutions decreased with increasing temperature, increasing salt concentration, and addition of amino acids. Viscosity of MAb1 solutions was lowest in the buffer containing histidine, arginine, and aspartic acid. Particle size parameters obtained from SAXS measurements correlated very well with the viscosity of MAb solutions at 200 mg/mL. MAb1 exhibited liquid–liquid phase separation at a low salt concentration. Conclusions Simultaneous addition of basic and acidic amino acids effectively suppressed intermolecular attractive interac- tions and decreased viscosity of MAb1 solutions. SAXS can be performed using a small volume of samples; therefore, the particle size parameters obtained from SAXS at intermediate protein concentration could be used to screen for low viscosity antibodies in the early development stage. KEY WORDS MAb . SAXS . Viscosity ABBREVIATIONS D max app Apparent maximum dimension EMS Electromagnetically spinning IFT Indirect fourier transformation p(r) Pair–distance distribution function q.s. quantity sufficient R g app Apparent radius of gyration SAXS Small-angle X-ray scattering INTRODUCTION Monoclonal antibodies (MAbs) and MAb-based drugs have become a major class of biopharmaceuticals for treating nu- merous diseases such as cancer, inflammation, allergies, infec- tious diseases, and cardiovascular diseases, and are seeing rapid market growth. Owing to the low potency of MAb, many dis- eases targeted by MAb therapy require injections of several mg/kg. Although MAb therapeutics for oncology are often administered intravenously, for chronic diseases (e.g., rheuma- tism) requiring frequent dosing it is preferable to provide a subcutaneous administration option that can be conducted by the patient at home and which thereby contributes to increas- ing patient compliance. However, an injection volume of more than approximately 1.5 mL is not suitable for subcutaneous administration. Therefore, MAb solutions for subcutaneous administration with a long dosage interval need to be concen- trated to 100 to 200 mg/mL, which presents several challenges. As previously reported, the high viscosity of MAb solutions is a major issue affecting many aspects, including their stability and also their manufacturability and usability for subcutaneous in- jection (1). For example, high viscosity may result in a decrease in the performance of the tangential flow filtration used to change the buffer and concentrate the protein, and in a Electronic supplementary material The online version of this article (doi:10.1007/s11095-015-1739-6) contains supplementary material, which is available to authorized users. * Masakazu Fukuda fukuda.masakazu76@chugai-pharm.co.jp 1 Production Engineering Department, Chugai Pharmaceutical Co., Ltd., 5-5-1 Ukima, Kita-ku, Tokyo 115-8543, Japan Pharm Res DOI 10.1007/s11095-015-1739-6