Monoclonal antibodies (MAbs) are increasingly formulated at concentrations >100 mg/mL as a means to deliver a high dose in a low volume (<1 mL). Such high-concentration solutions are commonly opalescent, an undesirable characteristic of biopharmaceutical products for several reasons. Although it may be only aesthetic, opalescent products are not considered pharmaceutically “elegant.” Of more serious concern, opalescence may be a precursor to aggregation and indicate a propensity toward decreased product stability or quality.

“MAb X” is a model IgG monoclonal antibody that forms opalescent solutions at high concentrations. We present here two studies on opalescent MAb X solutions to address the above questions. In the first study, solutions were monitored over one month to assess changes in solution turbidity, viscosity, and percent antibody monomer or hydrodynamic radius over time. In the second, we carried out a design of experiment (DoE) to examine the effects of buffer identity, buffer concentration, and NaCl concentration on opalescence. We analyzed select samples with differing turbidities by intrinsic fluorescence, isothermal titration calorimetry (ITC), and Fourier-transform infrared (FTIR) spectroscopy to determine whether secondary or tertiary structural changes could be correlated with opalescence.

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