Erratum: Studying excipient modulated physical stability and viscosity of monoclonal antibody formulations using small-angle scattering (Molecular Pharmaceutics (2019) 16:10 (4319-4338) DOI: 10.1021/acs.molpharmaceut.9b00687)

Abstract

In the original publication, we reported the second virial coefficient B22 measured for the National Institute of Standards and Technology Monoclonal Antibody (NISTmAb) reference material prepared under a variety of formulation conditions. The measurements for B22 span a range of laser power values, necessitating calibration of the laser attenuation in order to normalize all intensity measurements to a constant laser power. In the original calculations, calibration was performed prior to each B22 measurement. The Zetasizer utilizes optical density filters to reduce the incident laser intensity and to ensure the intensity is within the linear region of the detector. The attenuation factor for these filters should be constant. A subsequent review of the original results, however, indicated significant fluctuations in the attenuation factors across all of the B22 measurements. Subtle variations in the attenuation factors can lead to increased scatter in the concentration-dependent data and error in the calculated B22 value. In order to account for these fluctuations, the attenuation factors were averaged across all of the B22 measurements. Application of the average (constant) attenuation factor values yielded B22 results, which were much more repeatable and independent of sample preparation and/or the Zetasizer instrument used for the measurements. With the adaptation of the above-mentioned best practice method for making B22 measurements, we would like to update the published results with the newly measured B22 values for NISTmAb prepared in the same excipient formulations (Figure 1). We expect similar B22 results can be measured for NISTmAb by other laboratories, using the abovementioned method for attenuation factor calculations. As a result, minor changes should be made to the original manuscript. The changes in both kD and B22 values with the presence of various excipients were summarized in Figure 8 from the original publication. As compared to the previously reported B22 values, stronger correlations were found between kD and the newly measured B22 values (Figure 2 shown below). In general, significantly decreased kD and B22 values were measured with the presence of ionic excipients (salts, pH, and arginine), suggesting NISTmAb molecules were less colloidally stable in these excipient formulations. In the original publication, the B22 measured from NISTmAb prepared in phosphate buffer at pH 8 was negative, and this appeared to be the only sample whose S(0)exp did not agree with the B22 result as shown in Figure 9 in the original publication. With the improved method for performing laser calibration, the new B22 value measured from this particular sample was determined to be positive. The S(0)exp and remeasured B22 values are summarized in Figure 3, and great correlations can be found between the two data sets for all of the samples examined in this study. In the original publication, the predicted viscosity results based on kD, B22, and S(q)eff values were compared with experimentally determined viscosity results. Figure 10 from the original publication demonstrated that, as compared to kD, the predicted results based on B22 and S(0)exp values were in better agreement with experimental data for most of the samples. However, as shown in Figure 4 below, the correlations between the predicted and measured results became less strong with the newly measured B22 values. Therefore, on the basis of the comparison between the predicted and measured results on bulk solution viscosity, one can conclude that S(0)exp are better predictors than kD and B22 for the viscosities of concentrated NISTmAb formulations. The conclusion made in the original manuscript that "the disagreements found between the predicted and measured viscosity results imply other factors apart from the PPI contribute to the bulk rheological properties of concentrated protein solutions" still holds true with the new B22 results.