Formulation Design and High-Throughput Excipient Selection Based on Structural Integrity and Conformational Stability of Dilute and Highly Concentrated IgG1 Monoclonal Antibody Solutions

Bhambhani, Akhilesh; Kissmann, Julian; Joshi, Sangeeta B.; Volkin, David B.; Kashi, Ramesh S.; Middaugh, C. Russell

doi:10.1002/jps.23008

Cited by 58 publications

(51 citation statements)

References 51 publications

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“…Likewise, the concentration and kinds of surfactant and buffer component and concentration of protein are also parameters, which are known to influence the physical properties of proteins (Chi et al 2003a;Bhambhani et al 2012). Thus, tremendous efforts are necessary to evaluate all these parameters to optimize the formulation of biopharmaceuticals.…”

Section: Evaluation Of Intermolecular Interaction In Biopharmaceuticalsmentioning

confidence: 98%

Biopharmaceutical Evaluation of Intermolecular Interactions by AUC-SE

Saito

Uchiyama

2016

Analytical Ultracentrifugation

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Analytical ultracentrifugation sedimentation equilibrium (AUC-SE) is a useful technique to investigate the weak reversible intermolecular interactions among proteins in solution. It provides biophysical information such as the average apparent molecular weight, stoichiometry, and association constant of associating proteins. Several studies of intermolecular interaction in biopharmaceuticals by AUC-SE are introduced in this chapter. AUC-SE also provides the second virial coefficient (B 2 ), which represents the type, i.e., repulsive and attractive, and a magnitude of intermolecular interactions. The B 2 values obtained from the protein solution at low concentrations showed good correlation with aggregation and viscosity of MAb at high concentrations, indicating that B 2 can be an effective indicator of aggregation propensity and viscosity. These findings suggest that AUC-SE provides clues to understand the self-association in biopharmaceuticals and to establish effective manufacturing process, formulation, and administration of biopharmaceuticals.

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Section: Evaluation Of Intermolecular Interaction In Biopharmaceuticalsmentioning

confidence: 98%

Biopharmaceutical Evaluation of Intermolecular Interactions by AUC-SE

Saito

Uchiyama

2016

Analytical Ultracentrifugation

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“…This approach was used for the analysis of highly concentrated antibody solutions 115,116 and in other studies of antibody structure and stability. 117,118 …”

Section: Analysis Of High-throughput Formulation Datamentioning

confidence: 99%

Accelerated Formulation Development of Monoclonal Antibodies (mAbs) and mAb-Based Modalities: Review of Methods and Tools

2015

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More therapeutic monoclonal antibodies and antibody-based modalities are in development today than ever before, and a faster and more accurate drug discovery process will ensure that the number of candidates coming to the biopharmaceutical pipeline will increase in the future. The process of drug product development and, specifically, formulation development is a critical bottleneck on the way from candidate selection to fully commercialized medicines. This article reviews the latest advances in methods of formulation screening, which allow not only the high-throughput selection of the most suitable formulation but also the prediction of stability properties under manufacturing and long-term storage conditions. We describe how the combination of automation technologies and high-throughput assays creates the opportunity to streamline the formulation development process starting from early preformulation screening through to commercial formulation development. The application of quality by design (QbD) concepts and modern statistical tools are also shown here to be very effective in accelerated formulation development of both typical antibodies and complex modalities derived from them.

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“…79 generally limited to 1-2 mL. High protein concentrations 80 ()100 mg/mL) are needed to ensure sufficient therapeutic effect 81 in that small volume [5,6]. 82 There is consequently a certain need for understanding 83 development of highly concentrated freeze-dried formulations 84 (HC-FDF).…”

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“…89 For example, reconstitution time of freeze-dried products 90 increases, over a range from minutes to hours, as a function of pro-91 tein concentration. Very long reconstitution times might seriously 92 impair the potency or usability of a lyophilized product [6,7,9,10]. 93 It is therefore necessary to examine ways of reducing reconstitution 94 time (by controlling ice nucleation, for example) [11][12][13].…”

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confidence: 99%