Maddux, Nathaniel R.Joshi, Sangeeta B.Volkin, David B.Ralston, John P.Middaugh, C. Russell2017-04-262017-04-262011-10Maddux, N. R., Joshi, S. B., Volkin, D. B., Ralston, J. P., & Middaugh, C. R. (2011). Multidimensional Methods for the Formulation of Biopharmaceuticals and Vaccines. Journal of Pharmaceutical Sciences, 100(10), 4171–4197. http://doi.org/10.1002/jps.22618https://hdl.handle.net/1808/23779Determining and preserving the higher order structural integrity and conformational stability of proteins, plasmid DNA and macromolecular complexes such as viruses, virus-like particles and adjuvanted antigens is often a significant barrier to the successful stabilization and formulation of biopharmaceutical drugs and vaccines. These properties typically must be investigated with multiple lower resolution experimental methods, since each technique monitors only a narrow aspect of the overall conformational state of a macromolecular system. This review describes the use of empirical phase diagrams (EPDs) to combine large amounts of data from multiple high-throughput instruments and construct a map of a target macromolecule's physical state as a function of temperature, solvent conditions, and other stress variables. We present a tutorial on the mathematical methodology, an overview of some of the experimental methods typically used, and examples of some of the previous major formulation applications. We also explore novel applications of EPDs including potential new mathematical approaches as well as possible new biopharmaceutical applications such as analytical comparability, chemical stability, and protein dynamics.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 4.0 (CC BY-NC-ND 4.0), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.http://creativecommons.org/licenses/by-nc-nd/4.0/Phase diagramsFormulationStabilityProteinMonoclonal AntibodiesPlasmid DNAVaccinesCircular dichroismFluorescenceCalorimetryLight scatteringArticle10.1002/jps.22618PMC3949199openAccess