An increasing number of biological products require high-dose, high-concentration formulations to enable subcutaneous administration. High-concentration formulations are associated with several challenges, including viscosity limitations, Donnan effect, and flux decay. Early-stage development of these candidates frequently relies on iterative, empirical experiments to define operating parameters and reach the target final formulation composition.

A model-based method for predicting formulation buffer concentrations was incorporated into an ultrafiltration/diafiltration (UF/DF) process development workflow. The model utilizes stoichiometric charge balance between the solutes across the membrane, including structure-derived protein charge, to incorporate the Donnan Effect. An iterative evaluation of a range of initial and final ultrafiltration target concentrations with different combinations of buffer species and excipients is utilized to inform a streamlined minimal set of UF/DF experiments. Usually high-concentration UFDF development requires a large amount of material, however, modelling-derived experimental strategy enabled significant material and resource savings. This approach was implemented during for UF/DF step development for a conventional monoclonal antibody as well as ana Fc-Fusion protein. UF/DF runs were conducted with different excipients in the formulation buffer in order to quantify their impact on the resulting buffer concentration in the final ultrafiltration product. Integration of buffer-concentration prediction models with experimental UF/DF enabled accelerated process-development cycles and reduced the number of empirical runs and amount of material, required to identify suitable operating conditions. The combined experimental-computational strategy also yielded practical insights into the impact of Donnan equilibrium on buffer composition during UF/DF and provided guidance on mitigating its effects in rapid process-development settings.

The integrated modeling/experimental workflow presented here streamlines UFDF development for high-concentration biologics and provides a robust framework to manage Donnan-related shifts in buffer composition. This approach can reduce development resources, improve the efficiency of achieving final formulation conditions and better enable ‘right-first-time’ manufacturing.

Michael Hartmann

Merck & Co Inc

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