Buffer and excipient composition of a drug substance are, in regulatory submissions, registered details. As a part of late phase product development work packages, the formulation robustness is typically supported by stability studies looking at the effect of buffer and excipient concentrations. Excluded volume and Gibbs-Donnan effects have long been known to cause an off-set in the formulation of protein solutions when utilizing UFDF. These phenomena can result in a deviation from the target concentration when using diafiltration buffer at final formulation concentrations. The recent emphasis on the development of buffer and excipient methods has shown that those off-sets on the concentration of formulation components can be significant especially for formulation at high protein concentrations. In a few extreme cases, the concentration of formulation components can potentially be outside the range characterized by supporting stability studies. Here the principles behind excluded volume and Gibbs-Donnan effects are reviewed focusing on the process parameters that affect their magnitude. Different experimental approaches to reach the target composition during UFDF are presented. Both cases of platform (mAb) and non-platform (recombinant) protein molecules are covered. The results are then presented in the perspective of Quality by Design for the development of a control strategy for a late phase asset.

Development of a robust control strategy to reach target excipient concentrations during drug substance buffer exchange by UFDF

ACS Spring Meeting 2021

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