At the conclusion of monoclonal antibody (mAb) purification to generate bulk drug substance (BDS), a tangential flow filtration (TFF) unit operation is performed to concentrate the mAb and exchange the buffer into the final formulation. Traditionally, this approach uses a diafiltration buffer with the same composition (excipients & pH) as the desired final formulation. It has previously been observed that excipient concentrations in the BDS can shift from the diafiltration buffer due to bulk electrostatic interactions (excipient/ion-mAb) and protein volume exclusion. New advances in analytical assays have facilitated the measurement of most excipients. Moving forward, measurable deviations in excipient concentrations can be accounted for to ensure formulation development materials are more precisely controlled.<br/>In this case study, we present an approach for optimizing the TFF diafiltration buffer to reach the desired excipient concentrations in the final BDS formulation. Many factors including, but not limited to, mAb concentration, mAb pI, excipients, diafiltration buffer ionic strength, number of diavolumes and diafiltration buffer pH influenced the final excipient concentrations and pH of the BDS. Detailed work packages supported development of predictive models for modifying the diafiltration buffer. The models were experimentally validated at lab scale and the robustness of the approach was computationally analyzed with respect to process data collected at large scale. The outcome of these studies was an optimized approach that facilitated the development of a modified diafiltration buffer for excipient control in monoclonal antibody BDS. This approach alleviates the concerns for possible excipient deviations in formulation development studies.

Excipient & pH targeting in bulk drug substance: A modified approach to buffer exchange during diafiltration

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.