Many therapeutic proteins are stored frozen at bulk drug substance stage to improve stability and shelf life prior to drug product conversion. Although frozen storage can simplify manufacturing logistics such as transportation and inventory, physical and chemical stresses present during bulk freezing and thawing often require stringent control of process steps and conditions. The stresses incurred may include cryoconcentration, cold denaturation, liquid-ice interface, pH shifts, and crystallization of excipients. Many of which are affected by the freezing and thawing process conditions. Therefore, characterization of freeze-thaw sensitivity for desired applications should be performed to understand any impact. However, performing such studies at manufacturing-scale is costly; they require large quantities of drug substance and are logistically cumbersome. Here we examine a freeze-thaw scale-down model that has been developed to mimic manufacturing-scale freeze-thaw processes. Characterization shows that the model is capable of inducing cryoconcentration and controlling the duration of liquid-ice interfacial stresses that are consistent with manufacturing-scale. Studies using the model have successfully predicted the sensitivity of a drug substance to various manufacturing-scale technologies such as blast freezing, room temperature thawing, and active plate freeze-thaw. Further, the model has demonstrated effectiveness across multiple modalities such as Fc fusion proteins and fully human monoclonal antibodies.

Freezing and thawing scale-down model to characterize the sensitivity of biologics bulk drug substance to freeze-thaw processing

ACS Fall 2020 Virtual Meeting

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