Sterile filtration is one of the critical steps in the downstream purification process, providing high levels of bioburden reduction and aggregate / particle removal. The application of sterile filtration for the production of glycoconjugate vaccines can be quite challenging due to significant membrane fouling; however, detailed studies of the fouling phenomena have been limited to small-scale sterile filters with very uniform flow. The overall objective of this study was to examine the scale-up of the sterile filtration step using a single serotype of glycoconjugate drug substance, with a specific focus on the underlying fouling behavior. Experimental data were obtained at constant filtrate flux using 0.22 µm Durapore® polyvinylidene difluoride (PVDF) membranes in both small discs and in the Opticap® XL2 pleated cartridges. Additional insights into the fouling behavior were obtained using confocal microscopy by in situ labeling of the glycoconjugate captured within the filter media using an Alexa Fluor fluorescent dye. Glycoconjugate deposition occurred only near within the first 5-15 µm of the 0.22 µm Durapore® membranes at both scales, although the confocal images showed higher variability in the pleated cartridge, both within the pleat geometry and across the scale of the Opticap® XL2 filter. The initial transmembrane pressure increase was much more rapid in the pleated cartridge, which was likely related to non-uniformities in the flow and pressure distribution in the Opticap® XL2. These results provide important insights into the underlying fouling behavior during sterile filtration of glycoconjugate vaccines as well as a framework for the scale-up of the sterile filter step in biomanufacturing.

Scale-up issues during sterile filtration of glycoconjugate vaccines

ACS Spring 2022

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