Normal flow filtration (NFF) is ubiquitous throughout the purification process for biopharmaceuticals. Common applications of NFF within the downstream platform include removal of cell and cell debris, of precipitated particulates, of microbial contaminants, or of virus and virus-like particles.  In NFF the pressure-driven feed stream flows perpendicular to the membrane, where process- and product-related impurities are retained primarily due to size exclusion while allowing the product to pass through unretained.  While NFF is relatively straight forward to introduce into a batch process, implementation within an integrated processing environment is not immediately obvious due to the semi-continuous nature of the operation. This work explores the use of a duty/standby strategy to operationalize and allow NFF unit operations to fit within the integrated semi-continuous downstream processing framework. Using this approach, failure modes and thus links between quality attributes and process parameters must be reconsidered to develop robust control strategies that are informed by process analytical technologies (PAT). Processes for each NFF unit operation are defined based on small scale characterization of the system, as well as by the requirements and limitations of the manufacturing environment, such as overall process run time, desired filter change out rate, and capability of available PAT and automation systems.  A comprehensive analysis of a proposed duty/standby-based strategy for normal flow filtration within an integrated continuous process, relative to traditional batch processing, will be discussed, highlighting the benefits, efficiency, and level of robustness that can be achieved with this approach.<br/>

Integration of normal flow filtration into downstream continuous bioprocessing

ACS Fall 2020 Virtual Meeting

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