Abstract
Dead end filtration is a critical unit operation that is used for primary and secondary clarification during manufacturing of both microbial and mammalian cell based biotherapeutics. Dead end filtration is conventionally done in batch mode and requires filter pre-sizing using extensive scouting studies, along with filter over-sizing before deployment to handle potential variability. However, continuous manufacturing processes require consistent use of dead-end filtration over weeks or months, with potential unpredictable variations in feed stream attributes, which is a challenge currently facing the industry. In this work, a dead-end filtration skid is designed for continuous depth filtration, incorporating multiple small-sized filters along with turbidity, and pressure sensors with immediate switching to a fresh filter whenever turbidity or pressure breakthrough above a pre-determined cut-off is detected in real time. The skid has been successfully tested for manufacturing of granulocyte colony stimulating factor from Escherichia coli, human serum albumin from Pichia pastoris, and a monoclonal antibody therapeutic from CHO cells. The proposed skid can be directly applied for any dead-end filtration application with minimal prior scouting studies or sizing calculations for scale-up. It is a useful solution for continuous processing trains where the nature of the feed, such as its turbidity or host cell proteins content, may change over long continuous campaigns, rendering previous sizing calculations inaccurate. The skid also allows significant cost savings by eliminating the sizing safety factor of 1.5–2x which is generally added before filter deployment at manufacturing scale.
Highlights
The success of biologic molecules, in particular monoclonal antibodies, in treating various diseases has led to an increased demand and need for scale-up technologies (Ashton, 2001; Anicetti, 2009; Roger, 2010; Xu and Zhang, 2014)
We have demonstrated the application of the skid in various downstream steps, including harvest clarification and sterile filtration for E. coli, P. pastoris, and Chinese hamster ovary (CHO) cell expressed products
Multiple process streams from CHO cell, P. pastoris and E. coli expression platforms were used to demonstrate turbidity or pressure breakthrough of depth and/or sterile filters with appropriate pore sizes
Summary
The success of biologic molecules, in particular monoclonal antibodies (mAbs), in treating various diseases has led to an increased demand and need for scale-up technologies (Ashton, 2001; Anicetti, 2009; Roger, 2010; Xu and Zhang, 2014). Increasing demand has driven significant improvements in upstream process, with current commercial titers for mAbs as high as 10 g/L (Birch and Biologics, 2005; Kelley, 2009; Pollock et al, 2013; Tran et al, 2014; Grilo et al, 2017) compared to the older processes that would have titers of
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