Genetic Engineering & Biotechnology News

SEP15 2017

Genetic Engineering & Biotechnology News (GEN) is the world's most widely read biotech publication. It provides the R&D community with critical information on the tools, technologies, and trends that drive the biotech industry.

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GENengnews.com | SEPTEMBER 15, 2017 | 17 ➜ ductivity. High equipment utilization is key to maximize productivity (g/hr or kg/yr) and lower operational costs. When running in continuous mode, equipment utilization is, by definition, 100% during that campaign. 5 Downstream, the challenges vary by scale. At clinical scale, substantial focus is directed at reducing chroma- tography resin cost because the full lifetime of the resin typically cannot be used. Resin lifetime utilization is higher at commercial scale, so the main drivers here are maximizing both facility utilization and production rate. Comparing Different Continuous Bioprocessing Manufacturing Strategies CB describes a spectrum of op- erating modes. A continuous unit operation can be defined as having a continuous flow input for prolonged periods and a minimal internal hold volume. A continuous process can be defined as one where continuous unit operations are physically connected with minimal hold volume between them. 5 Processes can be fully continu- ous end-to-end or partially continuous (called hybrid or semi-continuous). Upstream CB traditionally refers to operating the N-stage production bio- reactor running continuously in perfu- sion mode, frequently in combination with continuous harvesting. Examples of more targeted CB unit operation methods include perfusion to generate high-density cell banks, seed expan- sion, and N-1 inoculum preparation. Another is concentrated FB, in which the perfusion system concentrates the cells and/or product prior to harvest, avoiding the complexity and risks of continuous operation. Downstream CB often refers to continuous capture. For chromatog- raphy-based processes, continuous capture can be accomplished using variations of a technique called pe- riodic counter-current chromatogra- phy (PCC) or simulated moving bed (SMB). In PCC, three or more col- umns are switched between the load- ing and non-loading steps to maximize resin utilization and minimize buffer requirements. Other options leading towards downstream CB are concur- rent buffer preparation (in-line con- ditioning) and continuous tangential- flow filtration. Batch, continuous, and other manufacturing approaches come with different risk-benefit profiles (Table 2). For instance, upstream CB processes offer lower scale-up risk, reduced capi- tal cost, and improved quality of un- stable products compared with batch and FB. Potential effect on COGS is highly debated and depends on many variables. 4,6 However, these benefits come with risks, including higher cell culture medium consumption and costs, which, coupled with the lack of real time in-line quality and contami- nation sensors for feedback/feedfor- ward process control, can translate to very expensive excursions and business risk (cumulative QC risk). Other reported risks include difficult- to-process high cell density and titer streams containing high DNA and host-cell protein contaminants. 7 There is also greater burden on QbD process development, validation, and training. Similarly, downstream manufactur- ing approaches have different relative risks and benefits, which require trade- offs (Table 3). For example, continu- ous processes typically impact resin utilization and consumption favor- ably, especially in clinical production. However, impact on capital cost varies when compared with batch processes, because more complex equipment is required. Also, the increased cost of more, although smaller, prepacked columns or additional column pack- ing, will offset some of the savings in resin utilization. Implementation Challenges and Opportunities Targeted continuous unit opera- tions can be achieved with minimal risk, but end-to-end CB faces some implementation challenges. These challenges center around three themes: regulatory, expertise/complexity, CO N T I N U O U S B I O P R O C E S S I N G Table 1. Configuration 100 kg/year 500 kg/year 2000 kg/year CAPEX COGS CAPEX COGS CAPEX COGS Option 1 USP: Fed-batch DSP: Batch $26.1 million $107.0/g $43.8 million $48.4/g $146.9 million $36.2/g Option 2 USP: Perfusion DSP: Batch $17.3 million $127.4/g $29.7 million $59.9/g $101.1 million $46.7/g Option 3 USP: Fed-batch DSP: Continuous $23.6 million $97.9/g $36.2 million $46.9/g $100.8 million $32.6/g Option 4 USP: Perfusion DSP: Continuous $19.7 million $133.6/g $26.4 million $54.5/g $60.9 million $40.7/g Process Economics Modeling: Analysis of Batch, Hybrid, and Continuous Bioprocesses Three scales of a monoclonal antibody process are modeled here, representing the range typically seen in manufacturing. Modeling is based on monclonal antibody titers typical for each upstream mode (5 g/L for fed-batch, and 1.2 g/L for perfusion). Adapted table used with permission from BioPharm Services.

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