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Genetic Engineering & Biotechnology News | GENengnews.com | OCTOBER 1, 2016 | 37 with faster processing times than chroma- tography resins in stainless steel columns. Modern resins offer adequate selectivity only at slower flow rates due to slow mass transfer kinetics stemming from long and re- stricted diffusional flow pathways. Moreover, unlike single-use-per-batch membranes, chromatography resins and col- umn hardware are expensive, labor-intensive, large in size and cannot be conveniently ad- justed to different production scales. These resin columns need to be amortized over many batches to be cost-effective and are of- ten underutilized. For the affinity chromatography capture step, a new Protein A hydrogel-based mem- brane, which is currently in development at Natrix, would be applied in the presented process. Lab studies with prototype Protein A membrane materials have demonstrated 45 g/L binding capacity with 6 seconds residence time with 95% yield (data not shown). As a hypothetical example, a 1 L Protein A membrane column would be rapidly cy- cled over 100 times to match the upstream mAb production rate in Figure 1 and enable completing the entire downstream process in approximately 24 hours. The Protein A membrane capture step could be followed by Natrix' hydrogel-based HD-Sb (cation exchange, CEX, and perhaps optional depending on aggregation) and HD-Q (anion exchange, AEX) chromatogra- phy membrane operations (Figure 2). These compact ion exchange (IEX) membrane op- tions are high-capacity polishing tools that would fit well in small footprint facilities. In the concept presented, a less than 1 L HD-Sb membrane column used in bind-and- elute mode for less than 100 cycles in approx- imately 3 hours would be sufficient to pro- cess the Protein A membrane eluate, and the HD-Q column would be used to process the HD-Sb purified stream in a single 30-minute flow-through due to a high loading capacity. Increase Productivity in Smaller Footprint Manufacturers can increase overall pro- ductivity and decrease the footprint associated with storage bags in this process by "stag- gering" downstream unit operations. For in- stance, earlier eluates of the capture step could be processed through the cation exchange pol- ishing step while latter cycles continue. The productivity of the entire process could be further increased by replacing one or more of the single-use fed-batch reactors with a single-use high-density perfusion bioreac- tor, and running the entire process in a quasi- continuous mode using multicolumn configu- rations. The fast processing features of the single-use purification technologies discussed above would allow the downstream purifica- tion process to run continuously. The conceptual process in Figures 1–2 would be capable of manufacturing up to 800 kg of mAb per year by coupling 6 to 7 single-use fed-batch bioreactors to one high- productivity downstream train. This manu- facturing output can be readily and economi- cally increased by adding single-use fed-batch reactor trains and coupling them with more downstream purification trains. With the exception of matching the run rates of the bioreactor operations to match the increased output, no other changes would be required. Manufacturing processes designed with these modern technologies are very flex- ible and can easily be adapted and scaled to changes in product demands. Unlike with traditional facilities where scale-up or scale-down is unfeasible due to the upfront cost of capital equipment, these high- productivity and disposable technologies en- able flexible manufacturing without wasting capacity, incurring less capital expense, and minimizing operational expense. These flex- ible, single-use technologies are also appropri- ately sized to be operated in relatively smaller manufacturing facilities. Finally, since exactly the same scale process trains could be used for both clinical and com- mercial manufacturing, a streamlined regula- tory filing would be possible, bringing addi- tional benefits including faster approval times and much reduced associated costs. Pick your platform Make your mark. Cells are complex. Turn complexity into c Cells are complex. Turn complexity into clarity by choosing the ideal cell analysis platform for your experimen cell analysis platform for your experimental design. You'll quickly get meaningful results from our cytometry p meaningful results from our cytometry platforms that combine simplified sample preparation with powerful data a sample preparation with powerful data analysis. Select from the intuitive guava easyCyte™ flow cytometer, the com guava easyCyte™ flow cytometer, the compact Muse® personal cell analyzer, and the enabling Amnis® imagi analyzer, and the enabling Amnis® imaging flow cytometers. Be the competition others are worried about—m competition others are worried about—make your mark. Pick your platform www.emdmillipore.com/cellanalysis Cell analysis solutions that help your research stand out. EMD Millipore, Amnis, Muse and the M logo are registered trademarks and guava easyCyte is a trademark of Merck KGaA, Darmstadt, Germany. BS-GEN-15-11125 02/15 ©2015 EMD Millipore Corporation, Billerica, MA USA. All rights reserved. EMD Millipore is a division of Merck KGaA, EMD Millipore is a division of Merck KGaA, Darmstadt, Germany Darmstadt, EMD Millipore is a division of Merck KGaA, Darmstadt, Germany Germany EMD Millipore is a division of Merck KGaA, Darmstadt, Germany BIOPROCESSING Tutorial Karan S. Sukhija (sukhija@natrixseparations. com) is product manager, Renaud Jacque mart, Ph.D., is director, vaccines process sciences, and James G. Stout, Ph.D., is vice president, process sciences at Natrix Separa tions. Website: www.natrixseparations.com. A more detailed discussion with support ing data can be found in Jacquemart, R. et al (2016). A Single use Strategy to Enable Manufacturing of Affordable Biologics. Computational and Structural Biotechnol ogy Journal, 14, 309 318.