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CONTINUOUS MANUFACTURING
REVOLUTIONISING UPSTREAM BIOMANUFACTURING: Supporting the implementation of continuous perfusion cell culture
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stablishing continuous manufacturing (CM) workflows is becoming increasingly popular for intensifying manufacturing processes within the pharmaceutical industry. This is particularly true for small molecule drug manufacturing, following the successful regulatory approval of several CM processes. However, for biopharmaceutical manufacturers, implementation of CM is more complex. Because biotherapeutics are produced using living cells, manufacturing requires highly specific process conditions. This is essential to maximise productivity and, most importantly, ensure the molecules produced fulfil the critical quality attributes (CQAs) which validate their safety and efficacy. A solution to meeting these required process parameters while intensifying production is a type of bioprocessing known as perfusion cell culture. By using a cell retention device and a cell culture media exchange system, this method enables manufacturers to maintain a high cell density under constant conditions for an extended period. This can improve productivity and allow for a smaller footprint. There are a number of different perfusion processes; the most suitable for integration into upstream CM workflows is continuous perfusion. ADVANTAGES OF CONTINUOUS PERFUSION As media exchange replenishes nutrients and removes waste products, a cell bleed prevents excess cell density. This allows continuous perfusion
to maintain a steady-state bioreactor environment. This state enables high cell densities and viabilities to be preserved for long periods of time—often for around 30–90 days—and product of consistent quality to be produced. By enabling manufacturers to intensify production, continuous perfusion can provide significant productivity benefits. Additionally, by removing the product of interest throughout the manufacturing process, improvements in overall product quality can also be achieved. These advantages can reduce overall cost of goods compared to traditional batch or fed-batch processes over the lifetime of the process.
WHERE IS CONTINUOUS PERFUSION NOW? Although there is significant interest focused on implementation of continuous perfusion processes, challenges remain. One of the primary obstacles currently facing manufacturers is the lack of comprehensive regulatory guidance. Although many regulatory groups are actively supporting the transition to CM and are continuing to issue advice to support its implementation, there is not yet a full set of “default” standards to which manufacturers can refer. This uncertainty makes many manufacturers hesitant to fully commit to implementing a continuous process. Outside of regulatory
challenges, there are also limitations with existing bioprocessing equipment, as many installed fed-batch workflows are not capable of facilitating continuous perfusion. There has been significant innovation to help support manufacturers, however, that requires installing new equipment in some cases. INNOVATIONS TO SUPPORT CONTINUOUS PERFUSION Process development solutions One of the primary challenges for manufacturers looking to establish continuous perfusion processes is the limited ability of current small-scale development tools. Specifically, existing small-scale bioreactors and high-throughput solutions are often unable to support
