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 | 15 and process analytical testing (PAT) are often linked. Even with the challenges large molecules pose, there are many companies presenting compelling small- scale data on continuous purification strategies. However, these processes are inherently more complex and are per- ceived to pose higher risk. To the ques- tion, it is unlikely that an existing com- mercial manufacturing process would shift to a continuous process unless there was an extremely compelling cost benefit in doing so. The benefits would have to offset the cost of process de- velopment, establishing a new process at-scale, process validation, and poten- tially, new clinical studies. Additionally, significant facility modifications would likely be needed to convert a fed-batch facility to a continuous facility. For this reason, it is more likely that a fully con- tinuous process would be developed for a new product. Dr. Lacki: A change of a legacy process to a continuous version will only happen if a second- [or] third-generation of a process is being considered anyway. However, change of the infrastructure might prove financially prohibitive. A different story is if a company is building a new facility for the legacy product or for a brand-new API; in that case, continuous operation will definitely be evaluated as the capital investment associated with a continu- ous plant, at least from the equipment- side perspective [and] should be much lower compared with batch-based manufacturing. Dr. Zydney: I am not aware of any biomanu- facturer that is currently looking to replace an existing batch process with an end-to-end continuous process. I think it is more likely that a fully con- tinuous process will be first developed for a new product that is particularly well-suited to continuous manufac- turing, or potentially for a biosimilar where the cost reduction would be particularly attractive. Dr. Morbidelli: It is now demonstrated that con- tinuous processes provide higher qual- ity and more homogeneous products, which are beneficial for the patient. This justifies the strong support that FDA always provided to the develop- ment of these new manufacturing technologies. In addition, these can also lower the production costs in the broad sense, which will obviously impact the growing market of bio- similars. This is why all major pharma companies are looking carefully at developments [in continuous manufac- turing], although I do not know which approach they will select to implement this important transition. Mr. Bonham-Carter: No biopharma would consider changing an existing commercial man- ufacturing process, in my view. Some might consider changes between Phase II and Phase III, for reasons of capital risk, uncertain market demand, tighter quality requirements, or manufactur- ing network management. GEN: What are the financial implications of a truly continuous biomanufacturing line? Mr. Bonham-Carter: Estimates range up to >80% cheaper in capital costs, but perhaps only 20–60% in cost of goods. Most models are relatively simple and do not take account of a company's portfolio of drugs, risks of failure at different phases, quality requirements for different drugs, and existing manu- facturing and engineering skill—each of which will impact true cost to the manufacturer. Dr. Morbidelli: It depends which parts of the pro- cess are exchanged to become fully continuous, and those which would benefit from intrinsic step process im- provements. A conventional fed-batch process can be nicely coupled to contin- uous downstream purification with one of several steps performing continuous batch (flip-flop) or countercurrent pro- cesses (capture and polish). If combined with membranes and single-use con- cepts, we expect a significant produc- tivity increase having an implication on both CAPEX and OPEX. We estimate that besides the improvement in prod- uct quality, both CAPEX and OPEX could be lowered by 50%. Mr. Zijlstra: Continuous and single produc- tion plants will be able to lower costs several fold and produce the same amount of product as current standard stainless-steel facilities. This facilitates greenfield investment deci- sions and reduces investment risks considerably. Dr. Lacki: A standard argument is that equipment for a continuous line will be smaller. At the same time, truly continuous operations run 24/7, which means that even the down- stream operation might need to be run in shifts, increasing labor cost. Undoubtedly, continuous operation will be more control-heavy. Cost of controllers, equipment maintenance, contingency plans—all of it needs to be considered when evaluating continuous processes. That said, advances in detection technologies and modularization of standard pro- cessing technologies (e.g., prepacked columns, flow paths, and even in- troduction of humanoid robots) will bring us closer toward continuous processing. To read more from these experts in an extended version of this article, please visit our website: www.genengnews.com. CO N T I N U O U S B I O P R O C E S S I N G

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