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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14 | SEPTEMBER 15, 2017 | that are already "clearly interested" in fully continuous biomanufacturing lines include Genzyme, Merck, Bayer, and Sanofi, among others. Also doing work in this space: Novo Nordisk, Novartis, Amgen, Shire, Pfizer, WuXi, and BiosanaPharma. In addition, some contract manufacturing organiza- tions (CMOs) are in the continuous biomanufacturing field (such as CMC Biologics), and these organizations are poised to help biopharma clients lower the cost to clinic by way of fully con- tinuous manufacturing strategies. Regardless of who is or is not inves- tigating continuous, "What is definitely a right development trend is that ven- dors do support the change and offer technologies that enable continuous operations," says Dr. Lacki of Avitide, a company that makes affinity resins. "At the end of the day, it will be up to the end user to decide how a process needs to be operated, but the choice will be made on a thorough assessment of commercially available technologies." GEN: What types of biologic medications are the best/most feasible candidates for integrated continuous manufacture? Dr. Najera: Any product with an expensive chromatography resin is a suitable candidate for continuous chromatog- raphy, especially for early-phase clini- cal products, where resin cost can be cost prohibitive. Continuous capture is also attractive for high-titer process- es, since several small volumes can be used instead of a single large column. In fact, facility fit limitations are com- mon for high-titer processes (>5 g/L), and continuous chromatography can help manufacturers avoid the capital costs associated with procurement of large stainless-steel columns (>80 cm diameter) and associated equipment. Finally, the concept of integrated continuous manufacture, (i.e., a fully continuous process), would be best suited for a well-established late-phase process with a stable market de- mand where cost-savings are realized through basic efficiencies related to batch versus continuous processing. Dr. Zydney: This is a difficult question to an- swer—it very much depends upon one's perspective. In some ways, the 'best' candidates for integrated con- tinuous manufacturing are products for which there are particular chal- lenges in using batch operations. For example, a highly labile product that degrades over time would benefit dra- matically from the use of a continuous process—this is why perfusion biore- actors were originally used for produc- tion of unstable clotting factors. On the other hand, integrated continu- ous manufacturing is well suited for products that have very high-volume demand or significant cost constraints. The successful development of inte- grated manufacturing systems will likely require considerable product and process knowledge, which today is most readily available for mAb products due to the large number of these products already in commercial manufacture. Dr. Lacki: I would rather ask a different ques- tion: What type of expression systems or upstream technologies are more suited for continuous operation? And my answer would be perfusion op- eration or even [use of] six-pack fed- batch bioreactors would make an op- eration quasi-continuous. That said, I think that a successful continuous bio- manufacturing process must be as sim- ple, or rather, as robust, as possible. For instance, a downstream process that relies on as few chromatography steps as possible will be more suited for continuous operations. From that perspective, one could argue that an affinity step is an enabler for continu- ous downstream operation. Cost of an affinity resin will be lower if it is operated in a continuous manner, but even without that, the benefit of normalizing a product stream through a selective capture step would deliver so many advantages from the process reproducibility and controllability per- spective that the cost of the resin need not even be considered. Mr. Zijlstra: I would say [the most feasible type of therapies would be] primarily labile products that require perfusion and immediate capture from the cell broth to prevent product degradation. Some cost-model studies also suggest that beyond certain annual production scales, integrated continuous bioman- ufacturing leads to lower COGs for mAbs and are preferable in that case. Finally, evidence is mounting that even for mAbs, (critical) product quality at- tributes can be controlled much more tightly [in continuous than] in batch operational mode. GEN: The manufacturers of Prezista (Janssen), a small- molecule drug, got FDA approval to change its processes to a continuous method. To your knowledge, are any biologics manufacturers looking into a similar manufacturing change? Do you think manufacturers are more likely to address the end- to-end manufacture of a totally new product, rather than for an existing product? Dr. Najera: While it is easy to understand why people draw parallels between small molecules and large molecules, it is im- portant to note that control of small vs. large molecules is significantly different. For small molecules, it is relatively easy to understand all impurities and vari- ants through analytical testing. This is not always possible for large molecules. For this reason, continuous processing Integrated Continuous Manufacturing of Biologics: Trends in the Field Continued from page 12 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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