Presented by Gerben Zijlstra
The need to develop protein-based therapeutics in shorter timelines while controlling development costs and delivering biologics to stringent quality and regulatory requirements is driving the biopharmaceutical industry to adopt more flexible biomanufacturing facilities. These facilities can accommodate large, midscale and small-scale production of not just monoclonal antibody (MAb) therapies, but also different types of therapeutic proteins (some of which are less stable). To further adjust production capacity to meet market demand and reduce cost of goods (CoG), the trend in such facilities is increasingly toward the use of disposable bioreactors and operating bioprocessing in fed-batch and (more recently) perfusion modes to produce higher titers and more potent products.
In this presentation, I described why many biopharmaceutical companies are assessing adoption of continuous biomanufacturing strategies, including the benefits and challenges of implementing them. Continuous biomanufacturing using perfusion cell culture can deliver about five times greater volumetric productivity than running fed-batch processes, and it provides an opportunity for dramatically reducing the footprint of manufacturing facilities. That is because the process requires smaller bioreactors and chromatography columns and eliminates some holding-tank operations. Operational costs are reduced by increasing chromatography resin use and decreasing the buffer volumes required. That also can result in faster scale-up by using small standard equipment modules to rapidly construct and commission unit operations during scale-up and validation. Some evidence has shown that using continuous biomanufacturing improves product quality because reducing the amount of residence time a biological is in a bioreactor results in fewer glycosylation changes. Eliminating intermediate hold steps also reduces the risk of product degradation. Additionally, maintaining cells at a high cell density and viability leads to fewer contaminants. So the number of purification and clarification steps required is reduced.
However, continuous upstream bioprocessing is challenging and requires stable cell lines with high productivity over two to three months and media that can support >50 × 106 cells/mL while perfusing only one bioreactor volume per day. The bioreactor systems for culturing those cells also must have automated cell density control, efficient gas transfer, and the ability to control foam formation by sparging. In the downstream phase, industrial-scale, GMP-grade continuous chromatography systems and continuous viral inactivation/removal (e.g, by filtration) are required. There is multicolumn technology available using time- or UV-based switching logic, but more data must be made available on it before adoption. And there is a need for good automation to balance and control all volumetric flows across the entire continuous biomanufacturing process.
Two types of continuous biomanufacturing models are in use currently. The hybrid model uses fedbatch cell culture with continuous downstream purification, clarification, and polishing. Cost modeling of such a process suggests that it is an attractive scenario for MAb manufacturing. The full-continuous biomanufacturing model, which links perfusion culture with continuous downstream processing, results in the most significant time savings due to parallel operation and thus the highest facility use and volumetic productivity rates. This model is being tested in proof-of-concept studies by Bayer Technology Services (Leverkusen, Germany), Merck (Kenilworth, NJ, USA), Sanofi-Genzyme (Framingham, MA, USA), and BioSanaPharma (Leiden, Netherlands).
I showed examples of 200-L and 500-L BIOSTAT® STR scale single-use bioreactors used by Patheon that have been used with XD® cell culture for perfusion runs to achieve viable cell densities of 130 × 106 cells/mL and >200 × 106 cells/mL, without oxygen or other limitations observed. I discussed the use of different types of harvest using filtrate or cell bleed for downstream processing and equipment such as a single-use centrifugation system (kSep® systems) and RHOBUST® expanded-bed adsorption technology that can be used with high cell densities. I also showed an example of a BioSMB® system (Pall) for continuous downstream chromatography to purify high–cell-density culture, which achieved 67 g/L/h compared with 12 g/L/h gram antibody per liter protein A per hour specific productivity from a regular batch chromatography step. As with column chromatography, solutions are required for harvest collection, virus inactivation, concentration, and diafiltration, all of which must be connected to an integral automation system.
In conclusion, continuous biomanufacturing promises to help deliver small footprint, flexible facilities, and lower CoG for the production of biopharmaceuticals. Although the technologies are available, they are not yet fully mature, and early adopters are leading the way to make them mainstream.