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Both upstream and downstream processes can benefit from continuous manufacturing advantages.
Continuous manufacturing, regardless of the application, can result in more consistent processes and products. Advantages include reduced energy, water, raw material consumption, waste generation, product losses, and downtime, in addition to lower capital and operating expenses. For the pharmaceutical industry, additional benefits include reduced human intervention. The biopharmaceutical industry is taking steps towards the realization of integrated, continuous manufacturing of biologic drugs with two changes. First, perfusion has moved from concentrations of 10–15 million cells/ml a decade ago to a now well-established upstream process at concentrations of 50-80 million cells/ml. Second, simulated moving-bed chromatography is in the adoption phase for downstream separation and purification. Some of the challenges include the large existing batch-based infrastructure, the traditional separation of upstream and downstream operations, and the need to develop new technologies for downstream processing steps.
Integrating upstream and downstream
“At Genzyme, we envision an integrated system in which media enters the system at the front end and purified drug substance comes out the other,” states Timothy Johnson, associate director of commercial cell culture development at Genzyme. “It will take numerous steps to get there,” he adds, “but we are moving one unit operation at a time towards continuous biopharmaceutical production, and there are no issues that are so technologically complex that we won’t be able to develop appropriate solutions.”
The biggest notable achievements, according to John Bonham-Carter, vice-president of business development with Refine Technology, come from CMO companies such as Gallus and Rentschler and from end users such as Genzyme, who have shown that continuous processing is possible today using existing equipment in a reliable setting. “It is the integration of different technologies that is novel, rather than any new technology itself,” he notes.
Peter Tiainen, a senior scientist with Novo Nordisk’s Biopharm Research Unit, adds that the work done at companies like GE Healthcare, Genzyme, and Novo Nordisk has helped demonstrate that continuous processing is not overly complex. “We have shown that going from batch to continuous is achievable and manufacturable. The technologies are available today; what is required is a fresh approach (and some guts) to switch to continuous processing.”
Hurdles do exist
In small-molecule manufacturing, the switch to continuous processing is hindered in part by the vast batch-based infrastructure (and associated skill/knowledge base) in the biopharmaceutical industry that is cost efficient and familiar. “Many companies have invested significant time and money in batch processes, and are thus understandably unwilling to make major investments in new techniques,” notes Tiainen. In addition to the need to convince the decision-makers at biopharmaceutical manufacturers of the advantages and cost savings, it is also necessary to overcome user “fears” about unknown processes, particularly linking upstream and downstream operations, according to Stéphanie Dubois, cell culture lab manager and application specialist with Pall Life Sciences.
With respect to technology on the upstream side, Genzyme has come to appreciate the crucial importance of media formulations and has invested in finding optimal solutions, according to Johnson. The perception of increased process complexity is another issue, but as the number of companies exploring continuous processing increases and wider application of this knowledge occurs, this issue is gradually diminishing, according to Bonham-Carter. Tiainen adds, however, that there is not enough down-scaled and laboratory-sized equipment to enable wider exploration of continuous processing, particularly with respect to downstream processes.
Once the needed technology is developed on the downstream side, the issue of integration of upstream and downstream operations for fully continuous production lines will need to be addressed, which will involve managing the impacts that changes in one process step have on other steps down the line, according to Bonham-Carter. Tianen agrees that the interdependency of unit operations is currently a potential issue for product quality.
This particular hurdle leads to another key challenge–overcoming the divide between upstream and downstream groups within biopharmaceutical companies. “Implementation of integrated continuous manufacturing projects requires collaboration between groups. There is definitely much more communication internally at Genzyme than previously existed, and the traditional boundaries of the organization are beginning to subside,” Johnson comments. He also notes that two-way collaboration with supplier of materials, equipment, sensors, and automation and control systems is necessary for achieving effective solutions for continuous processing.
— Cynthia A. Challener, PhD, is a contributing editor for Pharmaceutical Technology and BioPharm International. Further discussion on this topic will appear in Pharmaceutical Technology’s May 2014 Bioprocessing & Sterile Manufacturing e-book.