The Cost of Cleaning
Another strategy for reducing costs that was discussed at the conference was single-use technology both for production and purification of biologics. To show the level of process improvement that can be achieved with single-use technology, Nigel Depledge, Ph.D., staff scientist at Fujifilm Diosynth Biotechnologies, showed an example of a time-in-plant study comparing single-use Sartobind® membrane adsorbers, prepacked chromatography columns and ion exchange columns, which have to be packed, equilibrated, and cleaned. To purify 150–200 L of process material, using the column plus packing and cleaning took 64 hours; the prepacked column took 22 hours and the membrane adsorber three hours. Depledge states: “Single-use technology can decrease plant time for production by up to 95 percent and as a result significantly decreases operating costs.”
To increase biologics production, combining single-use technologies and changing from batch to using continuous processing was mooted as a good strategy of achieving even greater production capacity. According to Konstantin Konstantinov, Ph.D., vice president of late-stage development at Genzyme, Janet Woodcock, the director of the Center for Drug Evaluation and Research (CDER) at the FDA has said the still-existing technology concepts of the 1950s will be abandoned in the next 25 years and bioprocesses will be converted for cleaner, efficient, continuous manufacturing. This encourages companies to consider converting their batch stainless steel plants to more advanced continuous biomanufacturing plants.
For upstream processing, Dr. Konstantinov suggests that perfusion culture can replace batch culture and requires PAT sensors to monitor cell density and automated pumps to be activated to add feed to maintain it at a steady state. He presented data on perfusion culture for biomanufacturing to show that cells need to be maintained at 50–120 million/mL, which operationally means increasing cell density from those traditionally used in batch mode and using a low perfusion rate of 1–2 media volumes per day.
Dr. Konstantinov says: “With continuous perfusion culture you operate at steady state, which reduces product quality heterogeneity as the cells are not under the same stress as they would be when cultured in batch. This means more consistent quality and yield of our monoclonal and nonmonoclonal antibody-based therapies.”
For downstream processing, Konstantinov suggests that continuous processing requires working with multiple smaller columns at a higher binding capacity in lieu of one large industrial-scale column. He presented data to show that using a modified ÄKTA™ system from GE Healthcare operated according to the three-column periodic counter current chromatography (3C PCC) principle linked to a second PCC system involving a membrane adsorber resulted in processing time as fast as 22 hours from media to purified product. According to Dr. Konstantinov this purification normally takes days and the set up is faster because there is not any hold or cleaning steps involved. Using continuous processing instead of batch purification, the use of harvest and clarification tanks is eliminated and the use of buffers and resins are reduced, which in turn reduces costs.
Dr. Konstantinov concludes: “The FDA feedback we have had is that there is no new regulatory constraints to implement this continuous processing concept and currently we are running this at pilot scale in single-use systems. The small volume of the equipment provides the ability to rapidly increase or decrease manufacturing capability as we can number up the upstream and downstream components as and when we need to. However, one issue we have found is, for this process to become truly industrialized, there has to be one software that controls all the systems; currently each part of the process has its own control and this is where a good industrial academic collaboration could help to develop and an overarching control program.”