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Feature Articles: March 15, 2017 (Vol. 37, No. 6)

Continuous Bioprocessing Skips a Beat

Bioprocessing Needs a Tuneup If It Is to Run Smoothly and At Full Power

  • Continuous bioprocessing may be defined the same way it is often implemented—in stages. The stage-by-stage approach to a full definition was demonstrated at the 2014 International Symposium on Continuous Manufacturing of Pharmaceuticals, where a landmark paper was delivered by Charles L. Cooney, Ph.D., and Konstantin B. Konstantinov, Ph.D. These presenters began by describing unit operations, and they worked their way up to a fully integrated, final system:

    “A unit operation is continuous if it is capable of processing a continuous flow input for prolonged periods of time. A continuous unit operation has minimal internal hold volume. The output can be continuous or discretized in small packets produced in a cyclic manner.

    Dr. Cooney, a professor of chemical engineering at MIT, and Dr. Konstantinov, then a vice president of late-stage process development at Genzyme, proceeded to build on this idea. “A process is continuous if it is composed of integrated (physically connected) continuous unit operations with zero or minimal hold volume in between. To emphasize that all the unit operations are continuous and integrated, such processes are also referred to as fully continuous or end-to-end continuous.”

    The presenters not only also distinguished between continuity in upstream and downstream operations, they also described hybrid operations: “A process is hybrid if it is composed of both batch and continuous unit operations.”

    The previous year, at the bioProcessUK conference in London, Dr. Konstantinov (who later became senior vice president of manufacturing and process sciences at Codiak Biosciences) addressed a plenary session. Dr. Konstantinov’s lecture was summarized in a paper, “Continuous Bioprocessing: The Real Thing This Time?” that was later published in the journal Mabs.

    In his talk, Dr. Konstantinov suggested that despite its initial fits and starts, continuous bioprocessing was poised to take bioprocessing by storm, as it had in many low-technology process industries. Yet at the 2016 bioProcessUK meeting, there were just two talks on continuous bioprocessing, one an award lecture.

    While progress in the continuous manufacture of small-molecule drugs continues (albeit slowly), the FDA has issued a smattering of decrees and guidances, but not much in the way of direction on continuously manufactured biotherapeutics.

  • Treading Water Upstream

    GEN has extensively covered innovations and adaptations of perfusion cell culture. The systems are simple in concept: As Dr. Cooney has noted, all that is required is a cell-retention system that allows product to leave while keeping cells in place. Leading bioprocess vendors offer some variations on this theme:

    • Pall’s iCELLis single-use, fixed-bed, bioreactors use microcarriers to immobilize continuously perfused cells.
    • GE Healthcare’s Wave bioreactors are adaptable to batch and perfusion culture.
    • 3D Biotek’s 3D Insert, a small-scale cell-culture system, is based on constantly perfused porous 3D-polymer scaffolds.

    Then there’s Repligen’s XCell ATF, a cell-retention device suitable for perfusion cultures. By continuously removing waste products from the fermentor, the alternating tangential flow filtration (ATF) system achieves cell densities to two or three times higher than those reached in conventional batch fermentation. All things being equal, higher cell density equals higher volumetric yield, which improves facility utilization and reduces the size of the bioreactor required to manufacture a given volume of biologic drug product.

    With the recent (October 2016) introduction of a single-use version, the XCell ATF is now available in both stainless-steel (reusable stainless housing, replaceable filter) and single-use (single-use housing/filter combination) configurations.

    “The availability of XCell ATF in a single-use format eliminates the pre-use workflow associated with autoclaving, leading to an 80% reduction in implementation time,” says Christine Gebski, Repligen’s vice president for product management and applications.

  • Hand in Hand

    The potential advantages of continuous bioprocessing sound as if they were lifted from a marketing sheet for single-use equipment: reductions in facility size, utility requirements, and capital expenditure for equipment and maintenance of capital equipment.

    “As ancillary equipment associated with preparation and cleaning of reusable (as opposed to single-use) equipment becomes vestigial, facility size can be reduced, and the equipment and utilities required for support can be minimized,” Gebski adds. “Process areas can even be modularized and made more portable.”

    Imagine, then, how a continuous, single-use, modularized process could be described. “The equipment required to support a given unit operation can reside in a given module, and the module becomes self-sufficient,” Gebski suggests. “For example, if you reduce the complexity of your home and use standard equipment, a prefab house can be built at point A and fabricated/installed at point B in short order. Single-use equipment enables this same concept for bioprocessing.”

  • Monitoring Complexity

    The complexity of continuous processing demands a level of sensing, monitoring, and control unknown in batch operations. Real-time release in continuous biomanufacturing demands real-time online quality monitoring—a higher order of process analytics—to assure that data captured at one point can be aligned with the end result.

    Drawing on its experience in nonpharmaceutical process industries, Siemens offers the Simatic PCS 7 system, which controls and monitors both continuous and batch processes. Simatic PCS 7 is scalable, covering basic control functions in a laboratory environment up to advanced process control at manufacturing scale. The package provides virtual commissioning and process simulation while monitoring plant performance.

    Siemens also offers Sipat, which is a process analytic technology (PAT)-oriented software solution for quality monitoring.

    Combined, Sipat and Simatic PCS 7 provide control and oversight for continuous bioprocessing, explains Pamela Docherty, life sciences industry manager, Siemens Industry US. “Continuous operation of purification systems can, for instance, be achieved by cascading various chromatography, filtration, and purification skids, each with its dedicated control platform. PCS 7 orchestrates the functionality of these individual units to behave like a production line.”

    Sipat incorporates drivers for most third-party spectral analyzers, including near-infrared process sensors (from Mettler, Bruker, and Thermo Fisher Scientific), Raman sensors (from Kaiser), and high-performance liquid chromatography detectors.

    Siemens has been updating and expanding its control software drivers since getting involved with continuous manufacturing of solid dosage forms in 2008. Its expertise in continuous biologics goes back only about five years.

    Scale up is as challenging with process controls as it is with cell culture, chromatography, and other unit operations. Here, the issue is not mass or heat transfer, feed volumes, or dilution, but rather the shortcomings of standard laboratory practice. Software control is not often used at benchscale. Operators instead take measurements and turn knobs manually, developing the process with specialty or one-off tools, without anticipating the eventual transition to commercial manufacturing scale.

    The complications that may arise from manual control constitute another argument for scalability. To avoid these outcomes, try implementing automated control at the earliest stages of process development. “Even in a laboratory-scale continuous process,” notes Docherty, “an unmanageable amount of manual interactions would be needed in case of a disturbance.”