Peter Levison (senior director, Pall Life Sciences ) BPI Theater @ INTERPHEX April 26, 2016, 1:40–2:00 pm

Pall’s advancements in integrated continuous bioprocessing include new product launches. The company has built a continuous laboratory at its facility in Westborough, MA. It is 6 m × 6 m and can produce >2 g of pure monoclonal antibody (MAb) per hour. One continuous process flows through one step to the next, from cell culture to formulation.

Continuous manufacturing is being used successfully in other industries; however, it is not yet used much in the biopharmaceutical industry. Regulatory authorities are now actively supporting continuous biomanufacturing. Unit operations are well established. Levison says, “A continuous process is evolutionary, not revolutionary.”

One advantage to continuous processing is making a lean, efficient system that eliminates much waste from batch processing (e.g., defects, overproduction, used talent, motion, transportation, waiting, inventory, and extra processing). Other advantages include greater manufacturing flexibility with reduced processing time, operating costs, footprint, and capital outlay.

Pall’s vision is to be the “leading provider of integrated platform technologies for continuous manufacturing of biologics.” The company envisions its platform as robust across multiple molecules at multiple scales, able to complete process development in four weeks, producing high overall yields, and meeting or exceeding the current purity requirements for batch processes.

Upstream: The Cadence Acoustic Separator PD unit is a new product that performs cell clarification by acoustic wave separation (AWS). A transducer produces a low, three-dimensional, standing acoustic wave that crosses the flow channel and reflects back to create nodes. Cells enter the flow channel, get trapped in acoustic nodes, and clump together. As the clumps grow bigger, gravitational forces overcome drag forces, so the clumps drop out as sedimentation. This continuous process is effectively a “filterless filter.” Testing has shown minimal temperature rise with no impact on protein quality.

A benefit the system offers is an ability to use a smaller depth-filtration area after AWS than with traditional methods. One Cadence Acoustic Separator PD unit can process 3–4 L/hr and clarify a 20-L bioreactor within a working day. Next year, Pall will launch a system that can process 250–500 L per hour of cell culture from a 2,000-L bioreactor. Early testing is already demonstrating system scalability. Pall also plans to launch a benchtop acoustic-wave system for perfusion cell culture by April 2017. The expectations the company has set are that it must operate for 90 straight days, remain sterile, retain cells, be fully disposable, and maintain cell culture performance and product quality throughout the run.

Downstream: Pall also has been introducing chromatography equipment with the aim of making it continuous. The BioSMB technology platform (acquired from Tarpon Biosystems in 2015) is a system for continuous chromatography. Each single-use cassette can handle up to 16 column/capsule positions with a simple flow path.

Although tangential-flow filtration (TFF) typically involves recirculation, Pall’s makes a single pass flowing through an inline concentrator. Cadence ILC Single-Pass TFF systems can be used to improve the efficiency of a capture-chromatography binding step when placed ahead of it. A traditional batch process produces 10 g/hr; the BioSMB system alone can produce 45 g/hr. Adding the ILC increases productivity to 67 g/hr. Product quality remains the same with that seven-fold productivity increase. Using the benchtop system, users could produce the quality and amount of antibody they need for clinical testing rapidly and economically.

Downstream of a large-scale (2,000-L) bioreactor, typical processes use about 100 L of protein A resin during chromatography. By operating in multicolumn mode, companies can use just a few liters instead for a significant economic advantage. Pall is expanding its systems to work with 2,000-L bioreactors in good manufacturing practice (GMP) manufacturing. Those systems will be available commercially later this year.

Bioprocessors can implement Cadence Acoustic Separator, Cadence ILC, and Cadence BioSMB systems today. In production are BioSMBProcess GMP, AWS Benchtop for Perfusion, and AWS full-scale GMP systems. Next, Pall will focus on in-process monitoring and control, automation, and additional enabling technologies for continuous processing such as viral inactivation, virus filtration, and in-line diafiltration. All these systems will be designed to be responsive to regulatory and validation requirements.

“How is the evolution going?” Levison concluded. “Single-use technologies came in 10 years ago, and now single-use facilities are being constructed. Single-use technology allows you to intensify processes such as with the concentrator. New operations can be integrated together, and finally, you can move on to a fully continuous process.”

Listen to the full presentation at www.bioprocessintl.com/Interphex2016