Continuous biomanufacturing was a central topic at the fourth annual World Biological Forum in Oxford, UK, on 26–28 June 2017. A well-rounded lineup of presenters appeared at this forum held in Oxford University’s Lady Margaret Hall, an eclectic location that well captured the historic charm of the university. Delegates were well supported throughout the meeting with generous meals, refreshments, and assistance provided by helpful staff.
Papers were presented in Talbot Hall in the center of the college. The stately main hall building provided such lovely acoustics that no public-address system was required throughout the event. Subi (Ganapathy Subramanian) is an indefatigable organizer and an early believer in the potential of continuous processing as applied to biotechnology. Beyond this, he is a sincere believer in the value of attendees to enjoy robust discourse around the papers presented. He therefore thoughtfully designed activities in delightful gardens and libraries to provide an opportunity for such.
The program’s formal kick-off was a comprehensive review of the values and requirements of technologies contributing to the concept of continuous biomanufacturing. Parrish Galliher (founder and chief technology officer of Xcellerex, part of GE Healthcare) well described the benefits and costs of establishing such processes. He left us with the higher question involving the practical goals and investments required in a move toward this mode of biomanufacturing.
The overall agenda covered major topics within continuous biomanufacturing, including practicality, risks and benefits, gaps and industry adoption considerations, targeted and end-to-end applications, automation and feedback control, raw material consumption, economics, regulatory, and new technologies.
Presentation Highlights
The meeting continued with university professors and students, biopharmaceutical sponsors, equipment suppliers, entity sponsors, and contract manufacturers providing papers on a broad spectrum of topics. One recurring theme was the shift of biomanufacturing from purely exploratory research to scale-up and implementation. Another was the weighing of specific benefits enabled by continuous approaches against relative costs in their establishment and operation. A few speakers noted interesting synergies among many emerging technologies and continuous operations. For example, we observed that systems such as perfusion culture upstream and multicolumn chromatography downstream adapt well to single-use implementations. We also noted that technologies supporting intensified batch processing shift seamlessly to continuous implementations. Attendees convinced of the value of continuous biomanufacturing generally agreed that implementation of a single-unit operation in continuous mode (regardless of its extent) could provide some value independently of a future vision of an enterprise design with integrated, continuous process-flow and tighter product quality control. Throughout the three-day event, delegates enjoyed a balanced agenda of processing theory, case studies, and cost/benefit modeling. Discussions of a wide range of pharmaceutical products also contributed to the agenda’s diversity — not only monoclonal antibodies, but also products such as exosomes and vaccines. A comprehensive strategy presented by Yang-Ping Yang (senior director and head of bioprocess R&D at Sanofi Pasteur) involved Sanofi’s transcontinental initiative covering continuous processes for vaccine manufacturing. The syllabus included papers illuminating the newest thoughts on process development and design, sampling, monitoring, process modeling and control, and regulatory and quality aspects. Academicians, biomanufacturers, and material suppliers all provided their perspectives on those disciplines.
We saw portrayals of upstream process theory and case studies of technologies such as as hollow-fiber–based perfusion and plug-flow culture. Other presentations focused on a number of downstream approaches to continuous manufacturing — from countercurrent and simulated moving-bed chromatographies to even true moving-bed approaches. One topic that seems to be developing more rapidly is the emerging technologies of advanced process control and process analytics for robust (long-term) operation of intensified and continuous processes — including in-line process analytical technology (PAT) sensors and sampling for at-line measurements.
One enlightening presentation from Chase Duclos Orsello (global head of marketing at Merck) included customer interviews on drivers and adoption rates for “next-generation” and continuous bioprocessing and incorporated users’ perspectives. Most respondents consider reducing cost of goods sold (CoGS) and increasing flexibility to be the key drivers toward adoption of “next-generation” processes. And most respondents are already exploring some aspects of continuous bioprocessing in expectation of scaling up such processes in the 2020–2025 time frame.
Participants heard that adoption of a fully continuous process will be an evolution driven by regulators, continued technology developments, and increased industry experience. Throughout the forum, interesting discussions arose on the distinctions between continuous, quasicontinuous, cyclic steady state, and “clever batch” approaches.
Priyanka Gupta from Sartorius Stedim Biotech presented a case study with a small biosimilar company demonstrating that cost of production and time to market are two important factors for both gaining market share and supporting low drug costs. In this context, having continuous manufacturing within a smaller footprint is a desirable option. One important factor driving the need for intensified/continuous manufacturing is that large-scale manufacturing facilities require a significant upfront investment. Data here showed that choosing to work with a contract manufacturing organization (CMO) could increase drug costs. Thus a small suite in which all unit operations are connected (eliminating hold steps) with smaller equipment addresses major manufacturing concerns. Such approaches are producing about 10 kg/month of drug, with lower investment costs. Established multiproduct facilities are a possible, with different suites dedicated to different drugs.
The case study demonstrated that cell density volumetric productivity is higher in continuous mode than in standard operations, with a tenfold increase in product titer/liter. That and other gains can result in a net monthly productivity from a standard 5,000-L bioreactor equal to that obtained from a 500-L (or even smaller) bioreactor in continuous mode. Conducting process modeling for such a scenario can provide powerful insights into drug production costs by batch and continuous processes.
Morten Munk (senior technology partner at NNE) spoke on the potential effect of continuous manufacturing on facility design. The presentation involved four different scenarios and the impact on future biofacility design.
Panel Discussion
In addition to individual presentations, a panel led by Miriam Monge (global director of process development and bioprocess platform marketing at Sartorius Stedim Biotech) discussed roadblocks to continuous biomanufacturing implementation and how to remove them. Some of the more contentious or debatable themes that emerged as part of this panel included the definition, distinction, and value of “intensified” process technologies in the context of continuous manufacturing, the need and limitations of process and component standardization, and the different definitions of productivity in terms of product mass accumulation, process time, facility demand, infrastructure cost, and so on. Related questions include how to monitor, measure, and consider the values of such attributes in terms of ease of technology transfer and changes in process or product “flexibility.”
With the support of such incidental factors as lovely weather and generally high-quality food provided by the staff at Lady Margaret Hall, this year’s WBF meeting concluded on a high note of intellectual satisfaction, collegial interplay, and physical comfort. We thank Subi and the participants of the forum for providing such an exciting and comprehensive program.
Editorial advisor William Whitford is strategic solutions leader at GE Healthcare Life Sciences, 925 West 1800 South, Logan, UT 84321; 1-435-757-1022; [email protected]. Editorial advisor Miriam Monge is the global director of process development and bioprocess platform marketing at Sartorius Stedim Biotech, Z.I. des Paluds-Avenue de Jouques, CS91051, F-13781 Aubagne, France; 49-551-3082529; [email protected]. Gerben Zijlstra is platform marketing manager intensified/continuous bioprocessing at Sartorius Stedim. Chase Duclos-Orsello is global head of marketing at Millipore Sigma. Parrish Galliher is founder and chief technology officer at Xcellerex (part of GE Healtchare). Priyanka Gupta is global senior bioprocess modeling consultant at Sartorius Stedim, Morten Munk is senior technology partner at NNE pharmaplan, and Yan-Ping Yang is senior director and head of bioprocess R&D at Sanofi Pasteur.
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