Engineering Commons^™

Toward Development Of Continuous Bioprocesses: Comparison Of Fed-Batch And Perfusion Upstream Production Processes In Early Development, Jean Mclarty, Daryl Powers, Christine Hamel, Betsy Simons, Ken Karey

Cell Culture Engineering XV

Continuous Processing is an exciting development in the field of bioprocessing. The potential for quick response to market demands, decrease in infrastructure, increased flexibility and consistent product quality has resulted in a growing interest in Continuous Processing for production of all types of protein drugs (high or low volume, stable or unstable). Sanofi is developing a novel Integrated Continuous Manufacturing platform for biologics that utilizes an upstream perfusion process. While cell culture perfusion processes offer substantial benefits for commercial biologics production, implementation may present challenges in early development, where speed to first in man studies is critical. Here we present …

Towards Integrated Continuous Viral Vaccines Production Using Two-Stage Bioreactor Systems, Felipe Tapia

Cell Culture Engineering XV

Typically, many cell culture-derived viral vaccines are being produced in batch processes. However, with increasing demands of a growing world population for potent, safe and affordable vaccines, manufacturing technologies need to be further optimized. In particular, the establishment of two-stage bioreactors appears as an interesting option for continuous production of viral vaccines. In these systems cell growth and virus propagation are being performed in separated vessels [1], which make them suitable for production of lytic viruses, such as influenza and Modified Vaccinia Ankara virus (MVA). MVA virus has received much clinical attention, because it is as a promising vector candidate …

Evolution Of An Integrated Continuous Antibody Manufacturing Process, Christopher Kistler

Cell Culture Engineering XV

Efforts continue to reduce the timeline and cost of progressing biologics from discovery through preclinical development to product launch. Integrated processes, those that link upstream and downstream processing with control of product quality are an attractive way to achieve meaningful reductions in the overall cost of ownership of a biologics manufacturing process.

To start along this path, an integrated continuous processing laboratory, the PROLab (Protein Refinery Operations Lab) was built to pilot the concepts of an integrated continuous antibody manufacturing process under automated control. A perfusion process was developed capable of operating for >30 days using either TFF (Spectrum KrosFlo® …

Overcoming Process Intensification Challenges To Deliver A Manufacturable And Competitive Integrated Continuous Biomanufacturing Platform, Jason Walther, Neha Shah, Myles Hollenbach, Jonathan Wang, Marcella Yu, Jiuyi Lu, Yang Yang, Konstantin Konstantinov, Chris Hwang

Cell Culture Engineering XV

Groups in both industry and academia have achieved high densities and productivities in perfusion cell culture processes. At Sanofi, we have demonstrated perfusion densities greater than 100 million cells/mL (with associated high productivities) at a cell-specific perfusion rate of only 20 pL/cell/day. This process intensification reduces the footprint of upstream unit operations as well as capital and operating expenses of manufacturing facilities. The continuous nature of perfusion cell culture also creates opportunities for integration of continuous downstream operations, leading to further process intensifications and volume reductions.

In this presentation, we will discuss our work on several upstream challenges that must …

Enabling Technologies For Integrated / Continuous Downstream Processing Of Biologics, Jeff Salm, Marcus Fiadeiro, Raquel Orozco, Jill Kublbeck, Aaron Noyes, Jeff Horne, Daniel Lacasse, Ashley Sacramo, Suhani Gupta, John Coffman, Robert Fahrner

Integrated Continuous Biomanufacturing II

Pfizer Bioprocessing R&D is focused on developing enabling technologies that will reduce capital and operational expenses, decrease equipment scale, increase automation and utilize fewer FTEs.

To realize this vision, Purification Process Development has piloted new technologies and operational strategies that have enabled a fully integrated downstream process. Our current work has demonstrated a continuous process that includes tangential flow filtration harvest from a perfusion bioreactor, Protein A capture, inline viral inactivation/conditioning and AEX polishing. This process was fully automated and demonstrated at the 100 L scale. We have also shown feasibility of multi-day virus reduction filter operation and a continuous …

What Are The Facility Design Requirements To Fit Biologics Pipeline Demands?, Thomas Sauer

Integrated Continuous Biomanufacturing II

Decisions to install new facilities are typically driven by pipeline or capacity demands. While extensions to existing capacity typically restrict the level of freedom to design, this is different for pipeline products. Due to numerous unknowns in the development of drug candidates in a pipeline, maintaining a large degree of flexibility in future facility design is the most widely accepted de-risking concept. Looking more closely into the development of a biologics pipeline, certain elements help to control and limit the design space while others just effectuate the opposite.

Without question the key guiding principle for these future products is to …

Continuous Production Of Viral Vaccines With A Two-Stage Bioreactor System, Felipe Tapia, Yvonee Genzel, Ingo Jordan, Volker Sandig, Udo Reichl

Integrated Continuous Biomanufacturing II

Continuous processes can be particularly efficient for production of biologicals that are required in large amounts such as viral vaccines. One virus that has received much clinical attention is Modified Vaccinia Ankara virus (MVA), which is a potential platform for expression of recombinant viral antigens and can be used as a vector in gene therapy [1]. Recently, a new MVA virus strain has been successfully propagated at high yields in non-aggregated avian suspension cells [2] allowing the production of MVA virus in continuous bioreactors. MVA is a lytic DNA virus and therefore, continuous production strategies can be implemented using two-stage …

Toward Complete Continuity In Antibody Biomanufacture: Multi-Column Continuous Chromatography For Protein A Capture And Mixed Mode Hydroxyapatite Polishing, Anthony Grabski, Tom Van Oosbree, Beth Hammer, Alla Zilberman, Robert Mierendoff

Integrated Continuous Biomanufacturing II

Monoclonal antibodies (mAbs) are a predominant modality for a broad range of clinical indications including oncology and inflammatory diseases. Increasing manufacturing capacity and decreasing cost per purification campaign are critical factors for making antibody therapies more affordable. Cell culture mAb expression levels have steadily increased over the past ten years with titers of five grams per liter frequently achieved. Higher titers reduce production costs and allow processing of kilogram quantities for clinical trials from single use cell culture vessels. Drawbacks of increased titers include higher levels of aggregates, fragments, variants, and process impurities. These combined titer and impurity burdens further …

Pilot Scale Hybrid Fed Batch And Continuous Processing Of Biologics, Dave Sullivan, Michael O'Connor, Samir Gondalia, Matt Gagnon

Integrated Continuous Biomanufacturing II

Pfizer Bioprocessing R&D is focused on developing enabling technologies that will reduce capital and operational expenses, decrease equipment scale, increase automation and utilize fewer FTEs. To realize this vision, our Pilot Facility has partnered with our cell culture process development colleagues to adapt a fed batch platform 150L stainless steel bioreactor to run in hybrid perfusion, standard perfusion, low volume cell controlled perfusion, and continuous stirred tank modes. Through adjustments to impeller configuration, sparging strategy, and addition ports the bioreactor was able to deliver multiple batches that produced ~3X gains in cell density and volumetric productivity versus conventional fed batch …