High density perfused batch: Robustness and scalability of perfusion processes from lab scale to commercial scale
October 6-10, 2019
The advancement on cell retention technologies and downstream processing of the last decades has revived the opportunities for the continuous manufacture of biologics . At Novartis, the vision to make Advanced Integrated Biologics Manufacturing has matured over the past 5 years and it is ready for commercialization. The program is based on novel business strategies, operational approaches and process technologies to reduce time and cost, while increasing flexibility for the different pipeline modalities. As a result, the developed process allows producing commercial quantities in a 10-times smaller manufacturing scale. Over the past 3 years, 3 high-density perfused batch (HDPB) processes have been developed and scaled up showing scaling feasibility and technology robustness.
The HDPB concept has enabled a 1000L disposable bioreactor (reaching 3-4 fold higher cell densities with respect to fed batch) to produce the same mass, or greater, as a traditional ~10,000L bioreactor. The flexible nature of the facility enable a fast turn-around and the use of different cell retention devices (e.g. ATF, TFF). Both cell retention devices were evaluated in our HDPB continuous process at lab and manufacturing scale. The filtration technologies (ATF/TFF) were aligned at lab scale using common engineering criteria resulting in a comparable growth, productivity and product quality, while at manufacturing scale different operation strategies were evaluated in order to improve the process robustness. Overall interchangeability between ATF and TFF was demonstrated, though TFF showed significant advantage when comes to operation flexibility and simplicity.
The HDPB processes have been developed at lab scale for multiple products, including 1 NBE (new biological entity) and 2 Legacy molecules. Each of the HDPB processes demonstrated consistent process performance and product quality at manufacturing scale and on average delivered 6-10 fold more product, per liter reactor, relative a commercial fed-batch bioreactor. Additionally, a scale-down model (SDM) was successfully qualified, which enabled the start of process characterization for one of the molecules.
Novartis efforts to keep growing the technology are strong and include SDM development, screening/optimizing cell retention technologies, as well as, improving the operation of the final scale, among others. The next step in our journey to re-imagine the development and manufacturing of biologics is to bring the program to the commercial stage, which ultimately will help us to reach our patients faster and more cost effectively.
 E.S. Langer, 11th Annual report and survey of biopharmaceutical manufacturing capacity and production—a study of biotherapeutic developers and contract manufacturing organizations, Rockville, MD, 2014.
David Garcia, Ying Jing, Joerg Altekrueger, and Joseph Shultz, "High density perfused batch: Robustness and scalability of perfusion processes from lab scale to commercial scale" in "Integrated Continuous Biomanufacturing IV", Veena Warikoo, Roche, USA Alois Jungbauer, BOKU, Austria Jon Coffman, Boehringer Ingelheim, USA Jason Walther, Sanofi, USA Eds, ECI Symposium Series, (2019). https://dc.engconfintl.org/biomanufact_iv/58