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The modernization of advanced therapy manufacturing.
June 2, 2021
By: Dr. Karoline
Advancements in the field of advanced therapy redeem the promise of curative treatments for severe and life-threatening diseases. Meanwhile, ten gene and cell therapy products have been launched to the US market1 and more than 1100 advanced therapies are in the pipeline. Moreover, their application is expanding from rare and ultra-rare diseases to more common indications with larger patient population. Consequently, there will be an increasing demand for larger amounts of advanced therapy products. Manufacturing processes must undergo modernization to be fit for this purpose, overcoming the limitations of current production methods such as restricted scalability, low yield of viral vectors, and time-consuming and cost-intensive material sourcing. Cost-efficient process intensification is becoming even more crucial as viral vector-manufacturing capacity is estimated to be just 5-10% of the capacity need in the next ten years.2 In addition, payers´ unacceptance of the high prices for these boutique therapies sets commercialization at risk. Most recently, Bluebird bio withdrew its gene therapy for a rare blood disorder from the German market after failing to reach an agreement with health authorities there on the treatment’s price.3 Continuous bioprocessing has already introduced robust and efficient manufacturing of biopharmaceuticals. Continuous bioprocessing holds some promising elements for intensification of manufacturing of advanced therapies although there is no one solution for all advanced therapies due to their complexity and diversity: Ex vivo therapies require transfection and cell expansion, while in vivo treatments only require vector manufacture. Small-scale production is sufficient for autologous cell therapies, while large-scale production is required for allogeneic cell therapies. The choice of viral or non-viral delivery and the type of vector has a direct impact on the upstream and downstream manufacturing process. However, an intelligent integration of continuous bioprocessing aspects will streamline advanced therapy manufacturing. On the upstream side, vector yield is key as higher titer results in a smaller, more cost-effective production process. Current low yield by transient transfection requires optimization of producer cell environment. Cell line designs for suspension cell cultures are needed. Closed bioreactor technologies enable the transfer from adherent to scalable suspension cell culture for which working volume can run from only 2 mL up to 2000 L and thus, R&D scale can match manufacturing scales. Employment of stable producer cell lines is another approach. Stable integration of the required viral vector components and the therapeutic gene of interest into suspension cell lines produces highly functional vectors avoiding expensive transfection reagents and cGMP-grade plasmids. On the downstream side, better solutions are needed for viral vector recovery and purification technologies. Vector production generally generates significant quantities of contaminates, including host cell DNA and protein, empty and partially filled capsids all of which significantly increase the purification burden. Typically, purification operations occur in isolation from each other as a lengthy cost-intensive process. Intensification mechanisms increase throughput by connected or continuous operations, such as integration of multiple purification steps (continuous chromatography), thereby reducing the number of unique steps required in the overall process. Continuous processing minimizes the risk of contaminants introduction alleviating adventitious contaminate process controls. Automation of upstream and downstream processes by integration of digital technologies further transforms the field. Real-time data acquisition and analysis regulate the manufacturing processes through immediate feedback adjustments. This synergy will modernize the manufacturing of advanced therapies and ultimately, provide access to sufficient and affordable advanced therapies. Advancement of innovative manufacturing processes for advanced therapies are widely supported by the regulators although specific guidance is still pending. Advanced therapies are unique and demand for unique approaches by manufacturers and regulators. References 1. US FDA (Jan. 15, 2019). Statement from FDA commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research on new policies to advance development of safe and effective cell and gene therapies Accessed Sept. 9, 2020: Retrieved from US FDA (Jan. 15, 2019). Statement from FDA commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research on new policies to advance development of safe and effective cell and gene therapies Accessed Apr. 23, 2021: Retrieved from https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-peter-marks-md-phd-director-center-biologics. 2. van der Loo, J. C. & Wright, J. F. Progress and challenges in viral vector manufacturing. Human molecular genetics 25, R42-52 (2016). 3. Pagliarulo,N, Bluebird to withdraw gene therapy from Germany after dispute over price. BIOPHARMADIVE (Apr. 20, 2021): Accessed Apr. 23 2021: Retrieved from: https://www.biopharmadive.com/news/bluebird-withdraw-zynteglo-germany-price/598689/?utm_source=Sailthru&utm_medium=email&utm_campaign=Issue:%202021-04-20%20BioPharma%20Dive%20%5Bissue:33706%5D&utm_term=BioPharma%20Dive
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