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www.biopharminternational.com Emerging Therapies 2022 eBook BioPharm International ® 19 results in developers managing numerous external relationships. This might represent a small inconve- nience for large therapeutic developers, but for small start-ups, it can be a significant hurdle to hire nu- merous project managers and other subject matter experts to choose and manage external vendors. Fur- ther, because program development is many times iterative, delays occur at various points which put developers in a challenging position to realign time- lines across multiple external vendors. As a result, therapeutic developers are increasingly searching for a cell and gene therapy portfolio that can support them throughout program development. Evolving traditional manufacturing models The biggest hurdle to cell and gene therapies realizing their full potential is efficient clinical and commercial manufacturing. Therapeutic developers need practi- cal solutions so these potentially curative therapies can reach the patients that need them most. There are also business considerations; if stable, robust, cost-efficient manufacturing processes cannot be es- tablished, progress of therapeutics development for rare and ultra-rare disorders with small patient pop- ulations, where patient need is highest and little to no other therapeutic options exist, may be limited. Whether therapeutic developers are manufactur- ing viral vector gene therapies such as AAV or cell therapies like tumor-infiltrating lymphocytes (TILs), CAR-T or T-cell receptor (TCR-T), they are becoming increasingly sav v y in exploring closed, automated (and potentially scalable) manufacturing platforms. Amongst the field, most agree additional automa- tion is needed to reduce manufacturing costs, but the key question is when to implement manufactur- ing automation. As part of their early-phase clinical activities, specifically Phase I, therapeutic devel- opers are required to dose multiple patient cohorts with increasing doses of their experimental therapy. Focusing on cell therapy, dose-escalation studies often cover a wide dose range, typically low tens of millions to billions of cells. It is difficult to utilize a single closed, automated manufacturing platform ef f iciently that can accommodate all dose levels. Early-phase clinical activities also serve as a value inf lection point for many therapeutic developers in cell and gene therapy; until they see positive safety as well as potential efficacy signals, therapeutic de- velopers are hesitant to invest in closed, automated manufacturing platforms. Aside from decisions about manufacturing plat- forms, therapeutic developers also develop robust and consistent analytical suites for product release. Analytical development and qualification for cell and gene therapy products can be challenging, especially- the product-specific identity and potency (function- ality) assays. These assays are particularly challeng- ing in cell therapies where unmodified cells are used as the drug product and are truly personalized, such as autologous tumor-infiltration lymphocyte (TILs) or autologous neo-antigen T-cell receptor (TCR) ther- apies. The regulatory agencies have been clear that a significant (positive) clinical result is not enough to gain commercial approval and analytical develop- ment should start as early as possible to prevent any regulatory filing delays. As the industry continues to see development of next-generation cell and gene therapies, there is a need to reimagine how these therapies are manu- factured. Today, traditional centralized manufactur- ing models are employed for manufacturing other biologics such as monoclonal antibodies (MAbs) and antibody-drug conjugates (ADCs) candidates. In cell and gene therapy, this model may prove sufficient for plasmid, viral vector, and allogeneic cell therapy manufacturing, but autologous cell therapies may require a different approach. While centralized manufacturing is the current manufacturing model for autologous cell therapies, it's impor tant to remember the current commer- cial therapies are addressing small patient popula- tions (several thousand per year). This is likely to cha nge as add it iona l t herapies a re approved for larger patient populations, like patients with solid tumors or type-1 diabetes. Because autologous cell therapies require cells from a specific patient to be shipped to a manufacturing site where cells are good manufacturing practice (GMP)-processed into t he dr ug product and t hen shipped back to the patient, the logistics are complex. Generally, all cell and gene therapy products require ultra-cold chain logistics (below -150 °C) for shipment and storage. What's unique about autologous cell therapies is the number of logistics interactions that As the industry continues to see development of next- generation cell and gene therapies, there is a need to reimagine how these therapies are manufactured. Manufacturing