MANUFACTURING Downstream Technology Landscape for Large - Scale Therapeutic Cell Processing

T he cell therapy industry (CTI) is poised to grow rapidly over the next decade, treating millions of patients and generating annual revenues into the tens of billions of US dollars (1, 2). To meet that high-growth demand, large CTI system manufacturers (e.g., Corning, Nunc/Nalgene, and GE Healthcare) and leading contract manufacturing organizations (CMOs, such as Lonza) are developing and integrating new upstream technology platforms such as gas-permeable membranes and microcarrier-based bioreactors to significantly increase therapeutic cell culture productivity. As those upstream technologies mature, following the path that protein therapeutics took decades ago, cell yields are expected to increase to hundreds of billions to trillions of cells per lot (3). Increasing the number of cells per lot raises harvest volumes from current tens of liters to more than 100 L in one to five years (a conservative estimate) and up to 1,000 L over the following 10 years. Such largequantity cell harvests will need to be concentrated, washed, formulated for cryopreservation, filled into final containers, frozen, and stored. Those downstream processing (DSP) steps are the most critical unit operations in biotherapeutic manufacturing, for which product typically is at high concentration. Therefore, a small variation can have significant impact on product quality and/or recovery. Currently in the CTI, however, little attention is being assigned to scalable DSP technologies. In the mid-1990s, when production titers of monoclonal antibodies (MAbs) were as low as ~100 mg/L, DSP groups were pressed to achieve significant recoveries with minimal loss of product and thus keep manufacturing costs to a minimum (4). Bioreactor MAb expression has increased to more than 10 g/L, and DSP groups are strained, requiring dilution of harvested medium just to process such high-titer yields. Similarly, as lot-size requirements of therapeutic cells increase to address escalating market needs, DSP will experience similar bottlenecks unless the industry strategically plans and develops new, scalable technologies (5). The CTI has an opportunity to learn from protein processing and anticipate DSP bottlenecks by proactively developing technologies to address future scales. CTI companies are in a unique position to take their industry to the next level of scalable manufacturing by using functionally closed, single-use technologies that can process hundreds of liters of cell suspension in a single batch. Here, we propose some CTI downstream technology requirements. Additionally, we examine traditional technologies used in blood processing and compare them to newly developed, scalable downstream bioprocessing technologies in terms of efficiency, scalability, degree of automation, cost, and applicability to large-scale volume reduction and washing of therapeutic cells.