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Limitations in production platforms have impeded continuous manufacturing for advanced therapies.
A paradigm change, regulatory expansion, and some positive reimbursement outcomes have led to an inevitable trade imbalance between the supply and demand sides of the advanced therapy medicinal products (ATMP) field. “Demand for these often-curative therapies far outstrips supply, with a current inability to mass produce these personalized medicines” states Farlan Veraitch, founder and chief scientific officer at Ori Biotech Ltd.
“Alternative technologies in development—including donor-derived allogeneic approaches and in vivo gene-modified cell therapies (1)—are promising in many therapeutic areas, but are likely many years away and come with their own set of challenges and, therefore, are unlikely to obviate the need for patient-derived therapies,” says Veraitch.
Limitations of current methodologies for cell therapy manufacturing have been well documented. Processes that have progressed farthest have been modular, semi-automated processes that still contain manual handling steps. “This style of process is inherently limiting,” says Peter Yates, director of Product Management–Personalized Medicine, Cell and Gene, Lonza. “These processes may work well in early clinical trials where the numbers of doses produced is relatively small and demand can be handled with a specialized manufacturing team,” continues Yates. “However, the problems become abundant when trying to increase throughput … our goal is to standardize and automate as many unit operations as possible to simplify handling and reduce operator interaction. A key aspect of this is to maintain flexibility in programming, to allow the unique manufacturing specifications to be retained. So as iterative changes need to be implemented, you have a platform that accommodate changes in a controlled way,” he emphasizes.
Looking at the challenges in learning to scale based on past success in certain biologics, Yates clearly states, “The underlying issue in scaling autologous cell therapy manufacturing has been how to do so economically. Groups feel a push to generate clinical data as quickly as possible to support additional funding rounds. This can lead to manufacturing processes based on immediate necessity versus long term scalability. Essentially kicking the can down the road on the issue.”
The editors of Pharmaceutical Technology® have heard similar descriptions from multiple industry contacts. Nicole Faust, general manager Cell Line Development at Cytiva, has excellent perspective, encapsulating this point by describing “when we think about manufacturing, initially a lot of thought was put into the design of vector, how you have to make it an efficient therapeutic. Nobody thought too much about production methods. So basically, the first products went into the clinic, and even went to market, with the production methods as they had come out of university—using adherently growing H2K 293 cells doing a plasmid triple transfection. That works perfectly fine in an academic [setting], it also works well for a limited number of patients, but then when you really go to market, of course you need reproducible technology, you need scalable technology, and that challenge had to be tackled then for the adherently growing 293 cells and the triple transfection—elegantly solved by fixed-bed bioreactors, like the iCELLis by Pall for example, but the technology still faces limitations; the scale is limited and you still have to bring in plasmid DNA for each production batch; you have to bring in transfection agents for each production batch, reproducibility of the batch is a challenge; and when you go to the more prevalent disease, that’s when it gets really challenging. So, the first improvement that the field has taken is to move from adherently growing cells to suspension cells.”
Initial efforts to automate autologous CAR-T production focused on repurposing technology that was designed for single-batch manufacturing of antibodies and other therapeutics, including those based on viruses and stem cell therapies. The equipment had large space requirements and required a skilled workforce in order to scale up.
Veraitch points to liquid handling as a major bottleneck requiring new ideas. “Approaches based on typical bioreactors require extensive networks of tubing, which introduces a high degree of complexity and risk into the process. The staff required to manage such systems is difficult to deskill, as it requires a large GMP-level team with both scientific T-cell expertise and training in the complex protocols involved with tube engineering … Tubing needs to be accessible, which means that the entire system needs to be at bench height to allow operators proper access. If scaling up means adding identical enclosed automated systems, expansion is then effectively restricted to scaling out (in only two dimensions), as stacking would be impractical. Tubing, then, roughly correlates to a massively inefficient use of space. These two factors explain why such approaches have so far failed to significantly bring down the cost of goods: they don’t reduce the demand for skilled labor, and they fail to reduce the amount of GMP space required to make a CAR-T dose, even when using first generation automation,”
Himanshu Gadgil, CEO, Enzene Biosciences Ltd, agrees, commenting that “new filtration technologies that are resistant to choking” is of the highest priority. He goes on to add that “PAT [process analytical technology] needs to come to allow real-time process control,” along with “integrated at-line analytical methods for real time CQA monitoring… [inclusive of] inline bio burden and endotoxin control and Bioreactor design for high density cell cultures.”
Reem Eldabagh senior Upstream Processing Scientist at Merck, concludes this thought saying, “With the advances in automated technology, autosamplers have brought about a much-needed decrease in time-consuming manual labor increasing workflow efficiency and sampling frequency and enabling conclusions based on data-rich analyses. These automated technologies, however, are not free from challenges, a prominent one being their integration and seamless communication with reactors and analyzers and their own pre-existing software.”
Process intensification advances have recently been significant and, in some cases, surprisingly impressive (including higher yields per cell, and more full versus empty capsids), but replicating the same efficiencies of monoclonal antibodies, for example, remains an aspirational dream. Veraitch avers that, “Large-batch approaches that have worked for antibodies or small molecules will never be viable for autologous cell therapies, and even allogeneic approaches would operate at much smaller scales. As each patient-derived therapy dose will continue to require individual, sequential processing, the goal must be to intensify an automated workflow—shrinking the manufacturing footprint, increasing throughput, increasing quality, and dramatically lowering costs. To do so, the process steps should take place in an enclosed system that can multi-plex, without a high reliance on overly complex, tube-based liquid handling. As a result, the remaining manual steps would become deskilled, freeing PhD-level GMP manufacturing specialists for high-value tasks more suited to their training … But automation and flexibility are often at odds with each other. This delicate balance between automation and flexibility is a challenge that we continue to tackle and have support packages that cater to both.”
For his part, Yates is buoyed by recent successes, saying, “We are continuing to invest in onboard in-line analytics and see this heavily requested from the field. There is a need for robust analytical tools during process development that can provide real-time feedback. However, there still exists an integration and technological gap that allows these assays to be run inline and autonomously, especially with assays measuring functional capabilities and not just phenotype or viability. This need is further exacerbated as we inch closer to decentralized and point of care manufacturing as QC [quality control] will be central to its success. Moreover, automation and simplification of assays will be critical for their use in non-centralized
Digitization will be key for the more efficient logistical movement of products throughout production. The centralized manufacturing approaches that work for small molecule production have become extremely problematic for cell therapies.
Veraitch points to the future saying, “The cell therapy manufacturing space is approaching a critical juncture—with enough data to clearly understand why existing approaches are insufficient, but before they become too entrenched to dampen the field’s long-term potential. The goal remains to make the highest-quality therapies accessible to the most patients, which can only be done by reinventing both the physical and digital footprint of cell and gene therapy manufacturing.”
Challener, C.A. Technology for In Vivo CAR T-cell Therapy Advances, BioPharm International 2023 36 (2).
Chris Spivey is editorial director for Pharmaceutical Technology.
Vol. 47, No. 4
When referring to this article, please cite it as C. Spivey. Small Footprint Automated Closed Production Platforms for CAR-T and Other Advanced Therapies. Pharmaceutical Technology 2023 47 (4).