Is CGT ready for prime time?

It has been widely discussed that, despite examples of ‘billion-dollar’ CGT products like Zolgensma and Yescarta, significant growth of the CGT industry will hinge on successful commercial delivery.

While challenges with commercial rollouts have been attributed to clinical site readiness, reimbursement coverage and accessibility, CGT drugs to date have predominantly targeted relatively small patient populations, effectively sidestepping a critical question: Are CGT manufacturing capabilities ready to support the equivalent of a traditional ‘blockbuster’ drug?

Analysis via quantitative modeling 

In a recent analysis, Dark Horse Consulting (DHC) utilized our proprietary quantitative modeling platform, Pegasi, to explore whether, in its current state, the field could supply a CGT drug at a blockbuster scale.

We developed quantitative models to estimate manufacturing capacity requirements as production targets grow from current CGT clinical and commercial levels to typical annual targets of large-market biologics. The analysis considered two ‘prototype’ products: an autologous CAR-T and an off-the-shelf AAV with systemic administration. For each of these products we established a representative process, analytical testing, equipment and workforce required to complete production.

The analysis indicates that, in the current state, a successful commercial launch of a blockbuster CGT drug would be challenged by the lack of available unfragmented manufacturing capacity as well as by the availability of an appropriately skilled workforce.

How can these facility and labor resource needs be met? To answer this question, we referred to the production capabilities as they appear in our proprietary CDMO database of over 220 sites capable of producing CGT products. We compared this to the needs of the theoretical blockbuster prototypes. This makes it clear that, especially for an autologous CAR-T product, the facility capacity cannot come exclusively from the current CDMOs. Even a combination of 104 known facilities still fall over 2 million square feet short of the manufacturing requirements.

The AAV prototype example fares better at first glance, with seemingly sufficient manufacturing capacity available in theory. However, considering that the median facility size for the 118 vector CDMOs within our database is 55,000 square feet, this would require manufacturing to be heavily fragmented across over a dozen sites/providers. This strategy could be more challenging to utilize at scale in a real-life scenario, but companies engaging in (admittedly less widespread) decentralized manufacturing strategies have shown that the difficulties of managing multiple sites and site-to-site comparability can be overcome.

In contrast, therapeutic developers could build out manufacturing capacity internally. This has, to date, been the more common route taken by CGT companies achieving commercial approval. A build vs. buy decision is one we assist clients with regularly; using our Pegasi model, we can quantify hurdles to this approach, such as the large capital investment required. The total installed cost (construction, equipment and indirect costs) for a 1 million-square-foot-facility for the example blockbuster AAV product is estimated to be approximately $1 billion while the cost for the more than 8 million-square-foot facility for a blockbuster CAR-T could be more than $9 billion.   

Technology and manufacturing advances

Introducing technological advances — such as process automation utilizing end-to-end manufacturing technologies — can meaningfully alleviate these challenges. Another method could be process intensification to achieve higher throughput within a given footprint, plausible either through an increase in typical batch yields or via a paradigm shift from autologous to allogeneic product. Higher throughputs can also be achieved by reducing the process duration, a common approach for CAR-T developers. 

Unsurprisingly, methods to reduce facility cost and capacity needs also reduce workforce requirements. Process automation moves workforce needs away from operator-intensive, manual manipulations toward a ‘set it and forget it’ operational strategy where operators would only be required to initiate and terminate the batch production.

Ultimately, a combination of technology and manufacturing advances will be required for CGT products to compete with the volume achieved by traditional biologics. Developing a strategy that faces these challenges head-on requires forethought and planning informed by the intricacies and nuance of CGT-specific manufacturing and operational methods.