In 2018, FDA CBER received more than 150 INDs for gene therapy products, bringing the total number of active INDs up to nearly 800 applications. There are 250 clinical trials worldwide studying CAR T-cell therapies ongoing. As the FDA continues to approve more drugs in this space, cell technologies – from B cell, to T cell and CAR’S (Chimeric Antigen Receptor’s) – create a unique set of challenges of supply chain logistics. The first step of the manufacturing process is to draw the cell from the patient, and then send them to a site where they are genetically modified at a workstation, before they are sent back for patient infusion. Due to the continued success of cell therapies, there has been increased pressure on bioprocessing and manufacturing facilities to deliver scalable, safe and efficacious therapies to larger patient populations due to upstream complexity and variability.
First, the cells must be cryo preserved, and this time interval is imperative, since each patient is critically ill. Every hour of the GCP manufacturing process is integral. As the CAR-T and cell gene therapy market evolve, the manufacturing platforms that revolve around chain of custody, chain of identity, and chain of condition – tracking of human cells – are also evolving at a rapid rate due to the increase in IRB applications, and scalable demand for more cell therapies in expansive therapeutic domains. As opposed to traditional MaB (or Monoclonal antibodies) manufacturing which require safety stocks of drugs – should there be a drug shortfall or supply issue along the way (and even flexible batch start times, if required) – cell gene therapies have introduced new challenges to manufacturing that did not exist previously. Some of these challenges are the following: integrating highly complex IT systems, such s Syncade and Delta V (MES/DCS), tracking individualized shipments and keeping logs of a product’s temperature, are only a handful of some of the considerations that CGT companies are facing daily.
In this new paradigm, patients are themselves batches, batches are finite time slots, and processes are the product. Because autologous cell therapies are personalized products with a batch size of one, CAR-T manufacturing requirements, at least in the beginning, are highly labor intensive and manualized, whereas traditional supply chain logistics is more automated. However, as the facilities scale up, manufacturing transitions from open and manual, to closed and automated. Even more important, the bottlenecks around manufacturing are highly individualized, and in the cell gene space, they are around staffing, labor requirements, and anticipating time slots between patient apheresis and reinfusion. For example, the turnaround time from apheresis to reinfusion, is approximately 2 weeks. Scheduling these critically ill patients is now a critical part of the treatment process, with optimized real-time finite scheduling software platforms looking more like an airline terminal algorithmically assessing both patient time slots and the labor requirements per training level, equipment utilization, shift schedules (i.e. task duration), and capacity ramp up, needed to treat each patient in real-time to prevent bottlenecks from happening early on. Some of this software use predictive analysis, discrete event simulation, and sensitivity analysis.
Perhaps even more interesting, from a regulatory point of view, the FDA CBER is looking to industry to explain some of these key manufacturing challenges and emerging technologies, as companies scale up to meet patient demand, and CBER requires companies to validate their patient capacity along the way.
The advent of these new real-time software applications brings new demands on Project Managers at CRO’s as they adjust to the manufacturing throughout the process. For example, the role of the CRA is paramount as a critical point of contact since the CRA has exposure to the front lines of cell therapy due to the dozens of hand-off points throughout the process.