Advanced Therapies Aren’t One-Size-Fits-All, Neither Are Their Manufacturing Needs

To set the scene, since 2015, we've seen breakthroughs in hematological cancers and rare diseases, but we're still not reaching many patients. Oribiotech’s patient access tracker monitors the number of therapies delivered to patients. Even after these breakthroughs, only ~50,000 people have received cell therapies, which is not a massive number given the potential.

The new wave, which aims to achieve broader patient access, focuses on solid tumors, regenerative medicine, and in vivo cell engineering. There is much more diversity in therapy types, but as advanced therapy becomes more mainstream, there is greater scrutiny from regulators, and patients begin to expect lower costs.

But what are the complexities associated with this?

The diversity and novelty mean you need many experienced people to manufacture this next generation of therapies. But the ability to scale still isn’t necessarily there. For example, if you've got a process that only a handful of people in your lab can make, it isn’t particularly scalable. I also wouldn't say it’s going to be a cheap therapy to manufacture in the long term, either.

“The growing niche is scientifically exciting, but it’s not necessarily easy to execute.” — Dr. Stuart Lowe.

To explain this, I’d use the example of tumor-infiltrating lymphocytes (TILs). In this case, the immune cells are taken from a patient's tissue sample, which is quite different from isolating them from a blood sample. This is where the complexity happens; getting that tissue sample is a more manual process. Instead of working with suspended cells, you are separating them from tissue.

In TIL therapy, a section of the tumor is removed, and TILs are extracted, expanded, and reinfused with the aim of overwhelming the cancer. Extracting immune cells from solid tumors presents several challenges: surgical intervention is required to obtain a tumor section, the section must be handled delicately, and tumor tissue is highly diverse both between tissue types and individual patients, making standardization difficult.

If your secret sauce relies on a few highly skilled technicians in your lab, that's not a scalable process, and it's probably not a great commercial proposition. On the other hand, if you have a process that is easily transferable to robotic automation, then you're onto a winner. The difficulty is that the availability of automated equipment for many of the tasks required by next-generation therapies is limited.

“In terms of broader, common challenges, I would highlight that process developers and manufacturing teams tend to operate in different worlds.” — Dr. Stuart Lowe.

Typically, process development asks a handful of key questions: Do we have a therapy with the desired effect? Can it be taken into clinical trials? Is it suitable for commercial-scale production? It is always assumed that you'll be able to find a process or a piece of equipment that will help you move to the next step.

But what if they have reached the limitations of an existing piece of equipment, or a piece of equipment doesn’t exist? At this point, process developers can face challenges with tech transfer to their manufacturing teams, and vice versa. This happens time and time again. Here, they might spend a lot of time, money, and effort trying to work around that.

Bespoke approaches can de-silo the two elements [of process development and automation]. We bring process development and automation engineers together at the design stage, so bottlenecks are foreseen and overcome. We might already know, for example, that it won’t be possible to buy a piece of equipment that will solve the tissue-fragmentation step. In this scenario, we speak to the process development team before the bottleneck.

In one example, a client had several months before they needed to manufacture material at scale. We assessed their process, from obtaining samples from the hospital to fragmenting the tumor, liberating the cells, and so on. This workflow required a grade B cleanroom environment, biosafety cabinets, and a dedicated operator to perform the manual work. This was quite a vulnerable process; if you've got 10 tumor samples coming in a day, that's 10 clean rooms, and 10 people. The costs can spiral out of control.

We homed in on that step. If you can operate in a much lower-grade cleanroom, you can run many things in parallel in a single room, which saves on facility costs. If you can have someone load the material, walk away, and return for the product, that reduces labor costs. The equation for scalability and commercial viability starts to work.

Doing this modeling makes it less of a cliff-edge. Instead of “I've got this far, and I need to find a solution before I can jump to the next stage,” we help process developers and automation developers collaborate so therapies can seamlessly move to the next stage when they need scale.

In this case, the performance of the manual and automated processes was comparable, and variability was reduced.

Obviously, patient access is most valuable, but the development process is critical to achieve this. Therapies need to be developed within a reasonable timeframe so that investors are satisfied, profits are made, and the company can continue to manufacture therapies for patients.

“Ultimately, commercial viability, or balance, is using the resources you have available to you and hitting milestones within the timescale you say you will.” — Dr. Stuart Lowe.

Overall, the development time and costs are lower. It is front-loaded to some extent, but ultimately, the process is more future-proof. If you're going to invest that much time and money into something, do it securely.

There’s been a period of innovation in CGT, with different cell types under consideration. A key question is whether you make these therapies in a centralized facility or at the hospital site.

That’s another area where we could improve patient access, if we think more creatively about where we make therapies. Normal rules are slightly off the table, and advanced therapies are pushing the boundaries of people's preconceptions about the pharmaceutical industry and its interactions with patients. The University of Birmingham is currently running virtual reality training for NHS staff to manufacture CGT.

“It could almost be like a drive-through, a franchise within the hospital. ‘I’d like two cell therapies today, please.’” — Dr. Stuart Lowe.

There will be opportunities for creative solutions we haven't even thought of yet, in vivo therapy is a case in point. A lot of people would have thought that lentivirus was always going to be a reagent that you buy for manufacturing—now, lentiviruses are treated as drug products. There’s a lot of potential for different niches to evolve and grow substantially, which changes what bespoke developers need to do as well.

We’re currently in a very scientifically fruitful field; there are just waves of innovation. At the same time, the future is uncertain. Regulations might change, for example, in-line monitoring requirements. If your equipment doesn't have any integrated sensors, what are you going to do? The circumstances that you're operating in can change, as well as the modalities themselves.