Automating the Future

Biopharmaceuticals are typically more difficult to manufacture than small molecule drugs, but cell and gene therapy products pose even greater challenges. When working with stem cells, agitating the cells even slightly too much when they are growing on microcarriers, for example, could stimulate the cells to differentiate along the wrong pathway, affecting yields and potentially creating the wrong product. Other steps in the manufacturing process, such as cryopreservation, can also affect cell viability, so it is crucial that cell therapy producers understand both their product and every step of their processes. According to process engineer Kim Nelson, Senior Director, Strategic Consulting, at CRB, automation can go a long way to facilitate cell therapy manufacture. There is just one problem – integrated off-the-shelf automated systems don’t yet exist. We catch up with Nelson to find out his thoughts on the conundrum and the future of the field.

How did you get involved with cell therapy process engineering?

At university, I obtained degrees in chemical engineering and biochemistry/biophysics – and I became very interested in biomedical and bioprocess engineering. In grad school, I studied cancer chemotherapy mathematical modeling. For a while, I taught at university, and then I had the opportunity to move into industry to work with cell culture process development – mainly working with anchorage-dependent cell lines and large-scale production on microcarriers. Cell culture tied in well with my graduate work and it was the 80s – a great time to join the industry, which was seeing a real blossoming of vaccine scale up and production, as well as recombinant work. Some years later, I moved to the engineering industry, where I was thrilled to be able to work with a range of projects and technologies. I’ve never looked back. Today, I mainly work with process engineering for cell therapies, and gene vector production.

What trends have caught your eye in the cell therapy field?

I am fascinated by advances in immunotherapies – partly because of my original interest in cancer chemotherapy. Immunotherapies potentially hold awesome therapeutic power, but they also raise many challenges in terms of scale up and commercialization. Producing therapies for a small number of clinical patients is very different to handling a high-throughput situation, which is what many companies struggle with. They may understand the science, clinical importance,  and biology of their product, but translating that into a high-throughput system – one that is also commercially sustainable – is daunting. Smaller companies are especially challenged because they often don’t have the resources to staff the large and protracted development program that is needed to get a high-throughput system in place.

One of the biggest issues for the field is the fact that there aren’t many commercial systems available. There has been an explosion in the number of equipment suppliers moving into the field, but most offer systems that are more appropriate for clinical scale operations. Many offer closed processing (closed processing systems have been very successful) for individual steps, but there isn’t a truly integrated, high-throughput option available. Indeed, many of today’s options aren’t amenable to true automation – such as being able to introduce an apheresis bag, attach it, process the cells, incubate the cells, harvest the cells, wash the cells and then dispense them into the delivery bag ready to be frozen – all with minimal or no operator intervention. In most cell or gene therapy processes today, human workers perform the manipulations manually. The field could perhaps benefit from funding, such as from the NIH or other organizations, to develop integrated automation for different types of cell therapy systems.

What are the main challenges in terms of scale up?

From a process Quality-by-Design standpoint, characterization and identifying the critical quality attributes and critical process parameters that will translate to clinical outcomes is crucial. This is also the first step when moving to any type of manufacture and scaling it up. You need to understand the scale that you will need, and you also need to be able to work backwards (scale-down) to determine the appropriate working ranges. One example might be large-scale cultures of anchorage-dependent allogeneic cells in a microcarrier bioreactor system. You need to understand the total number of doses of cells you’ll need at market launch and the production growth, as well as the dose size. These will establish the throughput required, which then must be balanced between the number and size of the bioreactors. While this might be simpler at small scale, you can’t do all of the process dependent and early clinical work in static culture systems like cell factories, Hyperflasks or Hyperstacks – you need to use a scaleable bioreactor system relevant to the required commercial scale; in this case, microcarriers or perhaps a packed bed type bioreactor. Along the way, you also need to be investing in process development – don’t wait until things have moved too far along! Investing in the reliability, robustness, and repeatability of the process is very important. Automation can help by reducing operator interventions – thereby reducing the risk of errors and variability that occurs from one operator to another, as well as processing speed.

What are your top tips for scale up success?

Process definition and process development need to be a significant focus much earlier than companies realize. On many occasions, I have seen companies designing manufacturing facilities before they even have a defined process – key questions have not been asked and parameters have not been identified. In some cases, companies won’t even know the critical quality attributes, let alone the critical process parameters. If it is a company’s first product, they will need a good team to acquire the right knowledge. When it comes to a second similar product, it will be a little easier as some of the same parameters can be used as starting points – particularly if the company is working with a platform-type system. Start early, identify those critical quality attributes and the critical process parameters early, and select a scalable process – this information will improve your chances of success when it comes to scaling up to commercial manufacture. Without the right information, you’ll often end up “over designing” a facility or a process, increasing the project costs and the risk of a delayed launch.

Cost is always a significant pressure in today’s industry – how important is this for cell therapies?

Cost drivers for cellular therapies or other advanced therapeutic medicinal products are highly dependent on raw material costs, with media and growth factors being quite expensive and laborious. There are also fixed costs such as the facility and equipment costs to consider as well. The labor portion is particularly high for autologous therapies, where each patient’s cells are a separate batch, and the processes have many operator manipulations and incubation steps. It takes time to develop a more economical process. And once a product is approved there is always the time, effort and cost of getting regulatory approval. When Dendreon first launched their cell therapy manufacturing operations, the cost of manufacture was high, but more efficient operations and cost-effective materials have helped bring costs down significantly.

Getting the manufacturing cost per patient dose into a reasonable range is crucial for the sustainability of the field – and healthcare overall. There’s been much discussion about the pricing of the Novartis CAR-T product, Kymriah, and it seems as if Novartis will roll out an outcomes-based pricing model where payment is only required if the patient responds by the end of the first month after the therapy is administered. It’s possible that more therapies will follow this payment model in the future, but although it may suit some countries, it won’t suit all. Companies will still need to optimize their manufacturing costs and consider the final price of their product, particularly if they want to reach the widest possible range of patients.

Given the challenges that lie ahead, what are your thoughts on the future of the field?

Certainly there are challenges that must be faced in terms of manufacturing, but when it comes to treating disease I have a very hopeful outlook. Back in the 70s, there were dreams that cancer could be cured relatively easily with the knowledge that was being gained – and today’s immunotherapies offer real potential for achieving remission or total cures for certain cancer patients, rather than just extending life for a short time. I am very optimistic. And it’s not just cell and gene therapies that are making a mark on patient outcomes – there are many stem cell therapies in development which could have huge impacts in the biopharma space. Some will be major blockbusters, but others are for niche indications. In all of the cases where cells are the product, cost of manufacturing will be an issue, and automation of the operations has the potential to provide more robust, repeatable manufacturing, while reducing the facility and labor portions of the manufacturing costs equation. It’s actually fantastic to see so many niche products being pursued. Providing the industry can solve the manufacturing challenges – and tackle costs – there will be many more promising treatments available in the coming years.