Cell & Gene Therapy USA 2022

Sep 20, 2022 - Sep 21, 2022,

Pioneer a gold standard for CGT commercialization

Scaling CGT through automation

Delivering on the promise of cell and gene therapies requires significant process improvements to cut manufacturing time and costs

Cell and gene therapies need to be made cheaper. Much cheaper. With price tags in the millions, they will never be able to deliver on their promise of personalized cures at scale.

It will take time for the industry to take costs below $1m per dose from the typical current price in the $2m-3m range. And even this reduction is nowhere near enough to reach patient populations beyond the richest countries and health systems. 

More automated manufacturing offers one of the most significant ways to cut costs. The sector has been moving hospital lab manufacture towards more standardised and repeatable processes in dedicated facilities, but there’s still a long improvement path to travel. 

Production processes remain highly complex. The absence of established platform technologies means that bottlenecks and batch errors remain common features. 

The upstream and downstream processes from creation of the plasmid through to the bioreactor process and then to the creation of a pure, concentrated drug substance and final packaging into vials, require hundreds of quality tests and many variables. 

Even small changes in production parameters can result in a failure or low yields. “It’s not like a small molecule. There are so many variables and parameters to check,” says Oscar Segurado, Chief Medical Officer at ASC Therapeutics, adding that the regulatory documentation process, running to thousands of pages, is another non-trivial source of work and expense.

The only viable way forward is to develop highly automated processes that are faster and more reliable, that minimise process steps and human handling and as far as possible ease the documentation burden.

There are several paths to process improvement that will lead to falling costs, including:

Developing higher production volumes
Increasing production volumes to increase yields sufficient to make the quantities needed is one advance that is happening, says Segurado. “We don’t get as much material as we would like and we will require much more drug material as we go from early stage to pivotal clinical trials.”
Larger bioreactor vessels up to 500 litres are making their way into production processes, says Gary Potter, ASC’s Manufacturing and Operations Leader. “We will see process yields start to go up. Right now, the process is capped at 200-litre scale as we learn to better control the gene therapy manufacturing process. We will start to see the scale climb.”

Simplifying and improving production processes
The sector is also moving across to single use vessels, which simplifies production lines and cuts down on onerous cleaning validation requirements, adds Potter. “This really streamlines things. You can lose a whole bunch of processes, you use less space and you have a lot more flexibility.”

There is also potential to improve downstream yields, for example through improved column chromatography processes, Potter adds. “Right now, we might make a batch and recover 30%- 50% of it, so if you can do something downstream that increases recovery rates, that is the equivalent of increasing your batch size.”

Since most failures happen in the production reactor, higher success rates here will mean higher yields, from somewhere around the current 70% range up to 95%, predicts Potter. “As we figure out the important parameters, we can control to that. We will see the technology come round such that we capture full capsids much more efficiently than we do right now.”

Other closed processes along the production chain should help drive further improvements. At the batch initiation stage, attaching bags of frozen cells direct to the incubating vessel rather than starting a batch in a sterile biosafety cabinet is one such innovation.

At the other end of the process, filling vials in an automated, closed environment offers a more streamlined packaging process. “It can take the atmosphere right out of the equation and eliminate a lot of environmental monitoring,” adds Potter.

This cuts the risk of sterility failures but the chief advantage is simpler monitoring and so a lower documentation and regulatory burden.

As more contract manufacturers adopt single-use vessels and closed systems, this in turn brings more competition and more choice, which should then lead to better prices. The outsourcing of some testing to labs may also offer a way to reduce production and documentation overhead.

Deploying next-generation equipment and platforms
The advent of more closed processes in ever smaller manufacturing units – ‘gene therapy in a box’ - offers an order of magnitude reduction in required production space to hundreds rather than thousands of square feet, far lower labour intensity and, crucially, a significant reduction in error rates. 

Sumit Verma, Senior Vice President of Global Strategic Manufacturing at Iovance Biotherapeutics, has been evaluating the state of automation in the sector and is excited by much of what he sees. “We are getting closer to cell therapy in a box than I have ever seen. That is very promising.”

Physical manufacturing processes have seen great improvements from the sector’s initial lab-scale beginnings. ‘Vein to vein’ therapy production times have dropped from 44 days with the first gene therapies down to 22 days today. Verma sees a path to reducing this to 16 days.

New closed systems will help do this by reducing touchpoints and reducing the size of the operations teams needed to make a medicine for a single patient. Smaller, more flexible manufacturing facilities should also make it simpler and cheaper to move infrastructure closer to the point of care.

Automate data capture and build the capabilities to leverage it
Automating data capture is a vital part of the improvement journey in CGT. Paperless plants with end-to-end chain of custody are going to be essential to efficient scale-up.

The importance of being able to capture detailed data on critical process parameters from highly integrated processes, starting at R&D and ending in manufacture, is vital so that no data or knowledge is lost. 

“Everyone is realising that capturing data at the source is important. You have got to capture data electronically,” says Jeet Sarkar, Vice President and Head of IT at the Center for Breakthrough Medicines. “You cannot serve the patient well without those processes.  

“To continuously innovate, to scale up, you need this data available. By constantly monitoring you are reducing errors, making your processes more efficient. Over time you will have the data to understand which batches are going well. Getting to right batch, first time, every time is vital.” 

A new generation of ‘plug and play’ manufacturing equipment from active chromatography systems, automated cell culture systems and suspension bioreactors has been built to supply the real-time data required for this end-to-end monitoring and data analysis.

A further key to innovation and driving down costs for the industry will be building the data science teams with the statistical modeling skills to leverage these machines’ ability to gather data in real time. 

This essential requirement may be one of the key drivers of outsourcing, Sarkar suggests. More data will drive greater efficiencies and speed of scaleup, which will become core strengths for CMOs, leaving therapy developers to focus on research.

Learning from each other
Most development work in CGT is happening in silos but the potential for different players to learn from each other is great. ASC is part of the 20-strong NIH and FDA-led Bespoke Gene Therapy Consortium (BGTC) consortium convened to find ways to share knowledge and experience on improving and streamlining the entire process.

Despite the routes to improvement outlined above, a significant barrier remains: regulation.
A particular source of friction slowing the speed of improvements is the regulators’ bandwidth to keep up with new and innovative process improvements that are taking place in real time today. The task of evaluating emerging technology to ensure patient safety is of course essential but as currently configured the regulatory process requires the pioneers to take big risks up front and hope for approval at the tail end of their investment decisions.
It’s a significant source of risk from a regulatory approval perspective, says Verma. “If there is a way to meet with the FDA and discuss through issues ahead of time, this approach would help accelerate automating our products, but that capability and the resources are just not there. We have a sense of urgency, and the patients are waiting. How do we get the regulators to invest upfront time to review cutting edge automation and technology?”
Useful collaborations are happening at conferences, but more effort needs to be made on both sides of the process, says Verma. “We should not be waiting at this time to modernize the automation process but instead interacting with the agencies and showing them what’s new. It will go a long way.”

Cell & Gene Therapy USA 2022

Sep 20, 2022 - Sep 21, 2022,

Pioneer a gold standard for CGT commercialization