Continuous bioprocessing – the key to industrialising gene therapy production?

A new partnership, with funding from Innovate UK, aims to investigate the possibility of using continuous manufacturing processes in gene therapy.

Few people doubt the potential for gene therapies to transform the lives of people suffering the worst and rarest of diseases. Yet if we are to realise the full potential that gene therapy holds for biopharma and for patients around the world, we need to continue to find ways to improve the manufacturing process and increase outputs and efficiency without further increasing costs.

The problem is one of scale. As investment in gene therapy has continued apace and new gene therapy companies emerge on an almost daily basis, demand has risen exponentially for the pre-clinical and clinical-grade viral vectors that are crucial to the process of modifying a patient’s genome. But the industry hasn’t yet found a way of meeting these demands – partly due to the complexities associated with manufacturing viral vectors.

The process looks, on the surface at least, similar to that used for monoclonal antibodies (mAbs). But when you look at what’s required for each individual step, there is far greater complexity, with more risk at each stage of the process. For example, with viral vectors, the viruses themselves are toxic to the cells that produce them. This means that the use of stable cell lines, as are used for mAbs, is very challenging, with production systems relying on transient expression of the components required to produce a virus, severely limiting titers.

Until recently, viral vectors have typically been produced in academic settings using methods that are inherently only viable at small scale. To change this, Pall has invested heavily in developing an end-to-end integrated platform solution consisting of enabling technologies that can manufacture viral vectors at a genuinely industrial scale. These technologies will help us to tackle the huge disparity between demand and supply and establish manufacturing processes that are not prohibitively time-consuming and expensive.

“Following other sectors, medicine manufacturers are moving from batch processing to continuous, and are experiencing improved process economics, increased process design flexibility, shorter development times, and easier scale-up.”

Scale-up struggles

A lot of the industrialisation challenges for gene therapies come from very practical considerations around the equipment used in manufacture. Traditional laboratory-based systems, for example, are often difficult to scale-up simply due to the large number of vessels such as flasks or cell factories, that need to be manipulated during a clinical production run. In addition to the resulting challenges around available incubator space, the manipulation of a large number of culture vessels increases processing time and potential risks due to the number of steps that include open manipulation during aseptic processing.

To address this challenge and reduce risk during clinical manufacturing, the industry is moving to larger single-use disposable culture systems and bioreactors, thus reducing points of vulnerability. In fact, single-use systems have advanced significantly over the past couple of years and the flexibility they offer is helping numerous drug manufacturers bring their products to market faster.

Growing commercial product pipelines also require products to be characterised and consistently manufactured to within tight tolerances of purity, potency and safety. Safety testing is conducted to ensure that process intermediates or final products are free of detectable contaminating agents that can pose risks to patients. There are various characterisation assays available, with their applicability dependent on the type of virus. Accurate and reproducible analytical tools must be in place to monitor quality attributes in order to meet rigorous safety guidelines for gene therapy products. This need has only increased with the continuously advancing development of recombinant viral vectors for gene therapy – ensuring the virus is of appropriate quality, safe and efficacious, is a challenge.

Productivity innovations

The biopharma industry cannot keep falling back on the same processes that have thus far failed to achieve industrialised levels of production. We need to try something new. This is why Pall, Cobra Biologics, and the Cell and Gene Therapy Catapult has formed a partnership to investigate the possibility of using continuous manufacturing processes in gene therapy – a research collaboration that was last year awarded a £1.5 million grant from Innovate UK.

The key areas of focus of the partnership are around manufacturing approaches based on continuous chromatography platforms, with the goal of significantly increasing downstream process yields. Yields for downstream processing of adeno-associated virus (AAV) are currently low, and the production process is costly in both time and consumables. AAV production generally produces significant quantities of contaminants, including host cell DNA and protein, empty or partially filled capsids, and sometimes helper virus all of which significantly increase the purification burden. The virus must be separated from these contaminants, which is very challenging.

By advancing the AAV purification process, our goal is to increase purification yields by 25%. To achieve this, we are investigating systems to increase yields and decrease costs, while using novel analytical procedures, based on continuous chromatography platforms, to enhance the purification process.

Think outside the box

Continuous bioprocessing is already transforming how biopharmaceuticals are manufactured. Following other manufacturing sectors such as automotive and food and beverage, medicine manufacturers are now starting the journey from batch processing to continuous, and, as a result, are experiencing the benefits of improved process economics, increased process design flexibility, shorter development times, and easier scale-up.

Take chromatography as an example. Many manufacturers have been reluctant to move away from the traditional chromatography systems that have been critical in the production of new medicines for many years. But they are now simply unable to ignore the huge cost savings that continuous can bring to what is typically the most cost-intensive aspect of downstream bioprocessing.

For example, Protein A sorbents used in the primary capture step of monoclonal antibodies can cost over ten thousand dollars per liter. However, by optimising the number of columns needed to operate this process, manufacturers can enable reductions in buffer and decrease the volume of sorbent used by up to 90%. This vastly improves the efficiency of consumable use, while also reducing the need for large tanks, buffer-storage biocontainers and other equipment – all of which takes considerable cost out of the manufacturing process.

The potential cost efficiencies in gene therapy production are even more substantial. The resins used in AAV manufacture can be more than 2.5 times the cost of Protein A, so their streamlined use in a continuous manufacturing system can have a huge impact on overall cost. And this is just one part of the production process. Compared to batch processing, continuous can reduce the footprint of a manufacturing site by anywhere from 40% to 90% and reduce both OpEx and CapEx by up to 60%. This is not to mention the ‘soft’ cost savings from reduced build times for facilities, streamlined maintenance and management processes, reduced workforce demands, to name a few.

As we move from laboratory settings to full-scale manufacturing plants in gene therapy production, these significant cost savings will play a key role in improving speed to market and cost to patients for lifesaving treatments.

The devil is in the data

It’s also important to consider the role that data analytics and monitoring have played and will continue to play in moving the industry – and gene therapy in particular – towards a more continuous approach to manufacturing. One of the key areas of focus of the Innovate UK partnership will be to develop the innovative in-process analytical techniques that are needed to ensure robust data is collected about manufacture of viral vectors and mAbs through continuous processing.

There are perceived regulatory challenges around continuous which, while understandable, do not bear scrutiny. From a regulatory perspective, continuous processing is inherently no riskier than other processing approaches, and the robust datasets we will be able to gather from research, such as the Innovate UK partnership, will help to prove that these fears are ultimately unfounded. Indeed, instead of the classic model of regulators approving at each stage of batch processing, we could see the emergence of a more seamless, integrated drug approval process, improving speed to market for all types of treatments, including gene therapies.

Gene therapy production is an inherently complex process. There is no single silver bullet to increase speed to market, but if we embrace an integrated approach and learn from the continuous principles and techniques we are now perfecting in other forms of biopharma production, we believe we can create a scalable process that will transform productivity in gene therapy manufacture – bringing life-changing treatments to patients in ways that are safer, faster, and less expensive than ever before.

About the authors

Clive Glover is director of strategy, cell & gene therapy at Pall Corporation; Daniel Smith is chief scietific officer at Cobra Biologics and Damien Marshall is director of industrialisation, new and enabling technologies at the Cell and Gene Therapy Catapult.