An active area of research for many years, cell and gene therapies offer the potential to treat diseases that cannot be addressed by existing pharmaceuticals.
They are now emerging through translation and towards commercial development and patient access.
Among these exciting developments, cell and gene manipulations are providing potential cures for genetic diseases, blood diseases, cancers and much more.
In general terms, cells taken from and administered to the same individual are classed as autologous, while those derived from a donor are classed as allogeneic.
The EU regulatory classification of cell-based therapies discriminates between minimally manipulated cells for homologous use (transplants or transfusions) and those regulated as medicines, which are required to demonstrate quality, safety and efficacy standards to obtain a marketing authorisation before becoming commercially available (referred to as Advanced Therapy Medicinal Products or ATMPs). These can be subdivided into
- a gene therapy medicinal product
- a somatic cell therapy medicinal product
- a tissue engineered product.
There are some 50 cell therapy developers currently in the UK with more startups appearing each month.
One of the major challenges for the inventors is that such treatments are revolutionary in terms of their production techniques, production scales and short shelf lives, which creates unique issues in terms of production facilities and logistic requirements.
While today we see many of these products coming through to early-stage clinical trials, there are very few facilities where startups can scale up their lab process to GMP production or that offer the logistics and supply chain needs.
Recognising this fact, the Cell and Gene Therapy Catapult was set up in 2012 and is now located in Guy’s Hospital London, where it has established specialised development laboratories, and has since been given a £55m budget to build a large-scale cell therapy manufacturing centre in Stevenage.
Cell and Gene Therapy Catapult CEO Keith Thompson reflects that UK R&D has played a large part in cell and gene therapy research but says, when it came to the opportunities for taking on the manufacturing in the UK, the future looked less promising.
‘Unlike the development of small molecules and biologicals, where the developers largely don’t even think about how they will get it manufactured – they assume if it works and they can get it made at a cost that works, that they will get it to hospitals and patients – this is not the case with cell or gene therapies,’ says Thompson.
‘When cells are the active part of the medicine, the processes to manufacture and control it requires a great deal of development. People are still at the beginning, trying to go from a flask to a few litres and then to 50 litres.’
Manufacturing experience
Thompson is expertly qualified to head up the new build. His first foray with cell therapies was as a student, while developing purification technology for an antibody to beta-Interferon.
He moved into bio-manufacturing and has been involved in the manufacture of biologicals, both in the UK and the US.
His next move to the Scottish Blood Transfusion Service gave him important experience of single-use disposables, a key production feature that has speeded up the development of biological therapies.
He has witnessed the industry, once dominated by companies producing small (chemistry-based) molecules and a few vaccines, develop into one where biologicals are now a major part of the drug pipeline.
Speeding the route to market
Most cell and gene therapies currently follow two principal avenues: the autologous and the allogenic route.
In the former, cells are taken from the patient and modified or seeded onto a matrix to make a tissue-engineered (often live) product that goes back into the same patient. To bring such products to market requires significant work to streamline, automate and enclose the process.
The other route is that of allogenic therapy, which is more akin to what the industry is used to. These products are usually cryogenically frozen before being shipped to the patients.
Strimvelis from GSK – the first ex-vivo stem cell gene therapy, used to correct severe combined immunodeficiency due to adenosine deaminase deficiency (ADA SCID) (otherwise known as ‘boy in a bubble’ syndrome) – is an example of a potential cure that could save the healthcare system thousands, even though the therapy itself is expensive.
For some of these new therapies, the timescale to market is remarkably short at 5-6 years, says Thompson.
The speed is partly because the results have been so spectacular and, because of the patient-specific nature of the therapy, the clinical trials required are not as large as would be the case with conventional therapies.
As a translational centre of excellence for cell and gene therapies, the Cell and Gene Therapy Catapult will help to lower the industry barriers in getting such products to market.
To achieve this it has organised itself around three themes:
- Understanding the business-related aspects of cell and gene therapy – e.g. the logistics and reimbursement models.
- Understanding manufacturing, which may mean offering support in terms of analytical, process and manufacturing development, quality by design, cost optimisation, reliability and robustness.
- Understanding clinical trial design and regulatory issues.
‘There has been a lot of myth-busting about what you can and can’t do from a regulatory point of view,’ says Thompson, adding ‘We have found the MHRA to be a helpful regulator, willing to talk to those in early the development stages.
‘We recognised that while there are a lot of early stage, small-scale facilities, there weren’t any large-scale ones and those that exist are mainly in academia, which is why we proposed to the Government that the facility that we are building in Stevenage would be an asset.’
The Stevenage facility will take companies through Phase 1, 2 and 3 clinical trials.
Most companies want to come for 2–5 years, says Thompson, and the aim is to get a cluster of companies that will attract the supply chain providers to move in locally too.
As companies outgrow the facility, they will have all the specialist suppliers around them and thus remain local to the area.
Modular facility design
Many firms want to keep control over their process and, as the technology is moving at such a fast pace, they want to introduce changes quickly, but under control.
As a result, in terms of design, the new facility will have 12 individual, architecturally segregated modules, each accommodating a separate company while being fully supported with the wrap-around GMP envelope that the Catapult provides.
This will allow the companies to develop all the way up to do pivotal trials and help get them on the market.
Thompson explains: ‘All of the gene-modified projects have similar characteristics, so we mapped these processes and found seven that were common to all.
We sized the processes and then designed a flexible pod that can take these seven processes and then effectively multiplied the footprint of the pod by 12.
Designed with a classic Grade A and B setting, the first step for the companies is to semi-enclose their processes.
The manufacturing process is often viewed as a series of unit operations performed under GMP conditions.
‘In November, Autolus became the first company to collaborate in the centre to manufacture its pipeline of T-cell products for the treatment of cancer patients,’ Thompson says.
The facility, which is located next to GlaxoSmithKline’s site, in total measures 7200m2 and each cleanroom module unit is 100m2.
Each module has a dedicated single pass-through HVAC, is multifunctional and capable of taking a 1,000L reactor for allogenic products or 46 independent autologous processes, and each can work with either cells or viral vectors.
‘We use a virtual reality system to help companies design their facility within the module,’ says Thompson adding, ‘Each suite is designed at GMP grade B but can be toggled down to grade C or D to get a lower operating cost if required.’ (The airflow systems are all designed to GMP Grade B).
'Once inside, the work can focus on finding a systematic method of moving from an open process to a closed one, and from there you can move to a semi-automated process, then a fully automated one,’ says Thompson.
The ‘nirvana’ is to have the whole thing automated in a box, so that then the factory can move to the hospital – but that is some way off, Thompson admits.
'Part of the problem is that you have variable starting material. This means the more you can tighten up the process, the more reliability can be built in.’
The Stevanage facility is under construction and due to be completed in Q2 2017
Product shelf-lives can vary from as little as 24 hours to 3-5 days for those products that can be cryogenically frozen, so the facility is deliberately sited within reasonable distance of Heathrow Airport, enabling companies to fly products easily to European centres.
Thompson also suggests that companies need to look at the whole supply chain, not just at manufacturing. For example, on a recent project, once the frozen therapy reached the hospital it had to undergo thawing before it could be administered to the patient.
‘We soon realised that it would require a GMP-controlled thawing device to ensure the end user knew exactly when the cells were thawed and ready to use,’ says Thompson. ‘Here the system that was developed ensures that the hospital device can talk to the mother ship [the manufacturer].’
Thompson’s enthusiasm for new technology and experience of good process design is being put to good use and the potential for facilitating life-saving therapies makes it a rewarding role. He announces at our meeting that the facility has just been ‘topped out’ and he looks forward to revealing more when it opens to visitors next in Q2, 2017.