“These are very exciting times for cell and gene therapy in the U.K.,” comments Colin MacKay, CEO of Symbiosis Pharmaceutical Services, a CDMO, at the recent bioProcessUK conference in Edinburgh. He adds, “We have an increasingly connected supply chain, where we can undertake GMP manufacture of cell therapies, as well as aseptic fill finish, which makes this industry greater than the sum of its parts.”
Steve Bates, CEO of the BioIndustry Association (BIA), a trade association for life sciences in the U.K., echoes this sentiment by saying, “The U.K. is setting out its new industrial strategy and we believe that the sequel for life sciences will be better than the first and will highlight that the U.K. has an end-to-end process from R&D through to licensed CAR-T products being given to patients. We can offer translational science via the Cell and Gene Therapy (CGT) Catapult, manufacturing experts at Oxford Biomedica and Cobra Biologics, as well as staff in our National Health Service (NHS) that understand how to work with and administer licensed therapies to patients.”
Capacity and capability
The U.K. does seem to be steadily building its cell and gene therapy industry. According to Stephen Ward, PhD, chief manufacturing officer at CGT Catapult, in a recent report published by the CGT Catapult, since 2017, there has been a 40% increase in full-time employees with over 500 people now working in cell and gene therapy organizations across the U.K. Additionally, there has been a 60% increase in manufacturing space. This means that there is just over 6500 m2 of cleanroom footprint which meets GMP standards and is licensed by the U.K.’s Medicines and Healthcare Products Regulatory Agency (MHRA) for production of cell and gene therapies. This increase has been seen with the opening of the CGT Catapult GMP manufacturing center in Stevenage, as well as the expansion of facilities at CDMO, Cobra, and the Scottish National Blood Transfusion Service.
Ward states, “There is a great demand for manufacturing space in the U.K. and 81% of our capacity was booked in 2018 due to the increase in products in the clinical pipeline. We have gone from one product in 2017 to seven in 2018. Production space is set to rise by another 1500 m2 in 2019 making a total of 8000 m2 available, which we believe will be heavily utilized as the number of therapies reaching commercialization is increasing.”
To ensure that lack of manufacturing and fill-finish expertise, as well as clinical uptake of these types of therapies do not become limiting factors, the U.K. is funding a number of programs via bodies such as UK Research and Innovation (UKRI) and Innovate UK, as well as initiatives including the Industrial Strategy Challenge Fund.
One of these programs is an apprenticeship scheme. Fifteen apprentices have been recruited and are being trained in the manufacturing of Advanced Therapy Medicinal Products (ATMPs) by companies including Autolus, Cobra, GSK, Immetacyte, Oxford Biomedica, and Replimune. Ward explains, “Three or four years ago we needed post-docs for cell and gene therapy work. Now we need a different type of person.” According to Ward, more technician-grade scientists are now required to run automated processes as manufacturing becomes more industrialized and training these scientists via apprenticeships will strengthen the skill mix.
Another program is focusing on improving the expertise of viral vector manufacturing used with CAR-T therapies, for example. As part of this, Innovate UK has awarded Symbiosis and Cobra a 16-month joint grant of £1.9m to determine the right processes to support the fill-finishing of viral vectors. Murray McKay, a director of quality and regulatory consultancy, Mizar Solutions explains, “The timelines for getting a biologic to market are about eight to ten years, but with many ATMPs this timeline is being squeezed down to three to four. This has a knock-on effect of shortening timelines for stability and assay management with components of cell therapies such as viral vectors. Since patients who will benefit from cells therapies are in great need, the risk assessment is different, and work involved is compressed.”
According to McKay, fill-finish of viral vectors is not just a case of filling a vial. He detailed a number of challenges of working with viral vectors, these included stability problems, which can occur due to the amount of time taken for the processing steps thawed vectors go through before re-freezing the filled product. He also discussed that aseptic processing can cause viability issues as sterile filtration can reduce vector titer too much, resulting in increased costs.
“In recent years, vector production and fill-finish have begun to be done in different places. This key cultural change has meant vector production and manufacturing companies have had to work together. The grant Symbiosis had from Innovate UK means it can collaborate more closely with Cobra to develop flexible approaches to de-risk the manufacturing of viral vector products and the recent FDA approval of its viral vector fill-finish process shows Symbiosis now has a great deal of expertise in place,” he concludes.
Product to patient
A third program being funded is helping to encourage clinical application of ATMPs. Nick Medcalf, PhD, head of advanced therapies and enabling programs at Innovate UK states, “The U.K. wants to be attractive not just for our research but for our translation too. To allow our NHS to change to be able to support the use of ATMPs, the Industrial Challenge Strategy Fund is creating and funding a network of Advanced Therapies Treatment Centers (ATTCs) across the U.K.” These new centers include Innovate Manchester Advanced Therapy Centre Hub (iMATCH) which will cover the North West, Midlands-Wales ATTC in Birmingham, Wales, and Nottingham and the Northern Alliance ATCC will be in Scotland, Newcastle, and Leeds.
Medcalf adds, “The ATTC Network Program will operate within the NHS framework and will be coordinated by the CGT Catapult. It will allow staff there to develop and adopt standard operating procedures and become experts in working with and administering cell and gene therapies to patients.”
Cost is key
Having the infrastructure in place may enable the U.K. to manufacture and deliver ATMPs to patients, however, there is still the perennial problem of who can afford them. Dave Tudor, PhD, head of global manufacturing and supply strategy at GSK, provided delegates at bioProcessUK with a reality check on this, stating, “Only 100 million people globally can currently afford biopharmaceuticals such as cell and gene therapies.” To make them more accessible, he suggested pharma could drive down the costs by utilizing continuous manufacturing and digitization. He says, “Digitization could drive productivity gains of up to 40%. For example, digital health could lead to better trial recruitment and help monitor medicines in patients, post-approval. The oil and car industries have been using continuous manufacturing for decades, yet the biopharm industry is only just starting to implement it, embracing the latest continuous bioprocessing strategies could make biologics more affordable.”
A number of technologies presented at bioProcessUK focused on continuous manufacturing for cell and gene therapies but a stand-out was discussed by Martina Miotto, PhD, co-founder of CellulaREvolution, a spin-out biotech from the University of Newcastle. Miotto explains, “Many cell therapies are adherent cells and have to be grown with serum in the media, then detached enzymatically and harvested. This limits the number of cells that can be cultured and makes their production expensive.”
Miotto and her team have created peptide coatings that enable cells to self-detach while in culture, allowing continuous processing. To date, this coating has been tested with stromal cells, including mesenchymal stem cells (MSCs) in a steady-state process that was maintained for one month. Importantly, the cells also maintained their phenotype. “We estimate that using our coating, scientists could reduce their bioprocessing footprint by around 7000 times. With cell therapy this means you can take a culture area the size of a football pitch down to just one square meter. It has huge potential not only in cell therapy but also in applications like clean meat production, where you need cell numbers in the region of 1050 to make it commercially viable,” Miotto concludes.
“With small molecules, people can easily come and steal your lunch,” states Tudor, yet he believes this is not the case for cell and gene therapies. “Our ability to innovate in the U.K. is second to none, but our ability to grow is in translation. With our NHS and academic partners, I have no doubt that translation is our opportunity—that is the magic fairy dust which will grow our life science industry beyond all expectations. Also, our MHRA does a great job in the U.K. of setting high standards and this could give us a competitive advantage too,” he says.
Ward adds, “With continuing investment, the U.K. is building an advanced therapy ecosystem, which is second to none. Don’t forget we’re the first place outside of the U.S. where a CAR-T therapy can be approved and adopted by the NHS.” Ward did sound a note of caution, concluding, “There are around 900 companies worldwide involved in cell and gene therapy. We currently have 64 in the U.K., so we’ve got to keep really striving hard, if we’re going to be successful.”