In the genes — the challenges associated with manufacturing gene therapies

Here, Tony Hitchcock, technical director at Cobra Biologics and Joanne Anderson, business development director at Symbiosis, whose respective companies were recently awarded a 16-month collaborative grant of £1.9 million from Innovate UK, discuss the challenges associated with manufacturing for gene therapies.

They are cited by many as a ‘medical revolution’. Emerging gene and cell therapies to treat everything from cancer to haemophilia and blindness are being hailed as huge successes.

Such ground-breaking therapies do not come without risk, however. The use of gene-based medicine remains nascent; costs are high, timeframes are tight and quality standards are strict. Nevertheless, the Association of the British Pharmaceutical Industry (ABPI) estimates the global cell and gene therapy market will be worth up to $21 billion annually by 2025.

New therapies, new ground

Pharmaceutical and biotechnology companies are now racing to develop or acquire assets to develop these life-changing and life-saving therapies, many of which are commanding some of the highest prices ever seen for a medicine.

Due to the potential life-saving qualities of such therapies, clinical development programmes for innovative gene therapies have been actively accelerated by regulatory bodies such as the FDA and the EMA by the application of a ‘priority review’ or ‘breakthrough designation’ status, seeking to expedite widespread access to these new medicines.

The delivery vehicle that underpins many of the in-development cell and gene therapies and specifically those recently launched such as Yescarta and Kymriah, is a viral vector. Viral vectors are tools used to deliver genetic material into cells. Due to the pharmaceutical industry and regulatory bodies drive to get treatments to patients quickly, the speedy and adaptable production of viral vectors from companies like Cobra Biologics and Symbiosis is paramount.

The manufacturing challenge is quite unique. The handling and processing of such complex and delicate products like viral vectors needs specialist skills and expertise to create an integrated supply chain to minimise risk. In addition, costs are huge. Gram per gram, viral vectors are quite possibly the most valuable raw materials on the planet.

These are ground-breaking treatments. They don’t fit the normal criteria for conventional drug development and aren’t following typical timelines. The speed such products are moving through clinical development compared to classical biologics is creating a new paradigm, at three to four years for a vector versus eight to 12 years development is happening at breakneck speed. In reality, those involved in the supply chain are in fact setting the precedent for future manufacturing processes and strategies.

Challenges in the process

Whilst accelerated pathways are a positive for patients in the long run, shortened timelines for the manufacture of viral vectors make it more difficult to develop commercial manufacturing processes that can produce vectors at the right quality, in the required amounts, and at costs that are reasonable enough to secure reimbursement from healthcare providers while still making financial sense to the developer.

From a processing perspective they pose a number of challenges: firstly, in terms of size, they are 12 times the diameter of mAbs with diameters up to 120 nm and are processed at concentration in the region of pg to µg/L — compared to proteins processed at 10’s–100g/L levels, secondly the products are often highly labile and have poor thermal, physical and chemical stability.

The consequence to this is that from a technical perspective these products pose a significant challenge not only in the manufacturing of the active drug substance, but also during the production of the drug product to minimise product loss not least through 0.2 µm filtration steps but also during process manipulation steps can damage viral capsids and result in the loss of infectivity and functionality.

The handling of recombinant vectors also poses specific concerns with regards to biological containment and segregation from other products and the ability to remove these types of products from the facility also pose specific requirements in terms of operational expertise.

Consequently, drug developers are heavily reliant upon specialist providers for the production of drug substance and drug product.

There is also an ethical challenge; many of these products are life savers and have hugely transformative impacts on patient’s lives so are the development programmes being rapidly accelerated towards clinical licensing to allow patient access tosuccessfulproducts?

To achieve this, timelines and opportunities to develop and optimise manufacturing processes are at a premium. Consequently, there is a need for coordination between all parties in the supply chain to work together to ensure material supply during both clinical development phases and for licensed products whilst ensuring that all required safety and regulatory guidelines are met throughout.

Ultimately, if mistakes happen they will be very costly on all levels. Products will not reach patients, many with terminal illnesses and for whom time is of the essence.

The future

Gene and cell therapies are a huge opportunity, with potentially life-changing consequences for millions of patients across the world. As discussed, developing these therapies is not without challenges, but the industry has so far responded to these swiftly with the expertise needed to manage such specific demands.

Projects such as those ongoing at Cobra Biologics and Symbiosis’ will support a larger investment in the production capabilities of both companies, streamlining and de-risking the manufacturing of viral vector products through operational and commercial alignment. The resulting supply chain offering will help realisation of the clinical and commercial ambitions of drug developers, leading to more innovative gene and immunotherapy medicines reaching patients.

Moving forwards, we expect the massive impetus to get products to patients to continue to grow. The manufacturing path is not well trodden yet, it remains somewhat of a learning curve for all those involved, but as many of us are now working together to resolve manufacturing problems we expect the future of cell and gene therapies to be just as ‘revolutionary’ as predicted.