Clive Glover, strategy director and cell and gene therapy lead at Pall Corporation, explains why we need to take a more holistic approach to gene therapy manufacturing processes.
Industry 4.0
In just a few short years we have seen a huge surge in the development of new gene therapies. There are currently over 1,000 cell and gene therapy clinical trials underway worldwide. While the majority of these are still in phase I or phase II, there are over 90 trials in phase III. Scott Gottlieb, former commissioner of the US Food and Drug Administration (FDA) stated at last year’s BIO International Convention that he expects the FDA to approve 40 gene therapies by 2022.
The gene therapy revolution is happening. But despite all this promise and the rapid growth of an emerging industry, we’re still a long way from seeing gene therapies being manufactured in quantities even close to the level of current demand. This is arguably one of the biggest challenges in modern medicine manufacturing and an area in which we at Pall are investing heavily, namely how to scale up the manufacture of gene therapies and gene-modified cell therapies to industrial levels and do so in a way that remains efficient and cost-effective for those companies producing the treatments. If this revolution in healthcare is going to achieve its potential, we need to solve this manufacturing challenge first.
Overcoming the roadblock
Viral vector manufacture is a case in point that reflects some of the wider challenges faced in cell and gene therapy production. Demand is soaring for the pre-clinical and clinical-grade viral vectors that allow for the delivery of genes of interest, but the industry has not yet adapted to meet the demand.
Many think of the process as being very similar to the one used for monoclonal antibodies (mAbs) and assume it to be relatively simple to upscale. But there is far more risk and intricacy involved with each individual step. The viral vectors themselves, for example, are toxic to the cells that produce them, so the use of stable cell lines, similar to those used for mAbs, is challenging. Production systems depend on transient expression of the components essential to produce a virus, severely limiting titers. This is a serious issue in prevalent diseases such as haemophilia or Duchenne muscular dystrophy, where the number of patients appropriate for treatment is large and the doses required per patient is high, meaning that there is a need for larger viral vector batch sizes.
There are countless reasons why scale-up has proved challenging, and as a company whose expertise is in industrialised biopharmaceutical manufacture, Pall is heavily invested in tackling the gene therapy manufacturing challenge. One main focus of our investment in this area has been to develop an automated, end-to-end integrated, platform solution that is scalable and can address issues that arise when gene therapy products are manufactured using individual manual manufacturing steps.
Single-use technologies, for example, can save not just days but weeks by reducing cleaning and cleaning validation requirements, set-up time, in-process hold steps and the time needed for an operator to oversee equipment. Automation can also play a vital role. When assays for viral vectors, both off-line and online, are of poor precision and accuracy, automation can help bring a degree of process control, improve process reproducibility and reduce the risk of batch failure.
A fully integrated system ensures all unit operations are coordinated and that the consumables are appropriately specified and qualified for their intended function, allowing a process to run in exactly the same way each time. As long as the incoming raw materials are well controlled, it is likely that the process will routinely run at optimal productivity. Essentially, good integration and automation can be central to getting systems to work to certain performance measures every time.
Thinking continuously
Changing the way in which to approach the manufacturing process for viral vectors is just the first step to the industrialisation of gene therapy production. If we’re going to tackle the industry’s productivity challenges, we need to think smart and commit to finding innovative manufacturing solutions. Continuous bioprocessing, for example, could bring huge benefits to gene therapy manufacturing, if we can overcome some of the perceived – and often incorrect – assumptions about regulatory risks.
Continuous bioprocessing offers potential for transforming how biopharmaceuticals are manufactured. Continuous processing offers multiple benefits including improved process economics, increased process design flexibility, reduced development times, scalability, and cost efficiencies in terms of improved productivity from unit operations. Generally speaking, compared to a batch process, continuous processing can significantly reduce the footprint of a manufacturing suite, while offering additional ‘soft’ cost savings through reduced build times for facilities, streamlined maintenance and management processes, and reduced workforce demands. As the industry moves towards full-scale manufacturing plants in gene therapy production, these significant cost savings will be key to improving speed to market for lifesaving treatments.
A bright future
There’s no denying that the rise of gene therapy has been due to the remarkable clinical results that have been achieved. The rise of single-use facilities, process intensification, integrated unit operations and continuous manufacturing is improving facility efficiency and flexibility, yet at the same time reducing footprint and processing times – but we’re only at the start of this journey and it’s a long road ahead. The industry collectively needs to think beyond the status quo of siloed systems and batch processes and think more holistically about the fundamental way we manufacture medicines. As new breakthrough therapeutics continue to emerge and transform the healthcare industry, so do we as manufacturers need to think in groundbreaking ways about how we produce them. If we can get this right now, there is no limit to what’s possible and the benefits that these new treatments could bring to patients worldwide.