Claire Hill, solutions support manager at IDBS, explains why advances in technology could be key for helping manufacture cell and gene therapies.
Gene therapy
As innovations in the biopharmaceutical industry continue to push the boundaries of established scientific and engineering practices, the need for faster and more effective process development is greater than ever.
This is especially true for cell and gene therapies, one of the most exciting yet challenging growth areas in recent years. While the therapeutic potential is clear, the technical challenges of manufacturing and the costs involved are still severely limiting. Compared to other products such as monoclonal antibodies, cell and gene therapies are produced in very low volume batches using highly manual processes. An integrated development platform that can connect disparate data sources, support automation, and deliver process and product insight is essential for these niche products to start moving into the mainstream.
In 2019, it seems like hardly a day goes by without news of a new merger, acquisition, manufacturing facility, or other significant investments in cell and gene therapy. The potential to develop treatments for previously incurable conditions is a strong motivation and the recent approval of three gene therapies shows that the promise is starting to become a clinical reality.
Yet, while the therapeutic potential is incredibly appealing, the manufacturing process is fraught with difficulties. Within the field of cell and gene therapy there is a wide range of different product types and methods of administration. While some products have the potential to be manufactured using established bioprocessing methods, such as suspension culture bioreactors, others like Chimeric Antigen Receptor T-cell (CAR-T) therapies involve highly manual processes that are very different from traditional biomanufacturing.
The two CAR-T products currently on the market, Kymriah and Yescarta, are autologous therapies which means that the patient’s own cells form the basis of the treatment. At a high level, the general process for autologous CAR-T therapies involves removing white blood cells, including T-cells from the patient, and then sending the cells to a manufacturing facility for processing where a new gene is inserted to help the T-cells recognise and destroy cancer cells. Once enough modified cells have been attained, the cells are purified and tested before being sent back to the clinic and administered to the patient.
There are several limitations to this approach. The circular supply chain presents a number of logistical problems and the waiting time while manufacturing takes place - currently about two-three weeks - can be an issue for critically ill patients. Also, because the processes are predominantly manual, there is a heavy reliance on dedicated manufacturing staff to support 24/7 operations. Many companies are investigating the use of healthy donor cells to create allogeneic CAR-T therapies with far greater potential to scale up manufacturing, reduce costs, and ensure better continuity of supply. However, this approach has yet to demonstrate sufficient clinical efficacy, and using cells that aren’t patient-derived raises concerns about the immune response which must be addressed.
It seems likely that both autologous and allogeneic CAR-T therapies will be needed, both requiring efficient and cost-effective manufacturing solutions. One of the most promising approaches for autologous therapies is the use of closed, automated systems such as the CliniMACS Prodigy (Miltenyi Biotec) that can be operated directly in a clinic or hospital.
For allogeneic CAR-T therapies as well as gene therapy vectors such as lentiviruses and adeno-associated viruses, the use of continuous manufacturing platforms could greatly improve efficiency, while reducing manufacturing costs and improving quality. Cobra Biologics, Pall Corporation and the Cell and Gene Therapy Catapult recently received an Innovate UK grant to develop in-process analytical techniques and continuous manufacturing approaches using the Pall Cadence BioSMB system to significantly improve purification yields for adeno-associated viruses.
The stakes could not be higher; the need for better manufacturing technologies and process steps was highlighted when a patient died in an early-stage CAR-T trial, due to a single leukemia cell accidentally being processed along with immune cells(3). To overcome the current hurdles there needs to be a concerted effort across scientists, clinicians, engineers, and regulatory agencies. Still, effective data collection and analysis throughout process development and manufacturing is a challenge even for traditional biopharmaceuticals. The compressed timelines and the complexity of gene therapy products only exacerbate this problem. Finding and reusing data from previous runs is difficult, if not impossible, and in many cases the most valuable information is buried away in spreadsheets and documents.
An integrated development platform that enables automatic batch recording and connects directly to instruments and material tracking systems is needed in order to achieve valuable process and product insight in a timely manner. Ensuring quality is embedded into the process from the beginning is essential for patient safety and also helps avoid wasted effort. The platform should be flexible enough for early process development and also support automation including the use of robots.
As in traditional bioprocessing, however, one of the biggest challenges is standardising data across various technology platforms. There are initiatives such as Allotrope, for analytical data and existing standards such as OPC and the ISA-88/ISA-95 object models for manufacturing, but true plug-and-play interoperability has yet to be achieved. Industry consortia such as the newly formed Cell and Gene Therapy Phorum are needed in order to promote knowledge sharing, establish best practices, and define industry standards.
While there is still a great deal of work to be done, the potential for cell and gene therapies to radically transform healthcare now seems to be a question of ‘when’, rather than ‘if’. The FDA has announced plans to issue new guidance later this year and the growth in global investment will hopefully soon lower production costs and ultimately improve the safety and availability of these therapies for the patients who desperately need them.