As the industry begins to think broader around scalable manufacturing for cell and gene therapy (CGT), the closing and automation of upstream material and systems that feed into the core process has become critical, and importantly – now technologically possible. These ancillary processes such as media formulation, viral vector filling and packaging are all part of the labor-intensive formula that are entering into a period of innovation and automation.
While the initial focus was on the closed, integrated and automated core processes, the ancillary processes remain open. The next phase of growth in the CGT industry is expanding automation into these processes. Although lessons can be learned from the current biopharmaceutical sector, the material and packaging requirements for CGT are unique. As a response to this need, platforms have been established to support the specific needs of this industry.
More integration options are becoming available
For CGT developers, manual media formulation and preparation is one of the largest bottlenecks in CGT manufacturing followed closely by viral vector preparation.
Are these ancillary processes still pigeonholed as manual processes? “No,” says Randy Schweickart, Senior Director of Process Technology Development at Bristol Myers Squibb. “Now that we have some automated platforms, the scientists who are bringing the next pipeline product along can assume that we have those capabilities,” says Schweickart. “We are not working from the blank slate that we were [working from] when we started.” Similar to preclinical development, manufacturing process development has advanced significantly in the last several years.
Platform processes have emerged, making it easier to ‘plug-and-play’ earlier in the development cycle. For example, bag filling platforms are available to accurately dispense therapeutic products or processing material from formulated bulk into individual bag units.
These automated platform systems provide the benefits of a closed system including reducing manufacturing overhead by moving processes to class C or D cleanrooms. With expanded closed system-based automation, a facility will no longer be burdened with a large quantity of expensive A or B cleanrooms to support ancillary processes.
Manufacturing facility designers should be consulted as early as possible, as production feasibility assumptions made by scientists may be outdated and automation solutions may be available. Amy Shaw, Lead of Cell Therapies Engineering and Automation at Takeda, affirms that to support manufacturing preparing for commercialization it is important to push as much of the upstream processes into the lower-grade spaces early in the timeline.
Shaw states, “If you can bring in ancillary materials that are closed and clean it relieves a lot of the constraints on the core processes.” Facility designers are now able to leverage automation systems instead of devising home-grown engineered solutions.
For CGT manufacturers, to err costs more than money – it impacts lives. Facility designers and operators shoulder the burden of maintaining sterility and product quality throughout the process. When scaling up unit processes, the impact on manual manipulations and volume of materials is substantial. By reducing the cost of errors as well as the substantial cost of the manual operation, the result is a better, less costly and more scalable product.
Minimizing process variability is one of the biggest benefits of moving to automated, closed cell therapy manufacturing systems. By investing in manufacturing automation strategies and closing systems with the use of automation platforms and accompanying single-use sets, CGT developers can plan to minimize process variance. “I like to think of automation and enclosure working hand in hand,” says Shaw. “Taking it out of the operators’ hands and putting it into automation equipment gives the opportunity for any component of the process to move in a controlled manner. You can leverage sterile tube sets to really contain the system, close it, and provide extra sterility around the product as well.”
The use of sterile, closed single-use sets is accelerating as more products approach the commercialization phase and the supply chain adapts to the CGT space. Adopting a sophisticated supply chain is a must as therapies become more commercialized, however, the industry is somewhat divided on whether it is best to source single-use sets through their automation partner or through other providers.
Sourcing from a single provider can be risky due to supply chain challenges. However, some CGT developers prefer single-use sets through their automation partner, as the advantages of accessing single-use sets that are designed for the automation platform in question are significant.
CGT companies often find themselves educating their vendor on material needed, yet suppliers are unable to provide the material in the required format. Responding to this gap, automated formulation and fill platforms have been established with focus on the formulation of large-scale culture media, cell products for cryopreservation, automated bag-filling of cell products (both autologous and allogeneic) and packaging of viral vector products.
The challenge of data integration
The production of small-scale autologous therapies presents an automation challenge due to the small batch size. Automation platforms with integrated and linked data streams have been established in large-scale pharmaceutical production facilities but have not been readily available for CGT production.
Without linked and closed automation, data is not able to flow from one process to another. On-demand access to data is a critical factor in reducing the vein-to-vein cycle time of the therapy. Farid Ighemat, Senior Director of Manufacturing at GlaxoSmithKline highlights the importance of quick access to data during processing, “The more you do in reducing that release cycle time, the better you are off in getting that material back to the patient in a timely manner.”
With automation platforms available to support small-batch manufacturing, along with CGT processes starting their commercial ramp, data can now be shared between core and ancillary processes, and facilities can start to get closer to review by exception. For example, automated bag filling platforms are able to integrate seamlessly with various Manufacturing Enterprise Systems (MES).
The way forward
As automating cell therapy manufacturing and gene therapy expands, the time to automate ancillary processes is now. These manual and open processes are bottlenecks – as well as high-cost drivers – to commercialization. Initially CGT facility designers had to develop their own site-specific solutions to support the core process, but today, automation system and platforms are available.
Researchers upstream from commercial manufacturing can assume more automation options for processes such as media formulation, viral vector filling and packaging are available to ‘plug-and-play’ into the manufacturing environment. “Cell therapy is getting bigger,” says Shaw. “We are still using components off the shelf that are coming in bottles, such as serum, glutamine, etc. Cytokines are a huge issue for us, they are coming in small aliquots that we have to manually pipette a lot of times… If things could come in easily weldable formats that we could transfer in closed containers in a sterile fashion, that would be great for the field.”
It’s no secret that CGT manufacturing is in need of standardization to reap the rewards of process efficiencies. When it comes to ancillary processes, the industry is at an inflection point. Suppliers of base media, supplements and specialty reagents can help by providing plug and play packaging solutions that are compatible with automated and enclosed CGT manufacturing systems. Additionally, CGT developers have access to a growing number of enclosed, automated manufacturing options available to incorporate ancillary processes such as Invetech’s formulation and fill platforms. Both are needed for the industry to truly be able to remove bottlenecks around media formulation, viral vector preparation and unique cell therapy reagents.
Webinar: Automating Ancillary Processes in Cell and Gene Therapy Manufacturing
Access the on-demand webinar to hear industry experts share challenges encountered when closing and automating ancillary processes, and how improved scalability and reproducibility were achieved by moving to closed automated platforms.