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Achieving effective manufacturing processes and sufficient capacity remains a top priority across a diversified biologic drug pipeline.
In 2020, US biopharma companies face impacts from familiar business and policy issues-access to healthcare, patent protection, the cost of prescription drugs, the biosimilars debate, and the opioid addiction crisis-as the presidential and congressional election rhetoric heats up. In Europe, the United Kingdom’s departure from the European Union is certain; however, the terms of the departure are yet to be determined. Amid these political distractions, researchers and process scientists in the biopharma industry must focus on the familiar challenge of improving current processes and increasing productivity, as well as a new hurdle related to bringing emerging therapies to market.
A more diversified biologic drug pipeline-including bispecific monoclonal antibodies (mAbs), cell therapies, gene therapies, and nucleic acids-as well as gene editing techniques and new delivery methods hold promise for patients. The tedious work to establish manufacturing processes and controls could slow progress in bringing some of these therapies to market.
Cell therapies and gene therapies continue to generate strong research and investment interest, although investments have dropped off from 2018 levels. The Alliance for Regenerative Medicine (ARM) reports companies developing cell therapies, gene therapies, and other regenerative medicines raised $7.4 billion through initial and follow-on public offerings, upfront payments from corporate partnerships, venture capital, and private placements in the first three quarters of 2019 compared with $12.5 billion in all of 2018 (1).
More than 1000 clinical trials for cell and gene therapies were in progress at the end of Q3 2019 including more than 570 Phase II and more than 75 Phase III trials, according to the ARM report. With a significant number of therapies in the late-stage pipeline, biopharma companies, contract manufacturers, and equipment and materials suppliers must invest in innovative development, manufacturing, and supply chain procedures and practices to deliver these therapies to patients.
“Monoclonal antibodies have used the same manufacturing template for the past 30 years. Novel modalities currently don’t have that same foundation,” says Andrew Bulpin, head of process solutions, MilliporeSigma. “The development of reproduceable, industrialized manufacturing templates is desperately needed to provide successful and cost-effective cell and gene therapies. With that comes the need for quality and regulatory compliance standards.”
To bridge gaps in cell and gene therapy supply-while delivering cost-effective products-continuous improvement in both upstream and downstream processing is paramount to achieve higher titers and product recoveries, says Tania Pereira Chilima, product manager, Univercells. Incorporating processes into innovative, scalable, low-footprint, low-CAPEX systems can help reduce costs, she says.
Managing both the manufacturing process and a complex supply chain is vital. “Right now, cost-effective manufacturing is not really the primary challenge for cell and gene therapies, although costs can always be improved,” Clive Glover, director of strategy, cell and gene therapy, Pall Biotech. “What is more important is ensuring that the manufacturing process is robust and delivers a consistent product. We have seen manufacturing challenges associated with several late-stage and commercialized cell and gene therapies, which in some cases have delayed or halted their approval.”
“On the manufacturing side, cost effectiveness will be driven by increased automation, dependence on high-dynamic range cell production, and closing systems to avoid overheads of classified environments,” says Phil Vanek, general manager, cell and gene therapy strategy, GE Healthcare Life Sciences. “For logistics, better integrated operational and supply chain data management, purpose-built manufacturing execution systems, and reducing dependence on liquid nitrogen in storage and shipping will help alleviate risk and costs.”
While cell and gene therapies have generated excitement, conventional biotherapeutics represent the majority of the biologics market. A few trends, however, are changing the processing strategies of some manufacturers of these products.
“There is still a lot of growth around the globe in conventional biotherapies. Cost improvements are driving the need for efficiencies in smaller scale as well as manufacture in country for country,” says Michelle Stafford, global marketing leader, BioProcess Solutions, GE Healthcare Life Sciences.
Interest in emerging therapies has been sparked by their clinical performance, says Pereira Chilima. “However, I believe that there is, and will always be, sizable investments and capacity allocation for the manufacturing of traditional/conventional biotherapeutics as these are and will continue to be standard of care for a multitude of indications,” she says. “For companies trying to diversify their product portfolio and produce both conventional and emerging biotherapeutics, investing in flexible and modular manufacturing technologies will help them cater for different product classes and efficiently respond to market fluctuations.”
Bulpin notes that more niche therapies coming to market require smaller quantities of individual biotherapeutics. “This evolution will drive continued adoption of single-use, which will enable multi-drug manufacturing facilities,” he says. “In turn, the big thrust in manufacturing will be moving towards intensified, connected, and continuous bioprocessing, as well as Biopharma 4.0.”
To resolve a huge shortage of viral-vector manufacturing space, specialized viral-vector contract manufacturers are rapidly building more capacity, and therapy developers are investing in their own manufacturing capabilities, say Glover. “These investments in the viral-vector manufacturing space have not shown impact [on] the investment in conventional therapeutics. In fact, several new sites are still under commission or being introduced for more conventional biologics at companies like Lonza and Servier,” he says.
The clinical development of promising new cell and gene therapies is driving demand for capacity, says Vanek. “Capacity shortages for both [adeno-associated virus] AAV and lentivirus are being driven by the need for [current good manufacturing practice] cGMP plasmids for vector manufacturing, plus dramatic inefficiency in manufacturing yields of viral particles. As new facilities come online for cGMP-grade vector manufacturing and new manufacturing methods are developed for improving both upstream productivity and downstream recovery, these shortages will be eased,” he says.
“There is plenty of capacity for traditional biologics manufacturing. The demand and rapid growth of novel modalities has left capacity lagging,” says Bulpin. “The standardized manufacturing templates I mentioned will bring predictable yields to inform a capacity plan. Having standardized outcomes are a key element to better capacity planning.”
Pereira Chilima cites a combination of technology innovation and process optimization as the key to addressing capacity constraints. “Process optimization in scalable advanced technologies will enable manufacturers to exponentially increase their throughputs within the same physical perimeter,” she says.
René Gantier, director, process R&D, Pall Biotech concurs. “This is what is driving a lot of investment and interest in the industry now by looking at ways to create a smaller footprint with an increased output to optimize efficiency, time, and money in the process,” he says. “We also see multi-product facilities enabled by single-use technologies that have flexible manufacturing approaches (e.g., manufacturing modules, ballroom manufacturing concept in controlled, not classified space).”
“To respond to market needs for capacity, speed to manufacturing, modular platforms, and workforce training are at the forefront of any business strategy,” says Stafford. “Speed to manufacturing can include in-sourcing/outsourcing analysis, which will take into account the long-term business plan, [intellectual property] IP protection, capital expenditures, time to market, and the technical capabilities of manufacturing or [contract development and manufacturing organization] CDMO personnel. The result of this analysis will determine if capacity is outsourced to a CDMO or organic expansion and training is warranted.”
“For mammalian manufacturing, there have been significant expansions in CMO/CDMO capacity over the last year with many companies announcing new facilities,” explains Charles Christy, head of commercial solutions, Ibex Dedicate, Lonza Pharma & Biotech. “Single-use technology is facilitating rapid addition of capacity and process intensification is also playing a role in optimizing existing assets.”
The integration of both proven and new technologies-including continuous processing, automation, virtual reality (VR), and data management-are vital to meeting and advancing bioprocess capacity demands.
Automating bioprocesses is a crucial factor to realizing the benefits seen for other industries such as reduced time to market and time to process, process and product safety through reduced operator errors, improved consistency and reproducibility, says Gantier. “The systematic use of quality-by-design [QbD] principles, where all process variables are characterized in detail, enables building accurate and reliable process models. Also, advancing sensing technologies and analytics from monitoring to predictive, then prescriptive and finally cognitive helps to enable highly automated bioprocesses.”
“Data availability and mine-ability will provide us with better insights for process optimization and manufacturing efficiency improvements,” says Vanek. “While still early, the data we’re collecting as an industry can be curated to connect events with outcomes, and this, in turn, can lead to new insights and ultimately predictability of processes. Connecting sensors, biological data, and manufacturing performance in real-time will also enable improved automation and better decision making.”
“Big data and artificial intelligence will move us to descriptive vs. prescriptive methods of manufacturing control,” Bulpin notes. “A descriptive method moves away from a traditional biologic manufacturing standard operating procedure and tunes into the needs of the living organisms used to produce a biologic. Big data will develop the ‘golden batch,’ delivering consistent and optimized outputs in each run.”
“Although ‘Industry 4.0’ is not a totally new concept, it has taken more time to integrate new technologies into the complex and risk-averse bioprocessing world,” notes Christy. “There are many areas where advances in digital technology can and are making a difference, ranging from onboarding new operators with VR, reducing time for tech transfers and product release using more advanced data analytics, and modeling bioprocesses to optimize QbD.”
Pereira Chilima predicts that the industry will continue to focus on achieving higher production titers and move towards intensified, automated, and continuous processes to produce ‘more for less.’ This approach will enable manufacturers to dramatically reduce the footprint of operations, achieve higher productivities per production line, and install more production lines within the same footprint. “This will result in higher annual throughputs, lower CAPEX, and consequently lower cost of goods sold (COGS),” she says.
“Although process intensification and continuous manufacturing have been a discussion point for years, joining the different elements together or focusing on hybrid processes will move us one step closer to fully joined up solutions,” predicts Christy. “Real-time release is already a reality in small-molecule manufacturing and something that will considerably speed up biologics manufacturing.”
“The application of continuous manufacturing to monoclonal antibody production has been well studied. However, its ability to impact novel therapies such as viral vectors has not been well characterized,” says Gantier. “There are, of course, complications to applying continuous manufacturing to viral vectors, not least of which is the fact that the virus kills the cell that produces it. Nevertheless, there is the possibility for continuous manufacturing to drive unit operation intensification bringing greater process robustness and reproducibility.”
For cell and gene therapies, Vanek expects a better understanding of biological systems and how they are impacted during manufacturing, improved process analytics to monitor that biology, and digital integration to collect data and make process decisions based on real-time biological information.
Industrializing cell and gene therapies will continue, moving along the same commercialization and optimization curve as recombinant proteins and monoclonal antibodies, says Christy, “but hopefully faster given that the industry can apply some of the experience learned in fermentation and cell culture.”
“We also expect a resurgence in microbial manufacturing as some of the newer complex proteins in early phase not requiring mammalian glycosylation or the linker elements for some bioconjugates become more important. Improvements to expression systems, titers, and process intensification can further reduce COGS and production times considerably in this platform, providing distinct advantages for classes of molecules such as novel vaccines, protein-linker bioconjugates, and even biosimilars,” Christy concludes.
1. Alliance for Regenerative Medicine, Quarterly Regenerative Medicine Sector Report (Q3 2019).