BioPhorum Drug Substance Closed Systems in Controlled Non-Classified Workstream has recently published its room...
Overcoming unique challenges to support rapid development of diverse products
Realizing the challenges that arise in any new sector, BioPhorum took the initiative in 2018 to bring together companies with a vested interest in the area to form BioPhorum C> to connect drug development and contract manufacturing organizations in collaboration and enable harmonization and alignment across the sector. C> members realized that the rapid acceleration of the sector brought supply chain, manufacturing, testing, and regulatory issues to the forefront, and most importantly, while a one-size-fits all solution was not possible for such a diverse sector, they could not face these challenges on their own.
Growing pains – manufacturing and production challenges
The recent approvals of several cell and gene therapy products over the past year are likely the beginning of a significant trend in increased approvals across various disease areas in the sector. This increased development is associated with strong performances for biotech in 2020, as initial loses due to the pandemic quickly reversed, as evidenced by an 82% growth in cell-based immuno-oncology and a 70% growth in gene therapy public performances over the past year. Matthew Westoby, Director of Cell Therapy Process Science and Technology at BMS explained some of these trends and how this growth brings with it inherent challenges to the industry, including manufacturing and supply chain issues. “Now that the first set of products has been commercialized, I expect even more rapid acceleration in the numbers of products, which will yield its own challenges in regard to supply and raw materials. These products are really difficult to make, and the science is accelerating so rapidly, it is difficult for the manufacturing technologies and procedures to match the pace of that advancement. We need to close the gap between manufacturing and the rapid pace of scientific advancement,” said Westoby. Sarah Yuan, Vice President of Process and Analytical Development at bluebird bio agreed, “From the CMC perspective of the CGT sector, there is a tremendous manufacturing capacity shortage as of 2020. This is driving our timeline to clinical start and impacting value delivery to our patients. We need to determine how to get our drugs to the clinic faster and how to establish a robust supply chain for commercial products.”
Marian McKee, Vice President of Biosafety from Eurofins BioPharma Product Testing, explained that the rapid acceleration of product discovery and manufacturing, particularly now that clinical trials are restarting after pandemic delays, will significantly increase the amount of work for analytical testing laboratories. “We have an active initiative to provide the testing and services needed for CGT producers and manufacturers, developers, and CMOs. We have prepared for things to ramp up and grow and have made investments to allow us to offer the appropriate services, skill sets, and capacity to serve the increasing demand in testing for cell and gene therapy products. This high demand is occurring globally, and we recognize that this is a big opportunity for ourselves, as well as the entire sector.”
“We don’t just think about current struggles. A lot of the discussions we are having are also forward looking, and so from a strategic perspective, having that forward looking approach helps us innovate in a collaborative fashion and start to develop strategies to navigate challenges of the future,” said Max Tejada, Executive Director and Head of Analytical Development at Kite Pharma.
Unique challenges facing the CGT sector
CGT products are unique compared to anything the biopharmaceutical industry has produced to date. As a result, the knowledge, data, and expertise of these products is in its infancy. Companies specializing in CGT cannot simply take processes deemed relevant to protein products and translate them seamlessly to CGT products. For example, testing and validation procedures are limited by product yields, and the ability to scale up CGT products has proven challenging. According to Kathy Zagaroli, Director QC Operations and Microbiology at Ultragenyx Pharmaceutical Inc., “Yield presents many challenges to do required validation or routine testing similar to biologics. We need to think out of the box to determine how to do this testing and still be compliant with the limited yields we achieve. On the manufacturing side, we need to determine how to scale up with something that is commercially feasible. If you go to market and you have a patient population that needs treatment, one batch of product may only be able to treat a few patients.”
Companies have realized that unique struggles are also prevalent among interactions with regulators. Similar to the learning curve companies themselves have to undergo, regulatory agencies are also faced with increasing their knowledge of the complex processes involved in manufacturing CGT products. This can culminate in uncertainty among both companies and regulatory agencies, resulting in added work and delays. “Getting an understanding of what the regulatory expectations are can be challenging. With biologics, you know what to expect in regulatory submissions; whereas in CGT, things are more unknown,” said Zagaroli.
Considering all these challenges, the ultimate goal for CGT members is to produce products in a timely, cost-effective manner to benefit as many patients as possible. Yuan explained that a big concern for everyone in the sector is cost. With clear benefits for patients, companies are excited to bring these products to commercialization; however, how to keep manufacturing costs under control is a significant hurdle facing the sector. “The cost of CGT products is a big issue that limits their availability and accessibility to patients who need them. We need to determine how to modernize the manufacturing processes and practices so we can bring down the cost of manufacturing these drugs,” said Yuan.
“We are just starting to realize the benefit of CGT. The promise of having curative drugs for some of the previously untreatable diseases is amazing. The field will expand into disease areas that haven’t been previously considered for CGT. It really is an exciting time to be in CGT,” said Sarah Yuan, Vice President of Process and Analytical Development at bluebird bio.
A promising outlook for the future through collaboration
Despite these challenges, C> members are optimistic and realize that through their concerted efforts with BioPhorum, these hurdles can be overcome. Max Tejada, Executive Director and Head of Analytical Development at Kite Pharma, believes that the CGT sector will evolve much the same way as the protein therapeutics sector had. “As we gain experience with these products, there will be a level of maturing and understanding about CGT, not just in the industry but also with the regulatory authorities. There are a lot of unknowns which understandably create some hesitancy from regulators and result in an increased amount of work that is needed to move clinical programs along. But much like what happened in protein therapeutics, over time there will be more data and knowledge obtained that will alleviate many of these concerns,” said Tejada.
The C> members agree that their involvement in BioPhorum is proving to be beneficial to both their individual companies, as well as the sector as a whole. According to Pamela Rodriguez, Senior Manager of External Collaborations at BMS, “One of the advantages of being in BioPhorum is that we can really align with industry practices and understand what best practices are. By interacting with other companies and regulatory agencies we can help shape the creation of industry standards and create an industry consensus.” McKee agreed, “BioPhorum brings the players in the industry together in conversation and discussions at both high and in-depth levels to understand what the needs and challenges are in the CGT space and identify common solutions. Coming together as an industry, with manufacturers and testers, gives us more power in the aggregate as these solutions are identified and as we work with the standards and regulatory bodies to move the industry forward.”