In a Bioprocess International keynote last month, NIIMBL Director Kelvin H. Lee, Ph.D. illustrated the power of consortia and public/private partnerships in advancing next-generation approaches to ATMP manufacturing, and demonstrated how the Institute isn’t just talking—it’s building.
Launched in 2017, NIIMBL: the National Institute for Innovation in Manufacturing Biopharmaceuticals is what Institute Director Kelvin Lee, Ph.D. refers to loosely as a “$580 million investment activity, exercise, pilot program, however you want to think about us” that’s on a mission to determine how collective monetary, technical, and intellectual resources can move the needle in biologics manufacturing. While the terminology he uses to describe the NIIMBL initiative isn’t particularly well-defined, the work the organization is engaged in certainly is.
The collective of more than 200 member biopharma companies, colleges and universities, non-profit organizations, and federal, state, and local government agencies “come together to think about how we can collaboratively de-risk and demonstrate new technologies that are coming along through the development pipeline,” says Dr. Lee. “Ultimately, we want to see these technologies deployed in commercial manufacturing operations.” At the Bioprocess International Conference & Exhibition, Dr. Lee delivered a keynote, “Going First Together,” that demonstrated the work the collective is doing to that end.
Building A Collaborative Regulatory Experience
Since its inception, NIIMBL has launched more than 120 projects, funded by investments generally ranging between $1 million and $3 million per initiative. Those projects have focused on the development of technology innovation, assays, digital products and models, and the biopharmaceutical workforce. Dr. Lee highlighted a few of those initiatives, but before he did, he shared some important context on the work the Institute is doing to nurture regulatory collaboration.
“We recognize a culture in this industry of wanting to be fast, but there’s a notion that if you’re the first one to present a great new assay or unit operation to health authorities, you don’t know what kinds of questions they’re going to ask,” says Dr. Lee. These unknowns can cause apprehension. “There’s a sense among many in the community that perhaps they don’t want to be first. Maybe they want to wait until there’s a bit of comfort with a particular technology of paradigm on the part of health authorities, and then go second as fast as possible. That really isn’t the kind of mindset we want,” he says. “Maybe that’s why we still have certain vaccines being made in eggs.”
Central to NIIMBLs collaborative spirit is an effort to shift the culture to one where, per his aptly-named keynote, “everybody wants to go first together.” In partnership with the FDA, NIIMBL studied this phenomenon to probe the perception that regulatory authorities actually contribute to the problem; that regulators and the regulations they create are simply unreceptive to new technologies.
“As you can imagine, some of our friends at the agency said that in fact, the regulations are pretty open, they just want to see the data that justifies said new technology,” says Dr. Lee.
NIIMBL subsequently engaged in a project it dubbed an “Active Listening Workshop,” whereby it interviewed several large, global biopharmaceutical companies to understand their perceptions of the barriers to adopting and implementing new technologies. It collected and anonymized that feedback, then held an in-person workshop with FDA staff to review those biopharmaceutical companies’ biggest concerns about adopting new technology in terms of their interactions with the agency.
“Agency staff listened, very intently, and they were very receptive to that kind of feedback. There were moments of tension and moments of comradery,” says Dr. Lee. Ultimately, NIIMBL issued a report on its findings, which was published in the PDA’s Journal of Pharmaceutical Science and Technology. “One of the big takeaways was that it's not a regulatory hurdle as much as it is the business risk associated with speed to market. When you're trying to go very fast and trying to get your product on the market, you have to ask yourself a question: If I do it this new way as opposed to the way that I've done it in the past, how is that going to affect my timeline, and it is it really worth it?”
Dr. Lee says the “powers that be,” the people making those decisions, often tilt towards the more conservative approach and apply existing technologies in the name of staying on timelines to market. “It's a business decision. It's not necessarily a regulatory acceptance decision,” he says. “But there are opportunities to have dialogue with the health authorities before you file to try to develop that shared understanding.” To address the issue, the Institute launched what it calls its NIIMBL-led projects, which Dr. Lee describes as initiatives that invite some of the larger Institute member companies to work together to define and shape a program of work. That program of work, comprised of work streams and projects, he says, is meant to enable the ecosystem to move at scale and at a speed that can't be achieved through traditional NIIMBL mechanisms. “They're structured to enable a more deep and direct engagement with subject matter experts and thought leaders from the industry through steering committees, and they include a mechanism where small companies with innovative technologies or even academic partners with innovative technologies can advance specific initiatives.”
Ambitious Pursuit Of Process Intensification
To illustrate the concept, Dr. Lee shared an ambitious 10-year NIIMBL-led process intensification project led by Senior Fellow and acting Chief Technology Officer John Erickson, Ph.D. In lockstep with NIST and a who’s who of giants in the biopharma development and supplier spaces, Dr. Erickson’s team set out to “invent, design, build, and help commercialize drug substance and drug product manufacturing that enables flexibility to supply extremely diverse and changing portfolios of products to improve control, robustness, and security of supply, lead to faster product development and supply chain velocities, enable sustainable plastic and energy use, decrease capex and opex for mAb manufacturing, and ultimately integrate drug substance and drug products expertise in manufacturing.”
Ambitious indeed. To read the latest details on the project, see this article in Biotechnology & Bioengineering. Dr. Lee summarized in his keynote. “If you think about the most intense processes that we have today—intensity being amount of product for volume of factory-per-unit time—we've got a standard process for mAbs. We also know that many companies have developed first-generation process intense processes, or connected, or continuous manufacturing, but a lot of that lives in R&D labs,” he says. “We don't think anyone has gone fully commercial with it, but those first-generation technologies exist and they’re resulting in roughly an order of magnitude increase in intensity of process.” This program, he says, intends to encourage the adoption of these first-generation intensified processes in commercial operations producing licensed products.
Concurrently, Dr. Lee says some companies are working on second-generation processes with the potential to yield even greater results, up to 100x the current fed-batch standard. “We want to develop some of those technologies that need to be developed to the point of widespread adoption and then, acknowledging that it will require invention of new technologies, get to work on third-generation technology,” he says. “We think about this in the terms of generations and technologies, and where we need to invent versus where we need to collaboratively demonstrate the maturation of existing technologies.”
Addressing Supply Chain Constraints And Multi-Sourcing
Bringing multiple stakeholders together for the effort, many of them technology and equipment vendors, will go a long way toward the interoperability required to maintain operations during supply chain snafus like the one we’re experiencing today. In particular, one element of the project, dubbed the “flexibility workstream,” was able to demonstrate interchangeability of biosensors in real time without data loss. For instance, Dr. Lee says the team demonstrated the ability to be fully operational with one particular pH sensor, plug in a second sensor from a different vendor, and start collecting data on the new sensor from a different vendor using the same software interface. “All your data is still stored in your history in a real time,” he says. “Typically, to do that on the floor would require a two- to three-week changeover period to make the switch and transfer and validate the data.”
Dr. Lee says this project is one of a host of related activities under way at NIIMBL as part of a holistic approach to deploy technologies that constitute the biomanufacturing facility of the future, one that’s characterized by:
Control strategies and Quality by Design (QbD)
On the QbD front, Dr. Lee cited the Institute’s n-mAb case study, which is available here, and made a specific plea for feedback and commentary on that work, which he calls a living document designed to be updated by the benefit of shared experiences. “The n-mAb case study is a 250-page guide for control strategies in the context of continuous manufacturing, far more substantial that ICH Q13 Appendix 1,” he says. It’s meant to guide decisions based on agreement and alignment—as well as points of contention—among early adopters of continuous manufacturing. “It’s focused on antibodies, but it’s not specific to antibodies,” he says. “It’s designed to apply to many different types of modalities that can benefit from it.”
Dr. Lee also touched on:
NIIMBL programs in viral vector manufacturing, designed to explore platforms for AAV manufacturing with both mammalian and insect cells, the analytical tools required to drive convergence in the AAV field, and what lessons the AAV space can take from the development of platforms in the antibody community.
The Institute’s vaccine program, funded by the American Rescue Plan and the Bill And Melinda Gates Foundation, which focuses on developing standardized analytics and potency assays. “We have a number of workstreams planned to characterize and develop potency assays and build a structure around how one develops them, including modular, portable platform processes for mRNA and manufacturing technology to support the thermostability of vaccine.
Putting White Paper Theory Into Tangible Practice
Demonstrating the physical fruits of NIIMBL’s collaborative work, Dr. Lee took a deep dive into the results of its recent work with the BioPhorum Operations Group. “As part of its technology road mapping effort, this group had identified opportunities for advances in buffer management and buffer preparation, resulting in a nice white paper that described and justified the value that could be created with a new platform that might be open source and IP free,” he explains. “A number of our member companies thought it would be great to not have just a white paper, but to build a prototype skid based on the principles covered in the white paper and demonstrate that it works,” he says.
The idea was to illustrate an alternative to buffer prep using proprietary stock solutions and very large fixed stainless-steel tanks, which introduce a host of supply chain management risks including the sole-sourcing quandary. Dr. Lee says the project sought to answer the question, “how can we think about getting away from needing custom SKUs and moving toward a future where all the vendors have available stock solutions that can be mixed and diluted in real time to create whatever buffer you need on the fly?”
To cut to the chase, the NIIMBL collaborative brought the aforementioned white paper to life in the form of the NIIMBL-BioPhorum Buffer Stock Blending System, or BSB, a physical skid capable of inputting up to 16 concentrated stock solutions and producing buffer at up to 60 liters per minute. “It’s all based on mass flow control, sized for a 2,000-liter single-use upstream bioreactor, and it’s ready to go with clean-in-place and sterilize-in-place,” says Dr. Lee. “It’s also open source in its design, so you can actually go and download the drawings, IP, and diagrams for all the information you would need to contract with your own skid vendor and build a replica.”
Again, with security of supply in mind, the skid was designed to accommodate multiple interchangeable parts from multiple vendors to avoid the proprietary equipment stranglehold. Of course, concept cars are just cool to look at if they don’t perform. This one does. Traditional buffer prep approaches, says Dr. Lee, would basically be a 24/7 operation with four to five buffer prep stations. The BSB skid demonstrates 3x to 4x improvement in operational efficiencies including dollars per liter, takes less than 30 seconds to start up, and achieved more than 98% compositional accuracy for the buffers it produced. The BioPhorum/NIIMBL team built more than 100 of them, demonstrating less than 0.5% standard deviation in Ph and conductivity. It also integrates seamlessly with external skids from other vendors.
“This project illustrates how working together is probably a more efficient and a more effective way to demonstrate technologies and develop shared understanding,” says Dr. Lee.
For a comprehensive look at the ongoing collaborative work being lead by NIIMBL, and more of the fruits of that collaboration, visit the Institute’s website.