Perhaps the biggest achievement thus far at the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) has been disabusing companies that are members of the Manufacturing USA innovation institute that it is smart to be “a fast second” to market.
“Nobody actually believed when we started, except apparently us naively, that we could ever find a pre-competitive manufacturing innovation space” that would see companies in the same ecosystem collaborating and eager to be the first to market, said Kelvin Lee, who has led the public-private partnership since it was established longer than four years ago.
Of course, the companies that have joined the NIIMBL compete on products: “the molecular assets moving through the pipelines,” he said. “But a lot of companies do kind of treat manufacturing knowledge and knowhow as being a competitive advantage.
“This is an industry that sometimes proudly asserts, ‘We never want to be first in a manufacturing innovation; we want to be a fast second.’ And so, we’ve been able to take that idea and say, ‘By working together, we can all go first, together.”
Merck, Genentech, Pfizer, MilliporeSigma, AstraZeneca, BMS, GSK, Amgen, Lilly, Waters, Janssen, Cytiva, Sanofi, Takeda, Catalent and CSL Behring are all, in some sense, competitors “because they’re trying to bring medicines to market to treat cancer, to treat something else,” he said. “But when it comes to this shared vision for continuous manufacturing, all of those companies and many others are participating in hundreds of hours a week of meetings, sending their staff inside the walls of NIIMBL to talk about what is working for them and what is not working for them.”
NIIMBL can develop its own platform testbed that can be “a shared testbed for manufacturing innovation that is representative of what they do in their own labs but not the same of what they do in their own labs,” Lee said. “And that’s really a first of-its-kind approach to the manufacturing innovations field.”
Newark, Delaware-based NIIMBL managed to find “that space where a lot of companies are now willing to work collaboratively and make significant investments toward realizing their shared vision for manufacturing in the future,” he said.
The continuous manufacturing paradigm, a.k.a. smart manufacturing, is now something that NIIMBL member companies “can imagine” even though many of them still use paper records, Lee said. “They are still doing everything in batch. But the first inroads are being made to digitize the entire manufacturing process. Most of the companies have the in-house, proprietary portions of the process in a development lab, where they have done some continuous manufacturing. But it has all been walled off from each other. So, NIIMBL provided a chance for people to develop a shared understanding.”
The biopharmaceutical companies are also learning how to work in concert with the government agencies that regulate them, Lee said: “We can work collaboratively with the relevant agencies to develop a common vocabulary, understanding and principles—which would actually make it a little bit easier from a business perspective to adopt and implement smart manufacturing approaches.”
The mashup of biology and manufacturing is NIIMBL’s specialty. It works with companies and researchers on “therapeutic proteins, everything from insulin to the recombinant antibodies that you see a lot of commercials for these days,” Lee said. “It includes cell therapies and gene therapies which are some of the newest types of medicines to come to market. And it includes many of the vaccines available today.”
The industry, which is only about 40 years old, has figured out “how to effectively manage and produce high-quality medicines,” he said. “But a lot of the aspects of how those medicines are manufactured are really rooted in batch processing. And the easy problems, in terms of innovation, have been solved by many of the companies. But the really hard problems remain. And consortium like NIIMBL is an opportunity for everybody to work together to solve some of those major manufacturing technology challenges.”
Challenges include regulation of not only on the final product but also the entire manufacturing process. “And so, while technologies may exist that can do a certain step or a certain part of the manufacturing perhaps more efficiently than today’s technologies, the reality is you have to seek regulatory approval” for that step, Lee said.
The time absorbed in seeking approval is, of course, the main issue here: Going with “the tried and true” tech might be less efficient. But it means business risk to the timeline to get to market. “And the delay could only be one week. But if your product is anticipated to have sales of $5 billion a year, one week is very impactful,” he said.
Ditching batch processing for continuous manufacturing “requires a whole set of approaches and understanding to ensure that there’s good adaptive process control of the manufacturing steps,” Lee said. A company has to ask if it has the right sensors and the right algorithms for control. It has to ask if it is making the right measurements on the product as it is being made.
“There are a lot of issues on the technology side, and certainly there are a lot of issues on the data side,” he said.
On the technology side, Intabio joined NIIMBL to help prove out the value proposition for Blaze, an instrument that execs at the startup felt was going to be “essentially transformative for product quality analysis for biotherapeutics—intact proteins like monoclonal antibodies,” one of the drugs that can be used to treat symptoms of COVID-19, said Lena Wu. She led Intabio as CEO from its start in 2017 until this year, when it became an R&D unit of Sciex.
“Essentially, we were combining two of the gold-standard tests currently used in biomanufacturing a drug. The first test is used for quality control or detection: ‘Do I have a problem?’ And the second test is used to characterize that problem,” she said. “Biologics, or large-protein monoclonal antibodies, are really difficult to make because they’re very large and complex. They have something like 200,000 atoms. You have to use a cell to make them, and it’s hard to control a cell. So you have to constantly test to make sure you’re making the drug you believe you’re making.
“Right now, you have to use different instruments and it takes days, sometimes weeks,” said Wu, now a strategic advisor for Sciex. “We developed a technology and instrument that can integrate the detection and characterization tests into a single assay that takes 15 minutes to complete. So, it provides a really dramatic increase in productivity.”
Joining NIIMBL was transformative for Intabio.
“It’s really important to be working directly with pharmaceutical companies because if you build something in a dark room and you never test it with real companies, real customers, you could develop the wrong product, right?” she said. “You want to make sure you develop all the right features. Is it accurate enough? Is it sensitive enough? What does the data report have to look like?”
NIIMBL is “a community that we needed to be a part of,” Wu said. It provided the right network and some grant funding. “So, we got not only money for a project to test our technology with real samples but also four pharma partners”—Genentech, Merck, MilliporeSigma and BMS—who naturally have manufacturing problems to solve.
Intabio established so much credibility with Merck that its executives “went on to speak at conferences and present data they had generated in the collaboration with us,” Wu said, noting that while she continues to work with Merck and Genentech, Blaze has not yet been commercialized.
An underlying theme of all 16 manufacturing innovation institutes in the U.S. is global competitiveness.
In the work that NIIMBL does around R&D, Lee said “most people would agree that the U.S. is the world leader”—with the U.K. “not too far behind.”
“When it comes to manufacturing, of course the U.S. is a leader, but I think the biggest competitors are Ireland (for sure), Singapore, Germany, Switzerland and the U.K.”
NIIMBL about a year ago asked its member companies to develop a “shared vision for the factory of the future.” Since, it has pondered what moves are necessary “to move forward in a coordinated way to realize that vision,” Lee said. “That excited a lot of thought leaders in the industry: They don’t have to justify all of the costs themselves to realize that vision; they can be one of 15 or 20 organizations doing this collaboratively with the co-investment from the public side.”
In addition to continuing its work in continuous manufacturing and Big Data, NIIMBL in the next five years will also be focused on how to respond better to any pandemic.
“There is money set aside in American Rescue Plan for us, as well as the other Manufacturing USA institutes, to think about how we can be a part of pandemic preparedness and response,” Lee said. “We’ve put forward a whole bunch of ideas, which we can’t disclose just yet, to help.
A new program under consideration for NIIMBL is in vaccine analytics and assays. “We’ve seen significant interest—obviously because of the last year but not only because of the last year—in trying to bring the industry into alignment in that space.
Another is in the gene therapy vector space. “There, we’re expecting to launch a program in the coming year,” he said.
NIIMBL within the last year moved to a new headquarters facility that has shared demonstration labs and testbed labs—“places where some of our companies who are vendors and suppliers to the industry can showcase some of their technologies,” Lee said. “A lot of companies plan to send scientists to work here for six or nine months—to work alongside scientists from other companies.
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