How Will The CGT Manufacturing Paradigm Mature In 2022?
By Anna Rose Welch, Editorial & Community Director, Advancing RNA
Eye-opening. Heterogenous. Challenging. Changeable.
To Robert Hariri, CEO of Celularity; Matthew Durdy, CEO of the Cell and Gene Therapy Catapult; Beth White, CBO & SVP operations of Renovacor; and Geoffrey Glass, CEO of Kiniciti, the past year in the cell and gene therapy (CGT) manufacturing space has been all of these adjectives — and more.
I believe it was Elizabeth Barrett Browning herself who once wrote: “How does the CGT manufacturing paradigm vex me? Let me count the ways.” (Or something like that.) For one, operations have been stymied by a scarcity of talent, manufacturing capacity, and critical materials. In addition to facing long lead times for products and services, a number of companies found development timelines shifting thanks to unclear — or, in some cases clarifying — regulatory guidance and requests for more chemistry, manufacturing, and controls information. Predominantly manual processes, ill-suited or non-existent analytical and manufacturing technologies, production limitations, and a high cost of goods sold (COGS) mar these therapies’ paths to large-scale development. And, of course, we can’t ignore persistent concerns over the safety of cell and gene therapies, particularly as it relates to lentiviral and adeno or adeno-associated viral vector (AAV)-associated toxicity and oncogenicity.
However, patients’ need for these therapies today dictates that companies be resourceful and adapt as scientific knowledge, regulatory pathways, and manufacturing processes solidify. As Hariri, Durdy, White, and Glass shared their expectations for 2022 and beyond, what emerged was a benchmark for what the CGT manufacturing paradigm could realistically look like in 2022 and which in-the-works innovations will help the industry slowly but surely mature.
CGT MANUFACTURING CAPACITY IN 2021: A YEAR OF EPIC GROWING PAINS
In the past year, capacity was both everywhere and nowhere to be found. While there were many celebratory announcements of new facilities and acquisitions of existing facilities, articles and references to the dreaded (albeit pleasantly alliterative) “Capacity Crunch” were also plentiful.
To Durdy, the industry’s quest for capacity will continue to influence and inform CGT manufacturing strategies throughout 2022. Though some predict overwhelming spare CGT manufacturing capacity in the future, Durdy is not yet confident this will be a near-term reality. For one, COVID-19’s persistence continues to dictate the production of vaccines and therapeutics. In addition, Durdy noted a 20 percent growth in the number of CGT clinical trials, all of which require manufacturing capacity. While biotech firms have been keen to invest in their own manufacturing facilities, Durdy noted that the outsourcing industry — when it’s not consolidating — has been snapping up existing facilities, as opposed to constructing new manufacturing facilities.
If anything, Durdy argues, “The world became a much larger place over the past year or so.”
While companies typically operated research and development and manufacturing facilities in various parts of the world, the pandemic with its travel bans and border closures encouraged companies to prioritize co-location of critical facilities.
“Historically, companies’ development networks spanned multiple countries or territories. They may have housed their R&D in one area — for instance, the U.K. — and built their manufacturing facility in another area, like Philadelphia or Los Angeles,” he clarified. “Now, they’re more likely to prioritize keeping their R&D and manufacturing capabilities in the same vicinity to promote in-person interaction across departments and safeguard against the disruptions we’ve encountered with the pandemic.”
Much of this, Durdy surmises, has been reinforced by added pressure from investors who want to know up front how companies’ manufacturing strategies are equipped to mitigate current capacity shortages.
BUILD VS. BUY: THE ROLE OF THE OUTSOURCING PARADIGM REMAINS A SUBJECT FOR DEBATE
While capacity remains a coveted asset today for CGT biotechs, private equity firm Kiniciti’s Glass warns that we shouldn’t conflate capacity creation with value creation and innovation — especially when considering outsourcing partnerships. When the first wave of service providers entered the CGT arena, there was little to no capacity to be had. But today, Glass anticipates that the number of providers and the extent at which they’re increasing their capacity has made it inevitable that the supply-demand constraint will eventually evaporate. As such, having capacity alone is not enough of a value-add for the CGT space of tomorrow.
“We don’t believe the CDMO partnership of the past is going to be that of the future,” Glass explained. “The outsourcing partnership will not be just an exchange of funds for a basic bank of services. There won’t be enough value-add there.”
While traditionally, a biotech would license a specific technology from a tech supplier and go to a CDMO for batch manufacturing, Glass believes that those two services are going to have to converge under one roof.
“CDMOs will have to determine how to marry proprietary, high-value, transformative technologies with the ability to deliver GMP solutions at scale,” he said. “We believe those two offerings must come together for a CDMO to play a meaningful role in the future.”
As CDMOs weigh their approaches to this value creation, Durdy sees CGT companies keeping a tight hold on their manufacturing processes for the next five years (at least) because of the negotiation value this may provide them when outsourcing in the future. Because manufacturing today is a competitive differentiator, companies hesitate to hand development power and know-how to their CDMO partners. Rather, by keeping the development work in-house for five to 10 years, the company can find itself on much more solid footing if and when the time comes to approach a CDMO.
As Durdy explained, “Once you’ve established your automated processes and product-specific analytical platforms, you can approach a CDMO with a process that is completely defined and doesn’t need to be changed. The CDMO can simply be tasked to run it more efficiently than you can run it yourself, in turn altering the power structure and budget of the outsourcing relationship.”
Of course, the question then becomes: “Does the desire to keep manufacturing in-house today mean there will be too many players investing in their own square footage?” Before we start frantically tallying up a future of empty facilities, Durdy urges cautious optimism. After all, earlier this year, the U.K.-based cell therapy company Autolus announced it was shelving its Maryland manufacturing facility in favor of constructing a new facility in the U.K. The Maryland facility was then leased to another cell therapy company.
“Such a turn of events — should it become a trend — lessens the risk for those funding facility construction today because that facility could be acquired by an emerging firm somewhere down the line,” Durdy offered.
WHY IS ALL THE [PRODUCT] GONE? HOW TO EASE CGT SCALE-UP WOES
Arguably, increasing global access to CGT therapies is the industry’s chief long-term goal. However, to do so, the industry will need to answer some particularly gnarly scientific, analytical, productivity, purification, and supply-chain challenges to bring down COGS.
To Celularity’s Hariri, achieving maturity in these areas of the manufacturing process is not for the faint of heart. “It means controlling the systems engineering and process design around making a product,” he explained. “It means controlling the infrastructure and environment in which you do that manufacturing. Finally, it means writing the letter of the law for the quality systems and the standards to which you’re going to hold the products. Depending on the product, you may also need to ensure that it lends itself to cryo-preservation and long-term storage.”
In the predominantly autologous/ex-vivo cell therapy space today, manual and scaled-out processes keep large-scale development at bay. This is why both Glass and Hariri believe that the allogeneic cell therapy model is the most promising strategy for achieving large-scale, consistent, cost-effective cell therapy development and greater patient access. As Hariri argues, starting with a cell line of undifferentiated stem cells eliminates patient variability in starting materials which, in turn, promotes greater expandability, scalability, and consistency. (The type of stem cell a company can choose to start with, on the other hand, is up for debate and is a topic for a whole other article.)
“The autologous model was a phenomenal proof of concept that incentivized and fueled development in the field,” Hariri explained. “However, our healthcare system was not designed for a make-to-order model. Having an allogeneic model that is one-size-fits-all means that we can make and store these products within treatment centers and ensure on-demand access.”
On the gene therapy side of the industry, Renovacor’s White also homed in on the progress being made to bolster gene therapy scalability and consistency. Though COVID-19-related supply shortages were a tricky barrier to navigate industry-wide, White saw this barrier as a positive force, as it encouraged gene therapy players to improve their workflows and streamline development and manufacturing timelines. Technologically, the industry also continues to see some important advancements. In addition to cell lines being “on the cusp of maturity,” White noted that the purification of viral vectors — for which legacy biologics technologies are ill-equipped — has advanced significantly, thanks to the selective separation capabilities of affinity monolith chromatography.
Given such progress, some may argue that gene therapy has a leg-up over cell therapies today. However, as White admitted, reaching large-scale development continues to be just as much a pain point for gene therapies, due in large part to continued inefficiencies in the transient transfection process. White anticipates that the advent of stable producer cell lines, linear or synthetic plasmid DNA, and scalable separation technologies will be game-changers for improving AAV titer — particularly as it relates to bolstering the percentage of full capsids per dose (i.e., capsids containing the full-length of genomic material).
WHAT THE CQA? ANALYTICS REMAIN THE MOST PRESSING INDUSTRY NEED IN 2022
As a highly anticipated FDA Cell & Gene Advisory Committee meeting revealed this year, significant uncertainty remains over what impact — if any —empty capsids have on the clinical performance of AAV gene therapies. Given the current lack of pharmacopeial standards, regulatory guidance on acceptable full-empty capsid ratios, and corporate squeamishness over sharing such data, the industry, regulators, and pharmacopeias have their work cut out for them. (Important to note, however, there is a new collaboration between USP, NIST, and NIIMBL that aims to address measurement of AAV quality attributes — particularly that controversial full/empty capsid ratio.)
“While quality controls for vector production are currently being developed, there has not been a clear correlation at this point between critical quality attributes [CQAs] — including the percentage of empty to full capsids in the final vector product — and product safety,” White explained. “What is clear, however, is the importance of standardizing quality control measures on potency, purity, process impurities, and the percentage of empty to full vector capsids to ensure product safety.”
If there was one area on which all the experts were the most passionately aligned, it was around the need for better cell and gene-specific analytical tools (e.g., process analytical technologies) to understand not only what is happening within a process in real time but also how best to respond to certain measurements.
One of the CGT industry’s most common analytical “foes” to date has been the potency assay. In fact, just this year, the CEO of a prominent immunotherapy company resigned following regulatory qualms with a potency assay. “When was the last time you heard about a biopharma CEO losing their job over an analytical assay?” Glass asked, incredulous. “That turn of events is the best representation of just how essential it is to properly characterize your cell or gene therapy.”
There are a number of ways the challenge of characterization could be addressed. The use of AI and machine learning (ML) is of particular interest to Glass. Such technology, once perfected, could provide more detailed and accurate analysis on cell populations and promote better decision making around factors like cell viability or stem cell differentiation. Though he’s optimistic these up-and-coming AI technologies will become standard development tools, Glass acknowledges there are hurdles to overcome, including gaining regulatory confidence in the accuracy of such measurement approaches, as well as establishing the appropriate inputs. The challenge lies in humans’ abilities to teach the technology to interrogate, recognize, and properly distinguish among all potential outcomes so it can accurately make predictions.
Eventually, my conversations with each expert circled back to the importance of consistency in the CGT manufacturing paradigms. In fact, to all the experts, striving to achieve consistency across the manufacturing process should be every company’s forefront manufacturing goal in the next year — and beyond.
“As we head into 2022, the most mature manufacturing processes will comprise simplified processes that are both consistent and scalable,” White concluded. “This holds the potential to ensure cost-effective development while also lowering manufacturing risk and allowing flexibility.”