By Anna Rose Welch, Director, Cell & Gene Collaborative
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In the fall, I had several great conversations with executives in the cell and gene therapy (CGT) space. A majority of their comments and perspectives on what the year ahead has in store for the CGT manufacturing sector appear in Life Science Leader magazine’s January edition. However, though that 2,500-word article managed to capture a lot of what we discussed, there were inevitably snippets of each conversation that just didn’t fit into the page/word-count limits. Enter The Outlook Q&A: that versatile piece of content that everyone loves so much this time of year.
Below, I share several additional thoughts from Beth White, CBO, Renovacor; Matthew Durdy, CEO, Cell & Gene Therapy Catapult; Geoffrey Glass, CEO of the private equity-backed Kiniciti; and Dr. Robert Hariri, CEO and Chairman, Celularity. Together, their perspectives present a well-rounded overview of the areas demanding the most brainpower, financial resources, and innovation in the CGT manufacturing sector today.
Welch: What transformations are you watching, expecting, and/or hoping for in the CGT space in 2022 — and in the years to come?
Beth White: In 2021, the FDA released several guidance documents for human gene therapy with updated CMC requirements for consistency and improved understanding of potential CQAs. FDA’s guidance for CMC for human gene therapy emphasizes the need for additional product characterization in areas such as viral capsid and envelope structures, biophysical and biochemical characteristics, and product and process impurity characteristics. As we move forward, it’s critical for companies to work collaboratively with regulatory agencies to ensure they are adhering to requirements and meeting appropriate qualifications to ensure robust manufacturing processes for an approved product. We should expect to see continued guidance from regulatory agencies on clinical manufacturing as many preclinical assets advance through development into late-stage trials.
Geoffrey Glass: I’d love to see cell therapies demonstrate a meaningful, or even curative, clinical proof point. Once that breakthrough happens, we will start seeing more money invested in the space as a whole, which, in turn, will accelerate the pace at which the cell therapy space approaches standardization. Zolgensma was an incredible proof point that a curative gene therapy product could be a reality, and this has led to more accelerated evolutions on the gene therapy side of the industry. They’re in the third or fourth inning, while I’d argue that cell therapies remain in the first inning. In the next few years, I’d like to see the cell therapy side of the industry be able say, “We’ve cured this disease with a cell therapy; now, how do we make the process better and better?
Welch: Are there specific technologies we should be watching that will help bring the CGT manufacturing space to greater maturity?
Glass: Personally, I’m excited about the advent of induced pluripotent stem cell (iPSC) technologies, which eliminate the variability of starting materials seen in the autologous space and promise more reproducibility once a master cell line is established. Of course, the challenge facing the industry is making sure that the differentiation step in which you instruct the stem cell to become a specific type of cell — whether it be a T-cell, heart cell, or neuro cell — can be translated from that cell bank into a well-characterized and properly differentiated population of cells at a large scale.
Robert Hariri: This field is itching for innovation in the tools we use to collect, procure, transport, package, and clinically delivery these products. In the allogeneic space, one of the most important things we’ll need to demonstrate is that our products lend themselves to long-term cryopreservation and storage. That’s why I’m hoping to see greater innovation in the cryopreservation field. The cryopreservation agents used to freeze these cells date back to the 1950s. The transition cell therapy products go through, both during the freezing and thawing process, can alter the stability and quality of the cells, and there’s still a lot to be learned about the impact of these changes. I’d love to see the creation of a technology that would freeze-dry a cell, in turn eliminating the additional water content and strict cold-chain requirements. But such an innovation will require greater alignment and cooperation with many other special fields, like engineering and physicists.
Welch: This industry has already demonstrated that, if there’s a partnership to be made/had, it is fair game. How do you see collaboration evolving in the CGT space to better support manufacturing advancements and manufacturing technologies?
Hariri: The cellular medicine industry in immunotherapy is highly fragmented, and there are so many companies in the space. I’d argue that fragmentation does some damage to the field, because it dilutes the power of the capital brought to bear and makes it so much harder to win. Of course, I like competition. But instead of having 600-some companies battling toward the finishing line, can we figure out how to boil the industry down to 10 companies whose combined capabilities and proprietary technologies create strength and power? This, in turn, creates focus for investment. I’m a big believer that consolidation of the best-in-class players will accelerate this industry towards its endgame.
(*Editor’s note: Hariri’s thoughts on this topic were also featured in a recent Cell & Gene Collaborative blog entitled, “Is The CGT Industry Too Diluted To Sustainably Scale Manufacturing?”
Glass: It’s a tricky time in the CGT space. Look at any cell therapy company, and they’re going to showcase their platform, their manufacturing technology, and their approach to solving analytical challenges. Because most companies are looking at these different aspects as their secret sauce, there is a built-in barrier to sharing because everyone is striving to get a first-mover advantage, thanks to a more advanced process or technology. But I see things following a similar trajectory as the biologics space. For example, getting a CHO cell line to produce proteins, peptides, and monoclonal antibodies thirty years ago was a big challenge. Now, today, the novelty isn’t getting a CHO cell to produce these proteins, but it’s what can be added or done to the mAB or protein to impact its therapeutic profile. We’re in inning one for cell therapy, so everything is fast-moving and new, but I anticipate in the future the challenge and “secret sauce” will be less about the manufacturing platform and more about, for example, the specific edits a company makes to a cell.
Welch: What questions should companies be asking themselves to ensure they’re achieving the greatest level of manufacturing consistency they possibly can in the next year?
White: During the early stages of manufacturing, it’s very important to look towards the commercialization stage to address potential issues early in the process. Some forward-looking questions include:
1.) Can we manufacture therapies to scale while maintaining the level of quality that we have spent years developing?
2.) Can we do so in a way that makes it affordable for every patient?
3.) How do we improve consistency in manufacturing?
4.) How do we improve consistency in raw material quality?
5.) How do we increase scale and improve yield with higher quality? And finally,
6.) How do we best reduce product impurities?
Welch: How are you defining CGT manufacturing maturity, and in what ways do you see that maturity influencing the manufacturing sector in the upcoming year/years?
Durdy: I think one of the biggest reflections of maturity will be achieving efficiencies and implementing processes that limit the amount of space companies need to manufacture their product. Over the past few years, there has been a lot of conversation around building or expanding capacity, quite often in response to a lack of available CDMO capacity. However, I envision a future requiring less physical space. For instance, if your new processes produce 10 times as much product as your previous process, you may only need to run those processes for one week a year or one month a year as opposed to 10 months. This means you could do something else with the other nine months, or you could produce 10 times as much from the same facility.
Welch: If there was one change you could make to the CGT industry today that would re-route progress in the manufacturing field for the better in 2022, what would it be, and why?
Glass: If I could wave a magic wand, I would like to see every therapeutic company have a CMC expert on their board starting from the first day the company is in operation. VC firms and the industry in general are used to reacting to clinical proof points; as such, 80 percent of funding is traditionally allotted to the clinic, and CMC is lumped into the remaining 20 percent. There is no such thing as “too early” when it comes to having that manufacturing expertise represented within a cell or gene therapy company. Companies need an experienced manufacturing expert pushing them to attribute more resources earlier to establishing a robust manufacturing infrastructure even before the therapy is administered in the clinic.
White: We have already overcome so many hurdles with gene therapies, but the most persistent and important hurdles are the timelines for manufacturing development and the cost of goods (COGS). Reducing the timelines and costs for critical starting materials, such as plasmid DNA (e.g., more options for synthetic DNA starting materials) would greatly help address the currently high COGS. In addition, we should work towards investing in technologies like fully closed and automated manufacturing systems that will allow us to maintain quality while matching the scalability and speed of standard pharmaceutical production.
Durdy: The complexity associated with how these products are used at the point of care has a knock-on effect back to manufacturing. Everybody is manufacturing their products in slightly different ways to slightly different specifications. This results in outbound supply chain differences and raises questions on the hospital level around how and where certain processes should be carried out. Take for example, label printing; if every company walks into a hospital with their own label printer and printing protocols, a hospital would need a dedicated printing ward — and that’s just not going to happen. If we as an industry can standardize such hospital protocols, we should see those efficiencies trickle back through into the manufacturing and supply chain and further reduce COGS.