Blog | January 7, 2022

Cell & Gene Therapy Manufacturing Leadership: An Evolving Definition

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By Anna Rose Welch, Director, Cell & Gene Collaborative
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This article is the last in a five-part series unpacking the Top 5 Cell & Gene Therapy Manufacturing Evolutions in 2021. We started our countdown at #5 with the CGT talent crunch and progressed down through next-gen delivery (#4), cell culture challenges (#3), and knowledge management (#2). We’ve finally made it to what I think is the most exciting, evolving trend of them all.

But heaven forbid anything be straightforward. As I was working on this series, it struck me just how nicely the lyrics to some of Taylor Swift’s biggest hits complement the larger themes I’ve noted in the CGT manufacturing space. So, in addition to providing the big CGT picture, each article will offer an accompanying song recommendation (plus lyrics!), if only to add a touch of levity to the important discussions at hand.

Music & Lyrics: “Me!
Like a rainbow with all the colors/
Baby Doll, when it comes to a lover/
I promise that you’ll never find another like me [e-e-e]

It may be a questionable choice to start an article on leadership in the CGT manufacturing sphere by quoting a song that includes the lyrics, “There is no I in awesome,/ but there is a me.” I suppose we can at least admire the gumption.

But all jokes and egocentric “Swifty” quotes aside, these lyrics got me ruminating on the leadership dynamics that are slowly but surely emerging in the CGT manufacturing space. There are going to be (and already are) clear leaders in the CGT space. Behind all of these “awesome” market-leading triumphs, however, there is no “I” or “me;” there are decades of academic and industry research programs, partnerships, and in-house, cross-company teamwork carrying a company and its products across the finish line.

As in the other four articles in this Top 5 series, this final part aims to illuminate the dynamics I’ve observed taking shape — often under the radar — in the CGT manufacturing space. While it’s important to define what “leading” currently means in the manufacturing realm, an even more intriguing discussion to have now is how leadership in manufacturing could/will evolve in the upcoming years.

As I see it right now, there are three tiers of manufacturing leadership that successful CGT companies are progressing toward/will achieve, whether it be in less linear bits and pieces or in clearly distinguishable stages — as if ascending a staircase.    

It goes without saying that we are currently defining CGT manufacturing leaders (version 1.0) as those that are tackling the many manufacturing, regulatory, and commercialization hurdles that come from launching these new, complex products on the market. These are the companies that have either launched products on the market or are closest to the commercialization “finishing line” (as if finishing lines actually exist in medicine).

During the Alliance for Regenerative Medicine’s recent State of the Industry presentation, I loved the phrase one expert used: these pioneering companies are “paying the scientific debt” each time they face the big — but necessary — regulatory asks to further clarify aspects of their CMC programs. Though such requests for more extensive CMC clarity can lead to stress eating, hair pulling, and other general miseries (i.e., delayed timelines), there’s a wealth of knowledge that comes from taking that essential step back. Starting out on firmer CMC footing with more reliable processes means that companies can begin asking even more targeted questions about the biological and clinical profiles of their products which, in turn, can translate to more efficient patient access. In fact, some of the clinical data we were privy to in 2021 indicates that the days of earlier and broader access are just around the corner (…plus maybe a few blocks away). At the close of last year, we celebrated the news that two cell therapies (i.e.,Yescarta and Breyanzi) outperformed the second-line standard of care by bolstering event-free survival in relapsed/refractory large B-cell lymphoma.

But to achieve that coveted earlier patient access on a broader level, the COGS for these therapies cannot be ignored. On the flip side of such brilliant clinical news in the CAR-T space, 2021 was also the year we heard about Bluebird Bio’s withdrawal from the European market, thanks to its high price tag. While much of the resulting media focus and industry angst was (rightfully) pointed toward the limits of legacy healthcare systems, there were also some troubling implications for manufacturing that garnered little to no attention.

As I wrote at the time, Bluebird’s woes were a great example of how symbiotic COGS and access are. We cannot have greater access without a lower COGS, nor can we have a lower COGS without greater access. After all, in an ideal world, more patients equate to more data. While not all data is created equal, the more we can learn about a product’s safety/efficacy and its mechanism of action, the better able we are to control and industrialize the manufacturing process for that therapy — especially in the logistically and economically complicated ex vivo space.

This Bluebird Bio example delivers me quite nicely to the steadily emerging 2.0 version of leadership in the manufacturing realm, which will be defined by companies’ abilities to manage their COGS. It’s worth repeating, however, that this cannot be done solely on an individual company (I/me) level. In a previous blog post, I argued that it’s not a disadvantage to be a “fast follower” as opposed to one of the pioneers in the CGT gold rush. As many — including this fantastic podcast guest — have emphasized throughout the past year, a company’s grasp on the biology of its products isn’t the only important advancement that must be made; just as important — if not more important — the supportive infrastructure (i.e., outsourcing and service provider network) and equipment/tools available to CGT manufacturers must also progress from a canter to a gallop. The more advanced this supportive infrastructure, the stronger each innovator company becomes in managing and controlling its products’ CMC destinies.

In the past few years, innovator companies have positioned themselves as manufacturing leaders based on many of the following aspects: in-house talent; available manufacturing capacity (for in-house and/or outsourcing use); treatment turn-around-time (for ex vivo CGTs); analytical prowess; the (mostly still early-phase) promises of next-gen delivery approaches; and/or the modality/cell type(s) of choice.

We’re even starting to see the word “platform” appearing more regularly — perhaps one of the most high-profile examples being that of Novartis’ newly announced T-Charge platform.  This second-generation platform boasts a less-than two-day vein-to-vein turn-around time ex vivo and in vivo cell proliferation. (See ya, lengthy cell culture expansion step!)  

These factors are integral individually and collectively in improving overall COGS and will never go out of style (she says, casually inserting an additional Taylor Swift song here).

All that said, there are a few factors that keep manufacturing leadership 3.0 at a distance. Manufacturing in the CGT space today is defined by its small scale and, consequently, its small reach. In many cases, technologies and/or the processes for using those technologies in the CGT space are immature or ill-equipped. Companies are making do with their predominantly manual processes and reaching hundreds, maybe a couple thousand patients globally — and in many cases, as last-resort treatments. It can feel as though everyone’s manufacturing efforts today are each a small island in a long chain of fragmented, similarly small islands. Even when we discuss manufacturing advancements today — like Novartis’ T-Charge platform — the questions asked are about the competitive impact such advancements/platforms will have in one or two (often small) indications.

While it is my greatest hope this industry continues to devote its attentions and ambitions to addressing overlooked/untreated rare diseases, manufacturing also craves industrialization. While CGTs will never share the same manufacturing efficiencies and COGS as that of a small molecule or even those of certain biologics, it’s safe to say advanced therapy leaders (version 3.0) will have manufacturing platforms that, from a resource and talent perspective, embody a smaller operational footprint (e.g., require fewer floor operators) and can flexibly address a wide variety of indications, both large and niche. Instead of asking how a manufacturing platform will impact the competitive dynamics in one or two small indications, we will be celebrating its ability to address and reach broader expanses of deserving patient populations.   

Have your own thoughts? Feel free to email me or reach out via LinkedIn.

Click here to experience the full manufacturing evolutions "playlist."