From Capacity To Comparability: The Shifting Onus In Cell & Gene Therapy Outsourcing
By Anna Rose Welch, Editorial & Community Director, Advancing RNA
One of my favorite parts of heading up Cell & Gene Collaborative the past two years has been bringing together CMC experts with similar roles who may never have had the chance to meet and exchange brainpower otherwise. A few months ago, I sat down with two such like minds: Adam Haskett, head of external manufacturing for cell therapy company CARGO Therapeutics, and Joseph Graskemper, formerly the senior director and head of external manufacturing & supply chain at gene therapy company Intergalactic Therapeutics, now the founder and principal of Pathways Pharma Consulting. During two Collaborative peer group discussions, these outsourcing gurus provided us with a true insider’s look into the cell and gene therapy outsourcing sectors.
What started out as a well-rounded overview of the outsourcing sector’s health evolved into a lively back and forth in which Haskett and Graskemper doled out valuable tips and tricks on how we as CGT biotechs should be evaluating CDMOs’ emerging CGT platforms and approaching the art of contracting — particularly in this dynamic age of risk-sharing. As we continue progressing beyond the COVID (i.e., the seller’s) economy, both Haskett and Graskemper agree we’re steadily seeing biotechs taking on a much more empowered role in negotiating with and securing CDMO partners. But they also see several shifts in the CGT development landscape that could impact both biotechs and their outsourcing partners equally — for the better, or if we’re not careful, for the worse.
Here, in part one of this three-part article, I outline how these critical outsourcing inflection points should be shaping biotech partnership evaluations and informing outsourcing firms’ future service offerings and capabilities. (Stay tuned for parts 2 and 3, forthcoming!)
The 3 C’s Of Outsourcing And What These Should Mean To Us & Our CDMOs
- Capacity
It should come as absolutely no surprise to any of us that just two years ago, the first “C” that no one could stop talking about was capacity. If we wanted it, there was a great chance we wouldn’t get it from your desired partner — or any CDMO — when we needed it most. Even if we had a coveted slot or slots at a facility, there was no saying there was enough talent at the CDMO to get the product made efficiently to meet timelines.
With capacity being the rare commodity that it was, it’s only natural that it would become an “offering” that was just as prized as a partner’s specific technical capabilities, particularly in the rush to the clinic.
Now, we all know how this demand played out: CDMOs reacted to the demand for capacity by building and/or acquiring additional capacity — particularly late-phase facilities. While this has resulted in greater availability for biotechs seeking capacity, I also appreciated Graskemper’s humorous but also keen observation: “If you listen really closely, you can hear wind-chimes in many of these late-phase facilities; they’re empty.” In fact, we could even argue we’re currently living in a day and age of over-capacity — just as many predicted we might be a short year or so ago.
But just because our capacity concerns may be lessening today doesn’t exactly translate into smooth sailing of the outsourcing seas (or C’s…) moving forward. Now that the pendulum has swung to the other side in terms of capacity, it’s important we home in on how well that capacity is used moving forward. After all, as Graskemper and Haskett both pointed out, we’re at a point in the industry where our capacity and capability needs are growing increasingly mature in parallel with our products’ complexity.
A few years ago, the CGT sector was full of young companies with a molecule, a (juvenile) process, and the funding to make most of their dreams come true. The dream at that time was, of course, to achieve proof of concept to get into the clinic. And, as the latest clinical trial data from Alliance for Regenerative Medicine reveals, many of us did achieve our goals of getting into the clinic. As of June 2023, there are 1200-plus cell and gene therapy products in Phase 1 or Phase 1/2 trials. But as Graskemper also pointed out, companies in Phase 1/2 or Phase 2 trials account for more than half (850-plus) of the 1500-some assets in Phase 1, Phase 1/2, and Phase 2 trials combined.
“We’re on the cusp of transitioning from the perfect storm of early-stage products and processes to an era in which there are more mature assets requiring facilities that have the capabilities to support late-phase development and commercial manufacturing,” Graskemper explained.
Of course, capacity will continue to be a consideration in this transition — especially if there are a lot of products requiring high-volume production for a high-dose product. For example, though 2000-liter triple transfection suspension culture may be the end-goal for many AAV gene therapy companies, adherent processes remain predominant, particularly at the 500- or 1000-liter scale. In turn, a high-dose therapy developed using adherent processes would demand a lot of facility space.
But as we also know, capacity does not equal capability, and this transition to later-phase development demands a specific type of expertise on the second big “C” of outsourcing:
- Comparability
In theory, we’ve all been “keeping the end in mind from the beginning.” But for a variety of regulatory and patient-centric reasons, we have not always been able to balance our urgent need for speed with our urgent need to establish a commercial- and COGS-friendly process from the very beginning. As such, many of our early-stage-processes are destined to come face-to-face with hefty comparability exercises and/or growing pains as they approach late-stage development. In fact, Sarepta’s recent FDA adcom meeting provided us with a much closer look at the real-world implications of making big albeit necessary process changes to achieve a better COGS and scalability profile.
Moving forward, Haskett and Graskemper believe that the ability to successfully execute tech transfer and comparability exercises will be a critical differentiator for an ATMP outsourcing partner. Though the concept of technology platforms may boast the alluring promise of “turnkey” development, plug-and-play is not a current reality for our products/partnerships — at least not yet. As such, many companies with early-phase processes will need to prepare themselves — and have an outsourcing partner — that is well-equipped to transition or transform that early phase process into a commercial-ready process/platform process. This emphasizes the importance of weighing a potential CDMO partner’s analytical capability from the get-go — even if, internally, a company plans to keep analytical development in-house or to contract it out to a third-party testing site. This way, as Graskemper acknowledged, we know the CDMO will be able to support our analytical needs should we need them to in the future.
- Capability
As you may have already guessed, the third big “C” of outsourcing is capability. I’ll acknowledge, on the surface, this may seem a bit duh-worthy and/or anti-climactic. But throughout our conversation, Haskett and Graskemper continued to reiterate that all of us — innovator and CDMO alike — have plenty of room to grow, especially where late-stage development is concerned. As Haskett offered, much of the capacity construction in the past few years has been focused on meeting the needs of early-stage virtual companies (i.e., industrial processes and regulatory compliance). As such, there are not as many facilities that are ready from a regulatory standpoint or that have the necessary late-stage experience.
In drug development, we regularly emphasize the importance of partnering to access the capabilities and know-how we don’t currently have in-house. Just as we’re advised to play to our strengths as biotechs, both Haskett and Graskemper see our current and future CDMOs more carefully evaluating their strengths and the roles they wish to play as a partner. While the outsourcing industry did go through a Pokémon-style “Gotta catch-em all!” acquisition phase for facilities, technologies, and platforms in recent years, as Haskett went on to explain, he sees CDMOs beginning to take a much more nuanced, thoughtful approach to capacity and capability development.
“In the last two years, if you were a sponsor company giving up your facility or a facility was becoming available, there were going to be multiple bidders to acquire it,” Haskett shared. “Now, I see CDMOs pausing and reevaluating their acquisition or build strategies. They’re not just buying any facility. They’re starting to ask themselves more targeted questions around whether they want to be more firmly embedded in the early phases of development or the later phases.”
Haskett anticipates we will see more CDMOs homing in on their late-phase development capacity and capabilities in the future. But overall, this more measured approach to business growth is a welcome step and one that arguably bodes well for a more mature and capable outsourcing industry in the years to come.
Continue on to Part 2 in which Haskett and Graskemper delve into the current state of AAV and LVV/cell processing platforms.
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