A "Portrait" of Risk In Cell & Gene Manufacturing

By Anna Rose Welch, Editorial & Community Director, Advancing RNA

In college, I almost majored in art history. In fact, I had such a penchant for waxing poetic on the historical facts and symbolic interpretations of paintings that my professor admitted he often used my exams as his grading key. (#NerdStatus)

As my byline on this article/website will clearly prove, I didn’t “grow up” to be an art historian — nor does the world of art history typically appear in our daily conversations about ATMP manufacturing. But as I continue to reflect on the conversations I heard at the 2023 PDA ATMP Conference, I’d argue the artistic and manufacturing worlds have a bit more in common than we might anticipate. Just as every artistic movement (e.g., the Baroque, Rococo, Impressionism) is marked by its own stylistic principles, the mAb, CGT, and mRNA industry sectors are each likewise shaped by their own unique questions, technical constraints, and goals. Though we aren’t painting anything in the CGT space, it’s interesting to consider what our industry currently “looks like,” and what it could look like once we navigate beyond our current uncertainties.   

The eventual shape of our industry became increasingly top-of-mind as I listened to the final expert panel at the PDA ATMP conference, during which several experts shared the industry challenges currently keeping them up at night. Not surprisingly, many of these experts’ concerns revealed the tenuous relationship we as an industry have with our (often vastly different) assessments of risk in the CGT manufacturing paradigm. In fact, the many regulatory and quality-related conversations at PDA suggest we’re currently living within an “impressionist-esque” world when it comes to defining how our advanced therapies fit within existing regulatory/compliance frameworks.

It’s hard to say whether our CGTs will ultimately fit tightly within — or evolve — the traditional manufacturing regulations we have known and loved for decades. As some of my bigger takeaways from the PDA conference emphasize, our industry’s identity as a whole is still very much a work (of art) in progress.

The “CGT Brand” Of GMP Compliance: The Known Unknowns

Throughout the two-day PDA conference, there were many brave attendees who ventured to the microphone to ask their burning questions. But I was particularly appreciative of two questions posed about the industry’s current and future relationship with GMP compliance: Are there instances in which current cGMPs don’t fit the CGT space well, and in which arenas might or should we be more concerned about the state of our compliance?

I can understand how tricky such questions can be, given that we and the regulatory agencies are striving to and, upon approval are, providing well-made, high-quality treatments to patients. But if we go back to the world of art for a minute, I think our understanding of compliance and quality in the CGT space compared to that of the mAb space is nicely depicted through two different styles of painting. The mAb space, for instance, is best illustrated in the bright clarity of Realism painter Edwin Hopper’s portrayal of an all-night diner, “Nighthawks.” Alternatively, I see the CGT space currently embodying the “softness” of Impressionist painter Claude Monet’s “Water Lilys,” within which the shapes of the flowers seemingly defy concreteness.

As one PDA speaker explained, we all know what compliance should look like based on our experiences in well-established, commercial industries. But such expectations are not always “practically applicable” in the CGT space — particularly in the autologous cell therapy space or within future decentralized manufacturing models. Though we’ve often wondered whether we would see CGT-specific GMP manufacturing regulations or guidance, one speaker keenly pointed out that the FDA’s CGT guidances to-date have been predominantly CMC as opposed to GMP manufacturing-centric. In turn, we’re left to interpret how the broader GMP regulations and guidelines apply to our investigational CGT products. (ICYMI — As the title of the article, “GMP Principles: The True Star of CGT FDA Interactions” indicates, GMPs were a big topic of conversation at last year’s FDA’s town hall meetings.)

While we do not currently have cell and gene therapy-specific GMPs under the U.S. regulatory framework, things get a bit fuzzier in the European/global regulatory realms. For example, current debates over the relevance of Annex 1 to the ATMP space given the ATMP-specific Eudralex Volume 4/Part IV & PIC/S Annex 2A suggest some ideological separation of the “CGT church” from the traditional “manufacturing risk-management and compliance state.” (FYI, this debate is particularly relevant to the autologous cell therapy space, as opposed to, say, mRNA therapies.)

As one speaker went on to argue: “In a sense, CGT products are living on borrowed time. Sooner or later, there will be a push to enforce the GMPs as written in our current regulations, or there will be a push to introduce new GMPs that are specific to these products…. I don’t know how this is going to unfold. I think that the industry needs to engage the regulatory agencies around the world to push for new types of regulations for these products.”

While a future with harmonized cell- and gene-therapy-specific GMPs is strictly hypothetical, it got me thinking about the Claude Monet-like “impressionism” that new scientific and manufacturing approaches can introduce in our well-ironed quality ecosystem. It’s customary for every truly novel and paradigm-shifting therapeutic space to ask the regulatory-and policy-laden world, “Will you, World, be the one changing, or will I?” Gene therapy-specific payer reimbursement policies and the recent Sarepta FDA adcom meeting are beautiful examples of how “the world” can change for our science. But it’s also worth noting that, despite attempts to revise U.S. GMP regulations, very few alterations have been realized since the original regulations arrived in the 70s.

We also can’t ignore that our identity as an industry — much like our processes — are also evolving in a “phase-appropriate” manner. As our manufacturing “grows up” and we become more technologically capable of broadening our therapies’ reach to more patients, we may find that we must adapt and/or change to meet shifts in the risk vs. benefit ratios of our therapies.

As one expert concluded, “Today, the benefits in the small populations we’re treating tend to outweigh the risks that do arise. However, the moment the industry moves into a larger scale and each cell or gene therapy batch is used by thousands of patients, our consideration of risk will change dramatically.”

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