Manufacturing requirements are killing cell and gene therapy

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Manufacturing requirements are killing cell and gene therapy<br>Some of the most promising drugs are bottlenecked by a "boring" but incredibly important problem

Ruxandra Teslo<br>Jun 10, 2026

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Yesterday, ultra-rare disease company Grace Therapeutics announced it may be forced to shut down after the FDA requested a second manufacturing run before it can submit its new application for approval. This is a requirement the company says it simply cannot survive, as it would require another twenty million or so in funding. I explained in a tweet why the requirements the FDA has regarding this are absurd.<br>What I really want to bring home though is that the story of Grace Therapeutics is not unique by any means. Excessive manufacturing requirements are a pervasive problem, especially in the field of cell and gene therapy and they are killing countless of promising medicines before they ever reach patients. And they manifest at every stage: starting with Phase I, as explained here, all the way to post-approval.<br>Ruxandra's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.

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In this post, I want to focus on a story that happened post-approval and illustrates how even when a drug basically cures cancer it can be very hard to commercialize and turn into a profitable venture for the company making it. The drug in question is Carvykti, a CAR-T cell therapy for multiple myeloma that I wrote about at length last week for Works in Progress. If you haven’t read that piece, the short version is this: Carvykti is, by most clinical measures, one of the most remarkable cancer therapies ever developed. It is a one-time infusion that has produced durable, long-term remissions, and in some cases what looks like an outright cure, in patients for whom every other treatment had already failed. A third of patients in its pivotal trial remained disease-free five years later.<br>And yet, despite all of that, the company behind it nearly had its commercial launch derailed. This, I think, is a very good case study on why the cell and gene therapy field is in trouble and how much of it comes down to excessive manufacturing requirements. I should also warn at this point that much of the information below is not public. Instead, it was assembled from interviews with experts and paywalled industry reports and investor calls.

How the Carvytki launch almost got derailed by manufacturing requirements

To understand how that derailment happened, it helps to first appreciate just how difficult these therapies are to make. CAR-T therapies are among the most complex products ever commercialised. Almost all approved CAR-T therapies are autologous, meaning cells must be extracted from each individual patient, genetically engineered, and returned to that same person, making the manufacturing process exceedingly difficult. Johnson & Johnson (J&J), the large biopharmaceutical company that co-developed Carvytki, faced additional hurdles in securing sufficient quantities of materials to manufacture the cell therapies, compounding an already complex situation.

But perhaps the most surprising element hampering the therapy’s launch was a surprisingly high out-of-specification (OOS) manufacturing rate, estimated at 30 to 40% in the United States. Before any CAR-T product can be infused, it must pass a battery of quality-control tests. One of the most important is the potency assay, an in vitro experiment in which the patient’s re-engineered T-cells are placed in contact with myeloma cells, and their killing ability is measured. This test is meant to confirm that the therapy is genuinely therapeutic. A batch that falls short on any single measure is classified as out-of-specification, and usually cannot be administered.

Potency assays are in vitro experiments designed to test activity of the therapy. Adapted from here.<br>These rates were far higher than anything observed during the clinical trials, for several reasons. In a real-world setting, patient heterogeneity is considerably greater than in the controlled environment of a trial, where eligibility criteria are designed to select for patients most likely to respond well and manufacture cleanly. At launch, authorised treatment centres were immediately overwhelmed with advanced, heavily pretreated patients and who in many cases would not have met the original trial’s inclusion criteria.<br>But the strangest contributing factor was one that originated not in the clinic or the manufacturing facility, but with the FDA. Somewhere between the trial phase and commercial approval, the FDA had tightened its potency assay thresholds. Legend Biotech’s leadership later calculated that if those stricter commercial standards had been applied retroactively to the original trial data, the out-of-specification rate would have risen from...