Producing cell therapies isn’t easy—and that’s a fact Bristol Myers Squibb knows only too well. FDA hang-ups at a viral vector plant delayed CAR-T therapy Breyanzi, sinking a Celgene deal-related payout worth some $6.4 billion.
But with an FDA nod finally in hand, and fellow CAR-T therapy ide-cel lined up for an FDA decision this month, Bristol Myers is wasting no time kicking its cell therapy operations into high gear.
The company has a Massachusetts plant in the works that will ultimately take on much of its commercial cell therapy manufacturing, plus another up-and-coming production site in Europe. Meanwhile, Bristol Myers aims to more than halve the manufacturing turnaround for its CAR-Ts, executives said during a recent virtual manufacturing tour.
Bristol’s facility in Bothell, Washington, is now kitted out for commercial manufacturing, while its Summit, New Jersey plant is making the switch to turn out therapies for the market. The company uses its Warren, New Jersey facility for early-stage clinical manufacturing, and it also depends on contract manufacturing partners in Europe and Japan.
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Up for completion by year-end is Bristol’s facility in Devens, Massachusetts, close to Boston’s booming biopharma ecosystem. The company hopes to start engineering runs at the 244,000 square-foot plant in late 2021 or early 2022, Snehal Patel, global head of cell therapy manufacturing at BMS, said during the tour. That’s also where a good portion of the company’s commercial cell therapy manufacturing will eventually take place, he added.
Bristol Myers is close to announcing the location for a new manufacturing site in Europe, too, which will slash turnaround times for patients living there, Patel said. Currently, a CDMO in Europe performs the initial manufacturing steps and sends materials to BMS stateside, which the company must then ship back to Europe.
The manufacturing process takes weeks: The company’s approved CAR-T Breyanzi has a 24-day target turnaround time from T cell collection to delivery back to the patient.
Along the way, BMS identifies and tracks each patient’s cells “more than 500 times” so they don’t get mixed up with someone else’s. T cells are incredibly fragile, and there’s plenty of room for the manufacturing process to go awry, here and elsewhere, the company admitted.
BMS learned that lesson firsthand last December when the FDA slapped a Form 483 on the Lonza plant producing viral vectors for Breyanzi—which likely scuppered plans for a 2020 launch and cost company investors their hotly-anticipated Celgene contingent value rights.
Novartis’ CAR-T Kymriah offers another cautionary tale. The Swiss pharma in 2018 admitted it had run into manufacturing problems tied to cell variability when treating relapsed large B-cell lymphoma patients with the therapy, which stopped some doses from meeting specifications and hampered Kymriah sales. The company used its compassionate care program to provide the out-of-spec drug to patients, but couldn’t charge for them.
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BMS, for its part, handles most of its manufacturing process internally and begins by collecting T cells straight from the CAR-T patient, which it then ships to production sites in temperature-controlled containers. BMS washes and separates the desired T cells in an isolation suite, drains the cells into bags and loads them into cassettes. The cells are cryopreserved and sent over to a process suite where BMS introduces a viral vector to insert the eponymous chimeric antigen receptor (CAR).
BMS gets its viral vectors from its contract manufacturing partners, Patel said during the virtual tour.
At this stage, you essentially have your CAR-Ts, though a few more steps lie ahead before the therapy makes its way back to patients. BMS grows the cells over several days, producing enough material for testing and treatment. The CAR-Ts are then washed to remove cell culture media, diluted to hit a target concentration, and filled into bags or vials, which depart the manufacturing suite for freezing and, finally, shipment back to treatment centers.
The lag time can be problematic if a patient’s condition worsens during the manufacturing process, though Bristol is working on a platform that targets a turnaround time of less than 10 days, Ann Lee, head of cell therapy development and operations, said during the tour.
It also has its sights set on new technology to reduce testing time, which now takes eight days, Lee added.
Of course, the weeks-long production time BMS sketched out only applies to autologous CAR-Ts, in which cells are collected from the recipient. Allogeneic, or “off-the-shelf” CAR-Ts—where T cells are harvested from a healthy donor—could be turned around the same day a patient gets a prescription.
The company is working on platforms for these off-the-shelf therapies, which are theoretically easier to scale, too, Lee said. It could be some three to five years before BMS rolls out an allogeneic CAR-T—and other companies working on allogenic therapies have hit their stumbling blocks—but the company’s efforts should certainly bear fruit within the next 10 years, she said.
Beyond production, BMS says it’s working to provide end-to-end care for patients receiving its tailor-made cell therapies. The company has built Cell Therapy 360, an integrated digital platform that provides tools for doctors and patients, as well as a glimpse into the manufacturing process.
Plus, Bristol has introduced a disposable, digital wearable that connects to a smartphone to help patients monitor their temperature for potential side effects after infusion, Krishnan Viswanadhan, SVP of the company’s global cell therapy franchise, said.