A manufacturing shortfall likely cost Bristol Myers Squibb the chance of an FDA approval for CAR-T therapy liso-cel by the end of 2020—and sent a potential $9-apiece Celgene deal sweetener into the trash can. Investors looking for details of the expensive misstep now have the answers.
Lack of differentiation measures at storage areas, which opened up the potential for material mix-ups, and inadequate prevention of microbial contamination are among the problems FDA staffers noted during an inspection of a Lonza facility in Houston, which is under contract to make viral vectors for liso-cel.
The protocol breaches were summarized in a four-observation Form 483 (PDF) the FDA posted on its website. Bristol Myers previously said it had responded to the observations within eight days, once the inspection closed on Dec. 10.
The week-long Lonza plant inspection, which was part of liso-cel’s drug application review, came later than expected because of COVID-19, pushing back the FDA’s decision from a previous deadline in November. But when the FDA inspectors finally arrived, the facility didn’t exactly have its act together.
In the highly-redacted document, the FDA inspectors noted that there was no separate storage area for certain products to prevent mix-ups. Bottles intended for different markets, as well as materials derived from test runs were stored in the same bin, the inspetors found.
The same bin was also used to store an unidentified material that had been rejected by the facility’s quality unit. Manufacturing processes for liso-cel meant for the U.S. and EU are different, they pointed out.
Apart from their adjacent locations, the bottles' labels were also quite similar. For example, bottles of both accepted and rejected material bear a “RELEASED” label with the same color palette and font.
Facility workers were also accused of failing to verify the identity of each incoming batch of certain raw materials before releasing them for manufacturing. Some other written procedures were not always followed, either. Plus, the FDA inspectors observed one case of inadequate aseptic operation control.
The Lonza plant wasn’t the only liso-cel manufacturer that didn’t pass muster during an FDA checkup. Before it, Bristol Myers’ own facility in Bothell, Washington—a legacy Juno Therapeutics plant that the New York pharma acquired in its Celgene buyout—was also slapped with a Form 483.
Although the two manufacturing notices might not cost Bristol Myers an eventual green light for liso-cel—as long as the FDA’s satisfied with the company’s response and doesn’t escalate its actions—they definitely slowed things down. And timing was top of mind for holders of the contingent value rights tied to the Celgene buyout.
An FDA nod for liso-cel in third-line large B-cell lymphoma by the end of 2020 was one of the three conditions that would have triggered the $9-per-share payment. The multiple sclerosis drug Zeposia had met its own goal with an FDA go-ahead in March. And BCMA-targeted CAR-T drug ide-cel bears an FDA decision date that comes before its CVR deadline at the end of March.
On the heels of the latest liso-cel regulatory setback—which followed several others for both liso-cel and ide-cel—Bristol Myers’ former head of hematology Nadim Ahmed stepped down earlier this month. The company’s cell therapy division fell under his purview.
Lonza didn’t exactly have a clean slate when it comes cell therapy manufacturing. Back in 2017, the Swiss CDMO’s facility in Walkersville, Maryland, was hit with an FDA warning letter over issues including validation and aseptic process simulations.