Novartis' surprise radiotherapy production halt nearing an end as FDA docs shed light on plant woes

One month on, Novartis’ surprise radiotherapy production halt could be nearing its end, the company said Wednesday. Meanwhile, an FDA write-up has shed more light on the manufacturing hitches that likely played a role in the temporary supply squeeze on Novartis’ cancer meds Lutathera and Pluvicto.

Quality issues, record-keeping shortfalls and cleaning deficits are just a few of the problems the FDA flagged at Novartis’ Millburn, New Jersey, plant during an inspection last fall, Stat first reported, citing a Form 483 from the agency.

It remains unclear whether the production halt is directly tied to the FDA’s November inspection, but the regulator’s citation does illuminate some of the production hurdles plaguing the Swiss drugmaker at the plant where it produces neuroendocrine tumor therapy Lutathera.

Early last month, Novartis said it would pump the brakes on manufacturing of both Lutathera and its latest radiotherapy Pluvicto, which was approved in late March to treat prostate cancer. At the time, the company said it was pausing production “out of an abundance of caution,” citing “potential quality issues” in its manufacturing processes in Ivrea, Italy, where it makes Pluvicto, and Millburn, New Jersey, where Lutathera is produced.

The move prompted a delivery pause on Lutathera in the U.S. and Canada and on Pluvicto in the U.S. Simultaneously, Novartis halted enrollment for Lutathera’s clinical trials in the U.S. and Canada and temporarily put the kibosh on Pluvicto studies worldwide.

Now, Novartis is “in the process of implementing appropriate corrective actions at our sites in Ivrea, Italy, and Millburn, New Jersey,” a company spokesperson said over email Wednesday. The company is “preparing to restart radioligand therapy production” at the two affected sites and currently expects patients to start receiving doses again in a “phased” manner starting early this month.

“As radiopharmaceutical therapies are made to order for specific patients and require coordination of radioisotope components, there is a need to plan ahead in order to ensure on-time delivery,” the spokesperson continued. “As a result, Novartis has contacted treatment sites to reopen the ordering process as it prepares to restart production, so that it can more quickly and efficiently supply doses to patients.

"We expect that initial production supply may be limited as the different sites and lines restart, but we will do everything possible to address the accumulation of patient demand from these past few weeks as quickly as we can," the spokesperson added.

Novartis still sees “no indication of any risk to patients from doses previously produced at these sites."

Meanwhile, Novartis’ main offense in the FDA’s Form 483 was its failure to alert customers about Lutathera batches that were distributed despite failing to meet quality specifications, the regulator said.

The FDA said Novartis has a procedure to allow shipment of sterile injectables under quarantine status before quality tests conclude, but it argued this approach “does not ensure the quality of products prior to distribution.” Regulators added there was no evidence customers were informed to ensure drugs would not be “inappropriately” administered to patients.

Novartis attempted to rebuff those charges in a Dec. 2, 2021, response to the FDA, in which it explained that 11 of the 16 Lutathera batches in question were rejected before they were shipped to customers. The remaining five lots were rejected in transit and recovered before delivery. Thanks to Novartis’ early intervention, the company believed it didn’t need to inform any of its customers about the pull. None of the vials were administered to patients.

Distribution aside, FDA investigators said Novartis didn’t do enough to review unexplained batch discrepancies or failures nor to review whether any of its batch components met “any of its specifications whether or not the batch has been already distributed.”

The quality unit also dropped the ball when it failed to start an investigation after gloves used to make sterile drugs proved leaky, FDA said.

Moreover, equipment surfaces in the plant that contact drug surfaces were found to be “reactive, additive or absorptive,” which could alter the drug product being manufactured, the agency said.

Novartis’ Millburn site has been in the FDA’s crosshairs before, Stat pointed out. Back in 2018, shortly after Novartis paid $3.9 billion for radioligand specialist Advanced Accelerator Application, the FDA spotlighted more than half a dozen objectionable production issues including incomplete laboratory testing records and subpar software controls for quality control testing equipment.