Kymriah GMP issues in NJ led to FDA letter for Novartis

In November and December last year, the United States Food and Drug Administration (FDA) inspected the Morris Plains, New Jersey facility, resulting in it issuing a Form 483 with an undisclosed number of observations to Novartis.

But upon further review, the FDA sent a letter in August (but published this week) highlighting additional significant deviations collected during the inspection, relating to the production of chimeric antigen receptor (CAR) T-cell therapy Kymriah (tisagenlecleucel).

Among the deviations, the Agency found Novartis failed to establish laboratory controls, particularly citing sampling plan and test procedure issues relating to freezing bags – or ‘Cryobags’ – the primary container for Kymriah.

“[The plans] are not appropriate to assure that Cryobags are “free of…particulate matter” as required by your acceptance criteria,” the Agency states. “Between December 2018 and the date of the inspection, you identified approximately 100 batches of Kymriah contaminated with foreign particulate matter, such as wood, cellulose, brass, and steel. In November 2020, your firm concluded the Cryobags were the most probable root cause.

While the letter says Novartis responded by implementing enhanced visual inspection of incoming Cryobags, particulate matter in batches of Kymriah final product continued to have been attributed to Cryobags as recently as October 8, 2022.

The letter also slams Novartis’ procedures to prevent microbiological contamination for Kymriah drug product, citing approximately 100 action level excursions for mold in ISO 5/Grade A and ISO 7/Grade B areas where Kymriah is manufactured between October 2019 and the date of the inspection.

“Contributing factors identified by your firm include gaps in procedures relating to cleaning and sanitizing of manufacturing areas, equipment cleaning and sanitizing, equipment transport, material handling, personnel gowning, cleanroom behavior, and handwashing and sanitation as well as failure to follow some of these procedures.”

While corrective and preventive actions (CAPA) were implemented, mold in the facility’s Grade A manufacturing area was still evident in November 2022.

The third point the letter highlights focuses on procedures for production and process controls, criticizing Novartis’s response when identifying foreign particulate matter in single-bag batches of Kymriah with respect to identity, strength, purity, and quality.

“Your procedure for removing particulates detected in Kymriah in final product does not provide assurance that all particulates, including particulates that are not easily visible, can be identified and removed such that the final product, delivered through intravenous infusion, is free from contamination with foreign particulate matter,” the letter says.

Novartis acquired the Morris Plains plant from bedraggled cell therapy firm Dendreon back in 2012. In 2017, Kymriah became the first CAR-T therapy approved in the US and last year brought in $536 million in revenues for Novartis.

The FDA requested Novartis to respond to its letter within 30 days outlining specific steps taken or planned to be taken to correct the noted deviations.

Novartis confirmed to this publication it has responded to the FDA and has been working to address the findings.

“Patient safety is always our top priority,” a spokesperson said. “We remain confident in the quality, purity, and potency of every patient lot of Kymriah manufactured and distributed from our Morris Plains site.”