FDA Raises Significant Manufacturing and Safety Concerns Over Novartis’ CAR-T Therapy Kymriah

On Tuesday this week (December 5), the FDA released an untitled letter sent to Novartis in August. The letter pointed out that FDA inspectors found that Novartis, in New Jersey,Morris PlainsNew significant issues arise with Kymriah, the first FDA-approved CAR-T cell therapy produced by the factory.

FDA inspected Novartis from November 28, 2022, to December 9, 2022. During the inspection, FDA investigators found significant deviations from current Good Manufacturing Practice (CGMP) requirements in the manufacturing process of Novartis' licensed biologic Kymriah, including deviations from the Federal Food, Drug, and Cosmetic Act.

Although the FDA stated that they had issued an FDA-483 form outlining some of their early observations from the inspection at the end of 2022 and received a response from Novartis, further review of the information gathered during the inspection revealed "additional significant deviations."

Major deviations include but are not limited to the following points:

The factory failed to establish laboratory controls, including scientifically sound and appropriate specifications, standards, sampling plans, and testing procedures, to ensure that components, drug containers, closures, in-process materials, labels, and drugs conform to appropriate standards of identity, strength, quality, and purity.

In the letter, the FDA pointed out that from December 2018 to the inspection date, Novartis identified approximately 100 batches of Kymriah contaminated with foreign particulate matter such as wood, cellulose, brass, and steel. In November 2020, Novartis concluded that the freezing bags were the most likely root cause. Despite implementing enhanced visual inspections for the incoming freezing bags, particulate matter was still found in the final product batches of Kymriah as of October 8, 2022, which Novartis attributed to the freezing bags.

The factory failed to follow appropriate written procedures to prevent microbiological contamination of sterile drugs. There were no necessary control systems to prevent contamination or mix-ups, and during the inspection period from October 2019 to November 28 to December 9, 2022, approximately 100 operational level shifts occurred in the ISO 5/A-grade and ISO 7/B-grade areas for Kymriah production. The company found that non-compliant procedures were not followed in the manufacturing area, equipment cleaning and disinfection, equipment transportation, materials, operations, personnel gowning, cleanroom behavior, handwashing, and hygiene, and thus implemented 15 corrective actions. The most recent preventive measure (CAPA) for mold was on October 12, 2022. Despite these CAPAs, the factory still recycled molds in A-grade production.

The factory failed to establish adequate written production and process control procedures designed to ensure that drug products have the identity, strength, quality, and purity they are represented or characterized to possess [21 CFR 211.100(a)].

The FDA believes that since 2019, some batches of Kymriah at the plant did not follow procedures to remove detected particles from the product. The infusion of foreign substances through intravenous therapy has been confirmed to be associated with potential risks such as "infertility issues" and "thrombosis problems."

Although Novartis responded to the FDA's inspection observations (Form FDA-483) on July 14, 2023, the FDA believes that Novartis did not clarify whether its recent CAPA was implemented in October 2022. Additionally, it did not specify whether the Kymriah batches containing particles were from bags before or after the CAPA.

FDA Requests Novartis to Provide Post-Inspection Report on Occurrence Rate of Foreign Particulate Matter Incidents and Effectiveness of Preventive Measures Against Foreign Microparticles. In its response in July this year, Novartis stated it would select a new secondary supplier for the frozen bags, and FDA requires Novartis to report the specific progress of replacing the new bags.

Kymriah's sales exceeded $500 million in 2022, with commercial production taking place at five global sites, including the Morris Plains facility, which Novartis stated received FDA approval in October 2020 to expand its manufacturing capacity.