FDA Untitled letter to Novartis: Significant issues, Inadequate CAPAs Read More..

FDA had issued USFDA 483 in December 2022 to Novartis US site at Morris Plains, NJ over inspection deficiencies. In the Untitled letter issued in August 2023, USFDA cited additional significant issues based on review of the information collected during the inspection and responses from Novartis. The FDA concern is primarily about foreign matter (wood, brass, steel, cellulose etc) observed in over 100 batches of the CAR-T cell therapy drug Kymriah. The issue recurred from 2018 and in November 2020 root cause was concluded as Cryobags used, primary container for Kymriah. Enhanced visual inspection of incoming bags was implemented as corrective action (CAPA). However, the issues continued and particulate matter attributed to Cryobags was observed Kymriah batches even in October 2022. Obviously when root cause is identified in 2020, and if appropriate CAPAs are implemented the issue should not be recurring in October 2022. This raises the concern that either root cause determination or CAPA or both are inadequate. FDA also raised concern that the process /procedure for removing the foreign particles is not validated and procedure for removing particles observed in Kymriah final product does not assure that all particles are identified and removed. Kymriah is an intravenous infusion and particulate contamination of the product has potential risk of sterility issue[s] and thrombosis issue[s] for patients.

Another issue raised in the Untitled letter is the repeat excursions for Mold in ISO 5/Grade A and ISO 7/Grade B areas between October 2019 and November 2022. There were about 100 actionable excursions with various contributing factors – gaps in procedures relating to cleaning and sanitizing of manufacturing areas, equipment cleaning and sanitizing, equipment transport, material handling, personnel gowning, cleanroom behavior, handwashing and sanitation and failure to follow procedures. At least 15 corrective actions (CAPAs) were taken, but still the issue recurred as recently as October / November 2022. This again raises concerns of inadequate root cause determination / inadequate CAPAs and effectiveness of CAPAs.

In the letter FDA asked Novartis to provide foreign particle event rate in Kymriah, action level excursions trend data for Grade A/Grade B areas, and status of other corrective actions and also asked Novartis to attend a Regulatory Meeting with FDA.

Untitled letter