FDA Issues Warning Letter to Novartis for cGMP Violations

Novartis Vaccines and Diagnostics (Marburg, Germany) received a warning letter on January 24, 2008, citing significant deviations from current good manufacturing practices (cGMP) in the manufacture of its rabies vaccine (RabAvert) and diphtheria and tetanus toxoids adsorbed concentrate (without preservative), with regard to bulk lot production and process controls and investigations.

The nonconformities include deviations from the applicable requirements of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act, as well as requirements of Novartis’s biologics license application approved under section 351(a) of the Public Health Service Act and 21 CFR Part 601.

The letter describes the results of an FDA inspection that was conducted at the company’s site in Marburg, Germany, between September 20 and September 27, 2007. Some of the key deviations cited include:

• The sterility of the media lot used in the RabAvert vaccine upstream process could not be assured, yet final product lots that used the media lot were further processed and submitted to FDA for lot release.

• The media and buffers assigned to each group were not defined, and the rationale for determining which media or buffer represented the worst case for each group was not documented in the study.

• Stability study Q312-001, which was conducted to establish an expiry period for diphtheria and tetanus toxoids adsorbed concentrate (without preservative), was inadequate in that containers and closure systems used for stability sample storage were not representative of the final container.

• The validation study for the use of connectors for the media formulation area of building was inadequate.

Other deviations cited in the warning letter were related to incomplete investigations of sterility failures and failures to validate changes in cleaning procedures. The letter advised the company that the failure to implement effective corrective actions and preventive measures might result in the FDA taking regulatory action without further notice.

FDA warning letter (PDF)