Why was the Untitled Letter issued?
During an inspection of CSL Biotherapies (CSL) located in Victoria, Australia during April 2010, FDA investigators observed deviations from current good manufacturing practice (CGMP) requirements in the manufacture of licensed influenza vaccines (Afluria seasonal influenza vaccine and Influenza A (H1N1) Monovalent Vaccine). FDA is not aware of any findings that endangered any patients.
The observed deviations involved failure by the company to: 1) thoroughly investigate any unexplained discrepancy or the failure of a batch or any of its components to meet specifications; 2) assure that drug product containers or closures do not react with substances contained in the product and do not leach into the product; 3) assure that reserve samples from representative sample lots or batches are examined at least once a year for evidence of deterioration; and 4) establish testing procedures designed to assure components conform to appropriate standards of identity strength, quality, and purity.
The Untitled Letter reiterates the observations noted during the inspection and acknowledges the firm’s response to the list of observations. The letter also asks for additional information, and requests that the firm meet with FDA for further discussions related to the observed deviations and planned corrective actions.
A copy of the Untitled Letter is available on our website at: http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/
What is the difference between an Untitled Letter and a Warning letter?
An Untitled Letter is an initial correspondence with a regulated firm that cites violations that do not meet the threshold of regulatory significance for a Warning Letter. Examples of when CBER has issued an Untitled Letter include after its review of a manufacturer's advertising and promotional labeling, after an inspection under CBER's bioresearch monitoring program or by Team Biologics, and as a result of internet website surveillance.
For what products did FDA observe deviations from CGMP requirements?
The CSL facility manufactures Afluria (trivalent seasonal influenza vaccine) and H1N1 (monovalent) influenza virus vaccines in both single-dose thimerosal-free syringes and multi-dose vials containing thimerosal. FDA investigators observed deviations from CGMP requirements in the manufacture of these products.
Are the adverse reactions reported after administration of CSL’s influenza vaccine in Australia related to the deviations outlined in the Untitled Letter?
No, there is no direct connection between the adverse reactions of fever and febrile seizures reported in young children and the deviations noted in the Untitled Letter. The majority of the deviations noted in the Untitled Letter are related to the multi-dose vials that contain thimerosal. The adverse reactions that have been reported in Australia are associated with single dose syringes, which do not contain thimerosal.
What is the status of the investigation into the adverse reactions observed in Australia?
FDA was recently notified by CSL and Australia’s regulatory authority, Therapeutic Goods Administration (TGA), of an increase in the number of reports of febrile seizures in Australia in children under 5 years of age who had received CSL’s 2010 seasonal trivalent influenza vaccine manufactured for the Southern hemisphere. The vaccine, Fluvax, contains the 2009 H1N1 and two other influenza virus strains.
At that time, CSL began withholding further distribution of its 2010 pediatric seasonal influenza vaccine in Australia. Also, the Australian Chief Medical Officer suspended influenza vaccinations for all healthy children under 5 years of age until further notice.
The Australian CSL product is licensed as Afluria in the United States and is indicated for individuals 6 months and older. However, the formulation associated with the adverse events in Australia has not yet been approved by FDA for the upcoming 2010-2011 influenza season..
Various investigations into the cause(s) of these febrile seizures are still ongoing. FDA is collaborating with TGA, other international regulatory counterparts, and CSL to obtain additional information and stay apprised of the status of the investigations to assess any potential implications for the United States influenza season.
Are influenza vaccines safe?
Yes. Millions of doses of seasonal influenza vaccines have been given safely in the US for the last decade. These vaccines have a long and successful track record of safety.
The seasonal influenza vaccines have been well studied, and febrile seizures have not been a concern.
For the 2009-2010 influenza season, FDA and CDC enhanced vaccine safety monitoring for the seasonal and H1N1 vaccines. No concerns pertaining to febrile seizures were identified in this safety monitoring.