A vaccine product must be produced in compliance with good manufacturing practices (GMPs), as specified in the Code of Federal Regulations.¹ To ascertain compliance, FDA conducts periodic GMP surveillance inspections. In the case of vaccines, the inspections are carried out by a team of experts in GMPs and experts in the product in question, an approach adopted in 1999 under the Team Biologics program. The Team Biologics program is a partnership between CBER and FDA’s Office of Regulatory Affairs, designed to increase both consistency and focus in FDA’s inspections of biologics manufacturers. When a manufacturer makes a change in the facility or the production process that could have a moderate to substantial potential to affect adversely the quality of the product, the manufacturer must submit a supplemental application for FDA approval of the change.

Because vaccines are produced through complex procedures that depend upon living organisms, there are many points in the process where variance could be introduced into the final product. To ensure consistency, each lot of the product must be individually tested and approved before its release for marketing. The vaccine manufacturer must submit a sample of the lot along with a lot release protocol to FDA, which then reviews the lot testing data and, if necessary, performs additional tests.

In the case of AVA, BioPort resumed manufacture of the vaccine in 1999 after a pause for plant renovation. The BLA supplement for the renovations has been approved, and release of lots manufactured after renovation of the facility was approved in January 2002. One of the sources of difficulty in the regulatory history of AVA may be that the standard regulatory expectations for vaccines in general changed between the licensing of AVA in 1970 and 2001. Vaccines may, in some sense, have been victims of their own success: for many vaccines the decline in the disease burden from communicable diseases was so clear and the effectiveness of the vaccine was so great that there was little incentive to modify the production process. However, as part of its continuing quality improvement effort, FDA instituted more explicitly defined process validation requirements for the manufacture of vaccines and other products licensed before these requirements were codified. As a result, manufacturers of vaccines, including AVA, must now ensure that their production processes are validated.