Health Canada's human vaccine lot release program: impact on the 3Rs

Abstract Health Canada (HC) is Canada's national regulatory body that oversees the review, authorization, and lot (batch) release of human vaccines. All biologic drugs, including vaccines, are subject to the Biologics and Genetic Therapies Directorate's Lot Release Program (LRP) before approval and sale. The LRP classifies biologics into one of four risk managed Evaluation Groups based on pre- and post-market evaluation. The extent of lot release testing conducted at HC varies for each group. All vaccines submitted for a Clinical Trial Application or as New Drug Submissions are placed in Group 1a or 1b, respectively. Generally, only Group 1b (manufacturing consistency lots) undergoes targeted testing in addition to a review of manufacturer's test protocols. Targeted testing focuses primarily on potency and can include animal studies, although in vitro assays are favoured when available. In vitro safety assays may also be conducted. Once approved, vaccines are first classified as Group 2 products for which a protocol review and targeted testing are continued. Although HC reserves the right to test all vaccine batches, the percentage of batches tested and types of assays used depends on risk evaluation. Vaccines that are well characterized and have a strong history of consistent manufacture can be placed in Group 3, in which lot release is based on a protocol review with only periodic testing. Vaccines are not placed in Group 4, which is a rapid approval without protocol review for specific biologics. Since its inception in 1995, this testing strategy has led to a significant reduction in animal use at HC. All animal testing conducted at HC for the LRP is reviewed annually by an Institutional Ethics Review Board and subject to the guidelines established by the Canadian Council on Animal Care, which includes the application of 3R principles. HC remains open to the incorporation of alternative testing strategies for vaccine lot release by (1) reviewing and adopting new assays as they become available and are validated, and (2) contributing to the development of new assays for potency and safety through an active vaccine research program.