Each manufacturer of viral vaccines characterizes the cell substrate used in production. This characterization involves defining the history of isolation and banking, growth characteristics, karyology, identity (e.g. iso-enzyme analysis), tumori-genicity, and freedom from adventitious agents [1-3]. Adventitious agent tests include bacterial and fungal sterility (as promulgated in 21 CFR 610.12), mycoplasma (cultivatable and non-cultivatable; and, in the case of insect cells, spiroplasma), mycobacteria (animals and/or culture), viruses (by in vitro and in vivo methods) including acute (lytic, haemadsorbing, haemagglutinating) and latent (e.g. retroviruses or other oncogenic viruses), specific tests for retroviruses, other agent-specific tests (primarily polymerase chain reaction-based), and tests for bovine and porcine agents (as promulgated in 9 CFR 113). In addition, bovine-derived materials used in production should be sourced from countries in which BSE is neither known to exist nor which represent an undue risk for BSE because their import requirements are less restrictive than would be acceptable for import into the U.S. (as listed in 9 CFR 94.18). If the passage history of the cell substrate did not carefully document the sourcing of bovine-derived materials used in cultur-ing or if sourcing was from countries that have subsequently been identified to have a risk of BSE, risk assessment may be necessary to address this theoretical potential risk. It is important to note that not all tests are necessary for all substrates and a testing regimen should be selected considering the donor history and tissue source of the substrate, its passage history (exposure to animal-derived or human-derived materials), banking strategy, and intended use. So, for example, a master cell bank of a human or simian cell substrate should be tested for bovine or porcine viruses if, during its passage history, animal-derived (bovine or porcine) materials were used which were not adequately controlled for adventitious agents or not documented appropriately for such control. However, careful quality control of raw materials used during manufacturing might preclude inclusion of bovine or porcine virus tests on a lot-by-lot basis once the cell bank has been demonstrated to be free of such agents.
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