Current issues in viral assays and viral clearance evaluation.

Viral contaminants are less amenable then chemical contaminants to analytical detection due to the lower sensitivity, specificity and precision of existing assays. In combination with the potential for biological amplification of viral contaminants in cell substrates or product recipients these analytical limitations lead directly to potential risk of virus infection of product recipients. While less than perfect, a broad spectrum of assays is available to characterize cell banks for the presence of adventitious and endogenous agents. Each product lot can be tested by an appropriate subset of assays for selected viruses of concern. Engineering and procedural controls over facilities, equipment and operations are necessary to minimize the possibility of viral contamination. Processes can be designed to include unit operations to remove or inactivate specific viruses of potential concern; the efficacy of these measures can be evaluated. While each of these measures has value, each also has limitations. None is solely adequate by itself to the task of preventing potential exposure to viral contaminants in product recipients. Biopharmaceuticals (purified characterizable macromolecules) are prepared by using a combination of such preventive measures. Specific measures will vary from product to product, depending on the nature and origin of the cell substrate, cell bank characterization results, raw materials used, physicochemical properties of the biopharmaceutical, effectiveness of assays, available facilities, and the agents of concern. Thus, flexibility in approach is necessary, resulting in different combinations of measures for each set of circumstances. So far, this approach has been successful in preventing viral infection in large populations treated to date with cell culture-derived biopharmaceuticals. Current issues for discussion include appropriate assays for adventitious and endogenous agents, appropriateness of current control systems and the scientific basis for standards.