This document is concerned with testing and evaluation of the viral safety of biotechnology products derived from characterized cell lines of human or animal origin (i.e., mammalian, avian, insect), and outlines data that should be submitted in the marketing application/registration package. For the purposes of this document, the term virus excludes nonconventional transmissible agents like those associated with Bovine Spongiform Encephalopathy (BSE) and scrapie. Applicants are encouraged to discuss issues associated with BSE with the regulatory authorities.

The scope of the document covers products derived from cell cultures initiated from characterized cell banks. It covers products derived from in vitro cell culture, such as interferons, monoclonal antibodies, and recombinant deoxyribonucleic acid (DNA)-derived products including recombinant subunit vaccines, and also includes products derived from hybridoma cells grown in vivo as ascites. In this latter case, special considerations apply and additional information on testing cells propagated in vivo is contained in Appendix 1. Inactivated vaccines, all live vaccines containing self-replicating agents, and genetically engineered live vectors are excluded from the scope of this document.

The risk of viral contamination is a feature common to all biotechnology products derived from cell lines. Such contamination could have serious clinical consequences and can arise from the contamination of the source cell lines themselves (cell substrates) or from adventitious introduction of virus during production. To date, however, biotechnology products derived from cell lines have not been implicated in the transmission of viruses. Nevertheless, it is expected that the safety of these products with regard to viral contamination can be reasonably assured only by the application of a virus testing program and assessment of virus removal and inactivation achieved by the manufacturing process, as outlined below.

Three principal, complementary approaches have evolved to control the potential viral contamination of biotechnology products:

(1) Selecting and testing cell lines and other raw materials, including media components, for the absence of undesirable viruses which may be infectious and/or pathogenic for humans;

(2) Assessing the capacity of the production processes to clear infectious viruses;

(3) Testing the product at appropriate steps of production for absence of contaminating infectious viruses.

All testing suffers from the inherent limitation of quantitative virus assays, i.e., that the ability to detect low viral concentrations depends for statistical reasons on the size of the sample. Therefore, no single approach will necessarily establish the safety of a product. Confidence that infectious virus is absent from the final product will in many instances not be derived solely from direct testing for their presence, but also from a demonstration that the purification regimen is capable of removing and/or inactivating the viruses.

The type and extent of viral tests and viral clearance studies needed at different steps of production will depend on various factors and should be considered on a case-by-case and step-by-step basis. The factors that should be taken into account include the extent of cell bank characterization and qualification, the nature of any viruses detected, culture medium constituents, culture methods, facility and equipment design, the results of viral tests after cell culture, the ability of the process to clear viruses, and the type of product and its intended clinical use.

The purpose of this document is to describe a general framework for virus testing, experiments for the assessment of viral clearance, and a recommended approach for the design of viral tests and viral clearance studies. Related information is described in the appendices and selected definitions are provided in the glossary.

Manufacturers should adjust the recommendations presented here to their specific product and its production process. The approach used by manufacturers in their overall strategy for ensuring viral safety should be explained and justified. In addition to the detailed data that is provided, an overall summary of the viral safety assessment would be useful in facilitating the review by regulatory authorities. This summary should contain a brief description of all aspects of the viral safety studies and strategies used to prevent virus contamination as they pertain to this document.