The use of modern biotechnology for the production of biopharmaceuticals allows the treatment of diseases, which could not be treated previously. However, virus infection and replication is an inherent risk during cultivation of mammalian cells. Raw material testing, rigorous characterization of the master and the working cell bank as well as testing of the final bulk product (before downstream processing and virus inactivation steps have been performed) lead to a considerable increase in the viral safety. Although viral contamination might happen during production only preventive measures can be taken in fermentation and product biosynthesis. Thus the downstream processing is an integral part of the manufacturing process and has to be validated in order to assess its potential to eliminate, clear, or inactivate viruses. The downstream processing has two, sometimes contradictory aims: (i) purify the product to the required purity at high recovery using the lowest number of steps possible, and (ii) eventually increase the number of purification steps in order to assure the elimination of potential viral contaminants. The general difficulty resides in the physico-chemical properties of the product. The properties that maintain the beneficial effects of a product are often very similar to those carried by all viruses, in particular when the bioproduct is a live virus (for vaccination or for gene therapy purposes). Therefore only a limited spectrum of techniques can be used for virus inactivation/elimination. To assess the capability of individual process steps to remove viruses these steps have to be tested with live model viruses for which clearing factors can then be calculated. These, so called, viral clearance studies have the objective to demonstrate the capacity of different steps of the purification process to eliminate or inactivate adventitious agents acquired during the production process (contaminated cells, raw materials, process failure, etc.). They are performed via spiking experiments. As viruses vary greatly in properties such as size, resistance to inactivation, type of envelope, type and structure of their genome, the model viruses used for these spiking experiments have to be selected in order to cover the whole spectrum of potentially present viruses. However, in order to assure absence of viral contaminations derived from the producer cell line in the product, the downstream protocol has also to be validated for its capacity to inactivate or eliminte these specific viruses (e.g. retroviruses derived from hybridoma and CHO cells, or EBV derived from human lymphoblastoid cell lines). In general, it is difficult to show more than a five log removal on any given step due to the titers of the model virus used. More details can be found in the following references: Fritsch (1992) , Cartwright (1994) , Werz et al. (1997) , ICH Topic Q5A (1997), and Larzul (1999) .