Viral validation design of a manufacturing process.

ABSTRACT

In many cases, the viral safety evaluation of biological products does not derive solely from direct testing for the presence of contaminants, but also from the demonstration that the manufacturing process is able to inactivate/eliminate them. This is achieved by the voluntary addition of a virus load at various steps of the process and the evaluation of viral reduction during the subsequent steps. The major difficulty for such viral validation studies is less to calculate a reduction factor for each step than to identify clearly and demonstrate the contribution of each in-process parameter to the reduction. Consequently, the first approach consists of the identification of all the parameter which may influence viral reduction. The design of the viral validation needs to take this inventory into account and control experiments must be carried out in parallel with the main spiking experiment, i.e. mainly to (i) hold controls with and without the biological intermediate product; (ii) control experiments with each individual inactivating/partitioning parameter; (iii) control experiment without stabilizer if necessary. In addition to these process controls, cytotoxicity and interference experiments will allow the use of each in vitro infectivity assay for the testing of processed samples to be validated. For a viral inactivation step, the kinetics of inactivation will be studied and the data will show (i) a progressive decrease of the viral load over time. If the decrease is too rapid to plot the kinetics, the direct relation between the inactivation and the inactivating parameter has to be demonstrated in complementary experiments; (ii) the reduction obtained when in-process limits are used and (iii) the different phases of inactivation when they exist. Moreover, it is pertinent to evaluate for each treatment the margin of safety derived from the treatment time on the one hand and the strength of the inactivating parameter on the other.