Abstract

Many manufacturers of biopharmaceuticals are moving from batch to continuous processing. While this approach offers advantages over batch processing to manufacturers, demonstration of viral clearance for continuous processes is more complex. Regulators expect manufacturers to use an appropriate scale down model, based on solid scientific justification, to verify the viral reduction capacity of the manufacturing process. The output from chromatography columns operated in continuous processes fluctuates in concentration so that the load for the subsequent column is not homogenous. This must be considered when designing viral clearance studies. One way to approach clearance studies is to downscale the continuous process, using multi-column chromatography systems and in-line spiking of virus. The multi-column chromatography systems and experienced operators, however, may not be available at the CRO performing the study. Another approach is to evaluate each step in traditional batch mode, using existing chromatography systems, but to modify the spiking and loading conditions to mimic the variance introduced by the transition between the two connected process steps. Using a standard chromatography system, we have evaluated a flow through anion exchange chromatography step in a monoclonal antibody process using five different methods to introduce the virus to the column. We have shown that regardless of whether the virus spike is introduced in a well-mixed batch mode, introduced as a concentrated pulse of virus with homogeneous mAb or with a concentrated peak of mAb, the clearance of MMV was similar. This study introduces an alternative way to evaluate viral clearance in a continuous process.