How do you design and validate viral clearance studies?

Viral clearance studies demonstrate process capability to remove/inactivate viruses. Study design: select model viruses representing relevant classes (enveloped/non-enveloped, DNA/RNA, size range - typically MuLV, PRV, Reo3, MVM), scale-down process steps proportionally, spike virus at known titer, and process through the step. Calculation: log reduction = log10(input titer/output titer), accounting for sample volumes. Validation requirements: demonstrate clearance at process parameter extremes (worst-case), assess impact of process variability, and validate analytical methods for virus detection. Regulatory expectations: total clearance should exceed potential viral load, orthogonal mechanisms preferred, and dedicated inactivation steps (low pH, solvent/detergent) should be included. Documentation: detailed protocol, execution records, statistical analysis of titers, and clearance claims. Studies are repeated when process changes may impact clearance. ICH Q5A provides framework guidance.