Abstract:
Viral clearance studies are mandated prior to entering clinical trials and for commercial launch of biopharmaceuticals. These studies are a key component of risk mitigation to reduce the potential for iatrogenic transmission of pathogenic viruses. This paper reviews regulatory guidance and practical strategies for designing viral clearance studies. Essential elements of a developmental phase-appropriate viral clearance package are detailed. These include scale-down model qualification, virus spike experiments and validation (clearance evaluation) of manufacturing process steps.
The heuristics and learnings from available data are shared. Developments in this area including generic validation strategies, multi-viral spiking strategies and use of newer model viruses for nonconventional substrates are also described. This review provides a framework for a comprehensive viral validation package for regulatory submissions.
The infectious capacity of viruses is well known; additionally, certain viruses cross the species barrier, and with current globalization as it relates to travel, viruses not indigenous to a particular location can enter into new environments. Biopharmaceutical processes that produce product for human dosing need to be operated in a manner that significantly reduces the risk of viruses entering the final product. A variety of measures are taken to reduce this risk throughout the production process. A key aspect of risk mitigation is to conduct viral clearance spiking studies for several downstream purification steps to demonstrate the capacity and capability of the process to remove or inactivate known and unknown viruses. Contamination events in biomanufacturing are rare but can be catastrophic when they occur, consequences of such events range the spectrum from impact on patient safety and drug shortages to legal, regulatory and financial implications. The impact on manufacturing operations is significant; follow up on a contamination event includes investigation management, decontamination and other corrective actions. Although viruses have been detected in bulk harvests and manufacturing environments, to date there have been no incidents of iatrogenic infectious virus transmission through cell line-derived biopharmaceuticals.
