Abstract
Virus clearance steps – inactivation and/or removal of viruses – have to be implemented in the manufacturing process of biologicals to assure a high margin of virus safety of these products for patients in need. The implementation of virus retentive filters result in a robust virus clearance as only the size/shape of viruses is relevant in the context of the removal capacity of the filters – viruses larger than the mean pore size of a virus retentive filter are removed from the feed stream and the desired protein – and not the properties of viruses as enveloped or non-enveloped, single or double stranded DNA or RNA, and resistance to physicochemical treatment. When during the lifecycle of the product a change of the established virus retentive filter is required due to e.g., supply issues by the manufacturer of these filters currently implemented in the manufacturing process or an improved filter is provided by filter manufacturers, a change of filters has to or may be initiated. This post-approval change has to meet regulatory guidance, e.g., ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) guidelines, for licensed products.
When changing virus retentive filters, the critical parameters volumetric throughput of product intermediate and, when performed, buffer flush, pressure, pressure/flow interruption, and flow decay have to be validated for the new filter demonstrating the same or improved virus clearance capacity. Comparable drug substance properties regarding, besides virus removal capacity, e.g., impurities and protein aggregates, have to be demonstrated. Validation data comparing the current with the changed process, based on prior knowledge of established engineering principles and applied manufacturing experience, especially during the development of the drug substance, published literature and other information form the basis of the risk assessment prior to implement the change. After having assessed the impact of the change in virus retentive filters according to regulatory guidelines without negative effects on product quality and safety, the potential change has to be reported to the relevant regulatory authority in line with existing regional regulations and guidance.