Viral clearance studies for biotherapeutics are a critical step in viral risk mitigation and one of the three key elements to viral safety noted in International Council for Harmonization (ICH) Q5A and commonly known as the safety triangle. First, careful selection and testing of raw materials and product materials is performed. The assessment of these materials is to prevent virus from entering the production process. Second, the detection of potential viral contaminants during processing is assessed by testing of relevant process intermediates. The testing of cell lines, raw materials and in-process intermediates is an important step, because human cell lines are often used to produce gene therapy vectors. Third, the removal or inactivation of potential viral contaminants by unit operations of the downstream manufacturing process is assessed in a customized viral clearance study. These three elements should form the basis of viral safety from the very beginning of development, through Investigational New Drug (IND) application to Biologics License Application (BLA) and after commercial licensure of a biopharmaceutical drug product.
The design of viral clearance studies for monoclonal antibodies and recombinant proteins derived from Chinese hamster ovary (CHO) cell lines is well established within the industry. Similar purification steps are often evaluated, and clearance expectations are well understood. Rodent cell lines produce retroviral-like particles, and the clearance of these particles, or a surrogate virus, must exceed the number of particles in the bulk harvest. Viral clearance studies for non-enveloped viral vectors have been performed less frequently. Therefore, the virus inactivation steps and the model virus panel to be used for clearance studies may not be as clear. Here we address some of the questions with respect to viral clearance studies for AAV vectors.