Authored By: Kurt Brorson
To ensure patient safety, injectable biopharmaceuticals are required to be free from viruses. Because mammalian cells grown in bioreactor culture can harbor or become contaminated by viruses, a rigorous risk mitigation strategy is required for world-wide regulatory approval of biopharmaceuticals. The mitigation strategy is described in a 1997 ICH document, “Q5A(R1), Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin”. This guidance describes a system of testing (cell banks, raw materials and process intermediates like cell culture harvests) and removal/inactivation procedures in downstream processing (filtration, chromatography and chemical virus inactivation). These steps are evaluated for their ability to clear a panel of viruses, usually three to five that are chosen to represent a diversity of phenotypes. By adhering to the principles and practices in this guidance, the biopharmaceutical industry has provided safe products to consumers worldwide for the past 20 years.
While ICH Q5A provides high-level principles for conducting viral clearance studies, they are complicated technically and specific details of implementation are left to the firms conducting these studies. For example, ICH Q5A holds that viral clearance studies should be performed using appropriate scaled down models of the actual manufacturing scale unit operations (e.g. chromatography, filtration, etc.). However, ICH Q5A leaves it to the firm how to design the study in detail. For example, which process parameters are most important to match? Some are obvious, like pH and conductivity of an anion exchange column where the viruses bind electrostatically, or pH and time for a low pH inactivation step. Others are judgement calls, like residence time on a column where the kinetics of virus binding is nearly instantaneous.
Fortunately, a large body of scientific literature has been generated by industry and regulatory authorities over the past 20 years about these very detailed implementation topics. Windows of robustness for clearance unit operations have been established, for example there is now an ASTM standard for retrovirus inactivation by low pH incubation (E2888-12). Failure mode for other unit operations like small virus filtration have also been identified (e.g. overloading, flow pausing). Focused conferences, notably including the annual PDA (Parenteral Drug Association) Viral Safety Forum and an invitation-only, practitioner-focused Viral Clearance Symposium, have helped shape consensus concepts and approaches towards these implementation specifics.
Analytical methods for virus detection are also evolving, although certain legacy tests are hard-coded into ICH Q5A. As an example of the evolution, next-generation sequencing (NGS) is rapidly improving and have been proposed for adventitious agent detection. Currently, NGS is most commonly used for follow-up investigations to potential or actual viral contaminations. However, many thought leaders in the viral safety community have proposed they can replace older animal-based adventitious agent tests.
PAREXEL’s consulting group can provide our clients with advice when developing comprehensive virus risk mitigation strategies for biopharmaceutical development. Our recommendations are based on a deep knowledge and experience in viral clearance in a bioprocessing. Our tailored strategies consider a number of criteria including: What is the stage of product development (e.g. BLA vs. IND)?, What specific unit operations will be used downstream?, What cell substrates will be used for production? Finally, which global regions are targeted for product introduction?