A crucial issue for biotechnology products is that the mammalian cell lines commonly used in manufacturing are susceptible to viral contamination. Therefore, demonstration of viral clearance by the manufacturing process is mandated by the Federal Drug Administration to ensure patient safety. These viral clearance studies are a complex and costly challenge.
“We have learned a lot about viral clearance in the 20 years since ICH Q5A Guidance was published”, said John Mattila, Director of Purification Process Development at Regeneron Pharmaceuticals and lead author of a Retrospective evaluation of cycled resin in viral clearance studies—a multiple company collaboration.
Written by BioPhorum’s Development Group Viral Clearance Workstream, the paper will make a significant contribution to biopharmaceutical product process development, manufacturing and viral clearance assessment.
Chromatography resins are used in the manufacture of biotechnology products to remove product- and process-related impurities, including potential viruses. Manufacturers use an established approach of ‘cycling’ chromatography resins through repeated steps of conditioning, purification and cleaning to maintain performance parameters.
Historically, regulatory guidance has been interpreted as requiring small-scale, virus-spiking clearance studies to demonstrate the ability to remove viruses following repeated resin cycling. These studies are expensive and time-consuming, and there has been growing evidence that cycling chromatography resin does not reduce viral clearance, except when there is unrelated experimental variation.
The BioPhorum paper sets out a retrospective analysis of industry data, comparing virus clearance in new and repeatedly cycled resins for two of the most commonly used chromatography steps in biopharmaceutical manufacturing: protein A and anion exchange. The vast data, collected over several decades from 12 member companies, was analyzed by the authors with the support of a statistician. The result is a coherent data set in an accessible, collated format.
Mattila added, “Individual companies have published results of their own viral clearance studies in the past, but BioPhorum brought together member companies who could share and scrutinize the data to share the broader view of performance by diverse manufacturing platforms.”
The compelling conclusion of the paper is that viral clearance capability is not negatively impacted by resin cycling. This supports the view that viral clearance studies for repeatedly cycled resins are not necessary if appropriate cleaning methods are applied. Companies will be able to compare their own product-specific data with the collated data in the paper to provide an evidence-based rationale for health authorities and regulators for their own manufacturing processes.
For manufacturers with no history of product-specific data, the paper also provides details about what to expect and how to conduct necessary studies most efficiently. In the longer term, the plan is to track implementation across companies.
Mattila concluded, “We look for companies to continue to engage the health authorities on this topic, so we can be sure to focus on continuing to develop understanding of viral clearance.”
Dr Louise Bennett, a BioPhorum Facilitator also commented that this is not the end, “This paper shows the power of collaborative working to advance knowledge across the biopharmaceutical industry. It has been a pleasure to work with the authors of this paper and the Viral Clearance team will continue to work together on topics of interest”.