Preventing Human Infection
Depending on the process, virus removal (which includes both clearance and inactivation) can employ the normal purification operations plus a final virus filtration step, with or without inactivation. For example during mAb purification the first step, a protein A capture column, is conducted at a pH low enough to inactivate many viruses.
“Depending on how long product is maintained at low pH, protein A capture is a very good step to study because it can be quite effective and very robust for inactivating enveloped viruses,” observes John Bray, Ph.D., global business development manager for clearance services at the Bioreliance Glasgow facility. Other chromatography steps (especially anion/cation exchange) may also provide several log reductions in virus concentrations, depending on the media’s ability to retain viruses and the salt concentrations, Dr. Bray explains.
That many downstream unit operations used routinely during bioproduction remove or inactivate viruses is good news. The hurdle for bioprocessors is that clearance and/or inactivation by means of these steps must be demonstrated, quantified, and shown to be robust. Recently an online tool has emerged for selecting separations tools that help achieve both product purity and virus safety.
FDA’s Office of Biotechnology Products now maintains a database on viral-clearance unit operations for the production of mAbs. The viral-clearance database, which focuses on retroviruses and parvoviruses, holds clearance data from regulatory submissions for various types of chromatography (protein A, ion exchange), low-pH inactivation methods, and virus filtration.
The best time during a product’s development life cycle to conduct virus-safety studies is a matter of debate. The two competing philosophies can be termed “early” and “late.” The more traditional late approach, which evolves from the mandate to “fail early,” argues that expending resources on an early-stage molecule that is likely to fail is wasteful. The emphasis in the late approach is toward product yield and purity, and to worry about viral clearance only when approval seems likely.
Through the early approach, developers optimize (or evaluate) each production step for viral clearance as the steps are implemented. This involves investing in virus-safety studies long before molecules enter clinical trials.
As Dr. Bray notes, the early approach has its benefits. “You know that by the time you enter early-phase clinical trials that steps are in place that provide significant clearance.” The other way, if a virus problem surfaces identifying the cause and remedying it entails significant cost and delays. For example, processors may need to insert an inactivation or filtration step that was not part of the original process. “There’s definitely a cost implication for investing this time early in process development,” Dr. Bray says, “but it saves significantly at the end because you don’t have to go back and re-evaluate the process.”