MilliporeSigma - Viral Safety - 12

Viral Safety

Viral Safety in Monoclonal Antibody Manufacturing
Critical steps in the downstream process
are those dedicated to viral clearance,
including low pH and/or detergent treatment to reduce levels of enveloped
viruses, and virus filtration, which
removes both enveloped and nonenveloped viruses. Most processes rely
on these dedicated steps to make major
contributions to overall viral clearance
targets. However, the impact of unit
operations on the properties of the
molecule can be quite complex. Low pH
hold is highly effective for inactivating
viruses but is hard on therapeutic
proteins and may affect yield, highlighting
the interplay of product-quality assessments with requirements for viral
clearance throughout downstream
purification.
Similarly, upstream-processing conditions will have a direct effect on
performance of the downstream unit
operations, and higher cell densities and
volumetric productivity will also likely
affect the amount of virus entering the
purification train. These changes can all
impact the efficiency of the purification
operations for both impurity removal
and virus reduction.

Clearance Strategy
Establishing and conducting viral clearance testing for biopharmaceutical
customers is the focus of Kathryn
Remington, Ph.D., principal scientist
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| October 1, 2017

focusing on the BioReliance® portfolio
of MilliporeSigma. At a previous job at
a large biopharmaceutical company, Dr.
Remington collaborated with in-house
process-development groups to build
viral safety into processes from an early
stage, and then evaluated the viral clearance potential of the manufacturing
process. Today, services related to viral
clearance are largely outsourced, as the
time and cost of a dedicated viral safety
group and laboratories are beyond the
resources of most companies.
A process-centered view of viral safety
makes sense since downstream unit
operations serve as a "safety net" to clear
any adventitious virus that might escape
upstream testing. But Dr. Remington
cautions that "while some downstream
steps provide very good clearance, some
don't provide any at all. The level of
clearance is process-specific, moleculespecific, and even virus-specific."
Some measures, like chemical inactivation through detergents, inactivate
broad classes of viruses, as for example,
lipid-enveloped viruses. Low-pH inactivation provides good inactivation of
enveloped viruses. But, as mentioned
earlier, not all products are stable under
acidic conditions. As the pH increases
above pH 3.5, inactivation of enveloped
viruses becomes less robust. Chromatography clears viruses based on their interaction with the resin. "Each virus has its

A scientist developing a chromatography step at bench-top scale.

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