systems that allow
for efficient and
of a wide range
of volumes in a
broad series of
It is no secret that the transition to single-use technology for biopharmaceutical applications is often disruptive. Yet, as the industry continues to see the proven benefits of integrating these technologies, and in some cases fully
transitioning to them, the paradigm shift that happened in
the upstream is making its way into the downstream.
In the specific case of low volume mixing in the downstream, the go-to solution has always been to use traditional
stainless steel mixers. Now that is changing, and although the
technology transfer from traditional mixers can be complicated, the transition offers a new opportunity and assurance
of integrity that is unmatched by stainless steel mixers. The
following discussion investigates how single-use technologies
are advancing into the downstream and also investigates the
different innovations the market has to offer.
A PARADIGM SHIFT
Merely a decade ago, sin-
gle-use technology was
able; but, over time,
it flourished in the
duction world. Initially
used to replace tradi-
tional stainless steel
equipment for media
storage and make-up,
have become the go-to
ture. Yet, downstream purification has long been the one
part of the biomanufacturing chain that has not seen the
benefits of single-use—until now.
Once fermentation is completed, downstream processing
for biopharm manufacturing typically involves sampling, purification, and then resampling to prove the purification has
been successful. Mixing is required to create homogeneous
mixtures that provide representative samples, and prove
their efficacy. However, the smaller volumes and more sensitive materials involved in downstream processes introduce
additional challenges to achieve successful mixing.
IN THE MIX OF THINGS
Most single-use mixing systems work best in the 30- to
500-liter range, and even work with up to 1,000 liters. While
this is good for common processes such as buffer preparation, the solutions for mixing just a couple of liters are more
limited. It took many years to design away to achieve gentle and effective mixing at low volumes in a stainless steel
mixer. When it came time to convert this into a single-use
format, the challenge was amplified.
Materials need to be mixed as they drain from the tank
during, for example, a final fill operation. Mixing is also a
key part of downstream vaccine manufacturing. Adjuvants
are often added to the biological component to increase its
potency, and because these are rarely water-soluble, continuous mixing is required during the final fill to ensure the
correct composition of the final vaccine product.
Effective mixing is also essential for viral inactivation in
the downstream. This is a critical step in the manufacture
of biologics, as the cells used in cell culture processes can
contain viruses that must be removed before the final fill.
This is accomplished either by filtering them out, or chemically inactivating them. Mixing is particularly important in
the pH inactivation step, as it is vital that every single drop
of the product is exposed to the inactivation process. In addition to effective mixing, to prevent portions of the product
mixture from remaining activated or having contaminants
introduced, a dead leg free drain is necessary.
At least a dozen types of mixers and mixing technologies
are available in single-use formats. Recirculation mixers are
the most common, particularly for the final fill. A recirculation
loop leaves the bottom of the tank, passing through a peristaltic pump and returns the contents back to the top of the tank.
This constant motion of the materials results in gentle mixing,
and is particularly common in vaccine manufacturing.
However, more efficient mixing is often required for many
Mixing It Up
A look into single-use for downstream processing
■ By Eric Isberg, Global Product Manager, Integrity® Single-Use Fluid Technologies, ATMI
n a e st