Biomedical Engineering Reference
In-Depth Information
describes the TFF unit operation and provides a fundamental understanding of the
operation unique to the membrane, feed stream, and fluidics system. Each step will
conclude with a summary of the key “QbD Principles” required for the specification and
optimization of the TFF unit operation.
6.2 APPLICATIONS OF TFF IN BIOTECHNOLOGY
The tangential flow filtration unit operation encompasses microfiltration, ultrafiltration,
nanofiltration, and reverse osmosis processes. All are pressure driven membrane process
and are differentiated by the membrane that determines which species permeate and
which are retained [10]. In biotechnology, microfiltration (suspended particles 0.1-5
m
m,
e.g., cells) and ultrafiltration (macromolecules 0.001-0.002
m, e.g., proteins) are the
two most relevant applications of TFF. Concentration and diafiltration are the two TFF
operating modes used in biopharmaceutical production. In upstream applications,
TFF can be used to recover the target molecule and remove impurities from perfusion
reactors. It may also be an effective means to wash and harvest host cells or to recover
excreted products from the fermentation broth. In downstream applications, TFF is used
to concentrate the target molecule in preparation for a subsequent unit operation, such as
chromatography, or to adjust the product concentration to that required by the final
formulation. Diafiltration is used to remove unwanted species such as impurities from the
fermentation process (media components, host cell proteins, proteases) and buffer
excipients. In this manner, TFF is frequently employed to condition a feed stream to
the appropriate concentration, ionic strength, pH, and buffer components needed for
subsequent unit operations. TFF is often the unit operation of choice for such applications
because of its mechanical simplicity, robustness, and relatively low cost. However, an
improperly designed and scaled TFF operation will be plagued with membrane fouling,
low product recovery, long processing times, excessive buffer usage, frequent membrane
replacement, and inconsistent operation. Such problems can be avoided by applying
Quality by Design principles to understand and specify the TFF unit operation.
m
6.3 TANGENTIAL FLOW FILTRATION OPERATING PRINCIPLES
In tangential flow filtration (TFF), the primary driving force for permeation through the
membrane is an external pressure gradient known as the transmembrane pressure (TMP)
[13]. This pressure is much larger than the osmotic pressures across the membrane and
reverses the flow of solvent and permeable solutes from the concentrated solution to the
dilute solution. In microfiltration and ultrafiltration, the feed stream solute concentration
is generally low and osmotic pressure is typically negligible. As a result, these processes
are typically operated at relatively low external pressures in the range of 5-100 psi.
Solute rejection also increases with the external pressure gradient (TMP), and thus TMP
can also affect membrane selectivity.
As filtration proceeds, the retained molecules are unable to sufficiently diffuse away
from the membrane surface. This is caused by the rapid transport of solvent through the
