Biomedical Engineering Reference
In-Depth Information
500 cm/h
.
Bed height: 11 cm.
Flow rate:
.
The studies discussed here enable approximation of a design space for virus removal
by chromatography.
V
IRUS
F
ILTRATION
. Virus-removal filters operate primarily by a size exclusion
mechanism. Virus filtration, especially for larger viruses, is considered to be a robust
technique, that is, the size separation mechanism works regardless of virus type, feed
solution, and operating conditions. However, commercially available virus removal filters
vary from one filter manufacturer to another. They may differ in membrane materials,
surface chemistries, membrane thickness, pore structure, and pore size distribution, which
may lead to differences in virus retention, protein passage, and adsorption properties [20].
They may also be operated by normal flow filtration or cross-flow filtration.
During cross-flow filtration, a protein concentration polarization layer may form on
the membrane surface, which may be favorable in terms of virus retention. On the
contrary, during normal flow filtration, onemay experience a flux decline over the course
of the filtration. This may be associated with LRV decline that ranges from negligible to
severe. This effect varies widely among filters and may be process specific.
During the development of a virus filtration step, one should consider, among other
factors, the effects of protein concentration, aggregate concentration (exacerbated by
aging and freezing of the feed), flux rate, and buffer chemistry. Recognizing that today's
filters have inherent performance variability, one should evaluate the effect of membrane
lot on filter performance. These studies should be done on scale-down filter models whose
performance relative to full-scale filters has been characterized. In all of these studies, the
two main outcomes required are successful product recovery and virus clearance.
8.5.4 Select a Manufacturing Strategy that will Achieve
Viral Clearance
Generally, a manufacturing strategy is developed to achieve product CQAs related to
physical and chemical attributes (e.g., purity, aggregates, and pH). Certain purification
unit operations, such as chromatography and low pH elution from a protein A column,
will be identified to have proven capability in achieving virus clearance. Additional unit
operations designed solely for virus clearance (e.g., virus filtration) may be chosen to
reach the final clearance target.
The complexity of selecting a manufacturing strategy will vary widely with the
specific purification requirements of the drug product under consideration. More
challenging situations involve lesser proven manufacturing practices or expression
systems or less well-established categories of biopharmaceutical drug. These situations
limit the extent to which a manufacturer may take advantage of the technical
understanding and comfort level associated with existing technologies and practices.
Accordingly, the burden of knowledge generation for these newapproaches is likely to be
relatively high.
