For the majority of cell-based seasonal and pandemic influenza vaccines, virus titers obtained from adherent cell lines are
superior to those obtained from cells in suspension. GlaxoSmithKline Biologicals (Wavre, Belgium) recently presented data
on the impact of this technology on capital expenditure and time-of-construction.11 Because adherent cell lines produce more virus per volume, microcarriers help lower the volume of fermentation and the size
of the tanks from 5,000 to 1,000 L. In this example, the use of smaller fermentation vessels eliminated the need to construct
special room heights and thus avoided additional engineering expenses. According to the presented data, the overall savings
can add up to hundreds of thousands of dollars and significantly shorten lead-times for engineering plant construction.
Other examples have documented the process economics and operational cost savings regarding microcarrier-based rabies vaccine
production.12 As the size of such operations increases, so does investment in resources and personnel—and any failure becomes more costly.
Scalability of cell culture unit operations is therefore mandatory, and Baxter (Wien, Austria) has demonstrated the successful
operation of a 6,000-L scale mammalian cell culture based on microcarriers for the economic production of influenza vaccine.13
Process Development Strategies That Drive Time and Cost-Efficiency
Portfolio management dictates increased throughput of development candidates through the laboratory, preferably at constant
or even lower operating costs. A two to three-fold increase in projects per year compared to five years ago is not uncommon.
This challenge is reflected by the formats, tools, technologies, and workflows used. Statistical tools such as design of experiments,
and high-throughput tools like microtiter plates and robots, are being used to run large series of experiments in a short
time.
In process development for chromatography, this approach is used not only to select media for specific steps,14 but also to develop and optimize the parameters of a purification step. For MAbs, about 400 conditions for two chromatographic
steps could be tested in a one-day screen. Furthermore, less than one gram of MAb was consumed. The conditions arrived at
with these robotic systems were later confirmed with laboratory-scale columns.15
Another way to eliminate bottlenecks in process development is to use technology platforms. These may be defined as a standard
set of conditions and methods applied to all molecules of a given class.16
The biopharmaceutical manufacturing industry has communicated time savings of 3–8 months using such a fast-track development
approach when technology platforms are applied in all key aspects of development; cell line development, cell culture, downstream
processing, analytical concepts, and even filling. A head start of only three months into clinical trials can increase a product's
net present value (NPV) by tens of millions of dollars.17
If the platforms used for clinical manufacturing also can be used on a commercial scale with little or no modification, then
similar or even higher value gains can be achieved for projects and a lower risk from comparability issues can be assumed.
Technology and Product Choices That Drive Safety
The purification of modern biological therapeutics generally involves both membrane and chromatographic separations. Membrane
separations complement chromatography and offer a number of key benefits. They are fast, robust, and can bring greater effectiveness
to the key stages of bioprocessing by concentrating and washing feed streams before chromatography, for example. Cross-flow
filters (tangential-flow filters) are best suited to higher solid contents, more viscous feed solutions, or where concentration,
recovery, or purification of cells or target species is desired.
For vaccine manufacturing, particularly virus purification, fully scalable macrovoid-free hollow-fiber technology applied
to ultrafiltration and microfiltration offers great advantages. The defect-free surface allows the use of more open porosity
ratings (such as 500 and 750 kd), thereby enabling the use of ultrafiltration membranes as part of the virus purification
process. Moreover, the open-flow path design of hollow-fibers gently processes cell suspensions and other particulate feed
streams and reduces shear forces, thereby helping maintain the integrity of the virus. As a result, recovery rates of the
virus target and overall process economics are improved.18
|
