This invention is intended to reduce the time and cost of drug manufacturing. Two major steps, both requiring expensive equipment
and substantial time to achieve the same goal, are eliminated. It is anticipated that in the manufacturing of monoclonal antibodies,
this new unit saves a process time of approximately 50 h for a 2000-L batch. In addition, the limited handling of proteins
can improve the final yield substantially, sometimes as much as 20–30% (5).
Figure 5: Air-scrubbed filtration system for nutrient media perfusion, cell removal and volume reduction.
Proteins can be purified in the bag by using it as a chromatography column. Although the idea of using a flexible bag as a
chromatography column appears alien, nothing prevents a process from being developed by taking into account the geometry and
the physical state of resin suspension in the bag. The elution may include a step elution, a gradient elution, or a programmed
elution. An example is washing the bound resin to remove cells, and then equilibrating the protein–resin conjugate in a buffer
to elute the target drug. A buffer that would break down the binding can be used to collect a highly purified solution of
the target protein. Even if this process of purification does not achieve the quality that traditional methods do, the possibility
of eliminating a few steps in downstream processing would have a great effect on the cost of purification because no equipment
needs to be installed for large volumes to be fed through the purification column. An AKTA Pilot liquid-chromatography system
(GE Healthcare) might do the job of an AKTA Processor (GE Healthcare), for example.
Other uses of the new bioreactors include media and buffer preparation and sterile transfer to final containers. The unit
also may be used as a pressure vessel in pharmaceutical manufacturing. The air-septum bioreactor is suited to performing many
functions. As a complete system with no moving parts and the ability to be pressurized, this invention fulfills the bioprocessing
industry's needs for manufacturing recombinant proteins, monoclonal antibodies, and vaccines.
Other uses of the perfusion filter include concentration of slurries, reduction of volume of a bacterial nutrient media, water
purification, and sterile liquid transfers. The filter can be made in several shapes and combinations to fulfill the need
for a particular flow rate from a specific mixture. Using air to scrub a filter and keep the pores open enables new filtration
methods. This filter system requires a solid base to keep the filter from collapsing. The base can be layered with fine membranes,
such as a 0.22-µm filter, to separate bacteria and sterilize a solution. The filter system can be sterilized in situ and placed inside a bag for an unlimited time of operation.
The new technology described above is designed to take advantage of the properties of a flexible bag. By incorporating a bioreactor
inside the bag, the technology offers a transportable system that does not require extensive validation when manufacturing
sites are changed. Because users can link the units together to produce batches of practically any size, the technology could
expand the adoption of single-use systems for the commercial production of biological drugs.
A significant advantage of the new technology developed is its low capital and operational costs. The flexible bags are placed
on a heating or cooling platform (see Figure 1). The system monitors the nutrient media for dissolved oxygen, pH, and glucose
levels either by remote sensors or by direct sampling. Although other methods, such as fluorescence-based monitoring, are
available, Therapeutic Proteins believes that, in the long-term, the wired sensors inside the bags are the most appropriate
The systems described above are routinely used at Therapeutic Proteins's cGMP compliant facility to manufacture large-scale
cytokine and monoclonal-antibody production batches. Although the technology requires substantial modification and validation
of the process, the systems operate smoothly once these efforts have been completed because they contain few components.
Sarfaraz K. Niazi, PhD, is executive chairman of Therapeutic Proteins, 3440 S. Dearborn St., Chicago, IL 60616, email@example.com
1. S. Niazi, Disposable Bioprocessing Systems (CRC Press, Boca Raton, FL, 2011).
2. Xcellerex, "XDR Single-Use Bioreactors," (Marlborough, MA),
http://www.xcellerex.com/platform-xdr-single-use-bioreactors.htm, accessed Oct. 4, 2011.
3. GE Healthcare, "WAVE Bioreactor Systems," (Chalfont St Giles, UK),
http://www.gelifesciences.com/aptrix/upp01077.nsf/Content/wave_bioreactor_home, accessed Oct. 4, 2011.
4. R. Temam, Navier-Stokes Equations: Theory and Numerical Analysis (AMS Chelsea Publishing, Providence, RI, 2000).
5. J. Liderfelt, G. Rodrigo, and A. Forss, "The Manugfacture of mABS—A Comparison of Performance and Process Time between
Traditional and Ready-to-Use Disposable Systems," in Single-Use Technology in Biopharmaceutical Manufacture, R. Eibl and D. Eibl, Eds. (John Wiley and Sons, Hoboken, NJ, 2011).