Putting the best foot forward
Downstream processes play an important role in the production process

While much has been said and written about synthesis of active ingredients, the treatment process usually remains in the background. Yet separation of active ingredients from a suspension and the subsequent purification process are key factors in pharmaceutical and biotechnology production systems. Up to 60 percent of production costs arise in the downstream process alone.

Following years of effort, researchers finally succeed in discovering a promising active ingredient. Now what? The active ingredient is normally present in a murky fermentation broth or a complex mixture, or it could even be that only a single enantiomer is active. There is no doubt that the purity level of substances used in the pharmaceutical industry is significantly higher than it was just a few years ago. An additional complication is the need to speed up market introduction of active ingredients. All of this means that the purification process has become even more challenging. Even if good results have been achieved in the laboratory, at the end of the day the scale-up phase determines whether a purification method is suitable for use in the process. The choice of method coincides with another decision. For purification of pharmaceutical substances in particular, efficiency, cost effectiveness and the effect on the environment are the crucial factors that determine the success or failure of new products. Only methods that deliver highly effective separation and pure end products will ever reach the marketing stage. As a result, there is an ever-increasing need for cost-effective techniques. Demand is high for chromatography and electrophoresis as well as for extraction and traditional solid-liquid separation (filtration and centrifugation).

cGMP-compliant design
is a must
A whole series of new centrifuges for the pharmaceutical industry was presented at Achema 2003. cGMP-compliant design is a must for use in pharmaceutical production. The control strategy plus process monitoring must also support this design objective, including parameters such as filling, emptying, cleaning and diagnostic capability. Other key factors include repeatable process conditions such as residual moisture and purity. On Ferrum’s HPZ horizontal scraper centrifuge, a key design goal was to make it easy to inspect the basket. The entire housing can be opened up and swung out. An inspection port on the front provides a view of key components such as the filler tube, the scraper unit, the CIP nozzles and the sensors. If operation is interrupted, the centrifuge containing the product can be opened without opening the entire housing.
The new VZU vertical centrifuge made by Krauss Maffei has been specially enhanced to handle processing of preliminary and intermediate products in the pharmaceutical and fine chemical industries. Standard features include ease of inspection, minimal dead space and maximum ease of cleaning. To achieve this goal, surfaces were reduced, especially at the solids outlet. A dynamic filling system ensures ideal distribution of the product regardless of supply concentration. The bed is removed using the raker, eliminating the need for tube connections in the process chamber. Installation is simple because the filtrate drains out at the bottom.
Drying is often required following solid-liquid separation of fine crystalline or fine dispersion suspensions. This normally means that washing must be included in the centrifuge process to clean the suspension fluid from the end product. Drying is usually performed in separate equipment in an additional process step. There are considerable costs involved in handling the wet product, and it is also more difficult to achieve reproducible results and maintain batch identification. Centrifugal dryers such as the products made by Fima make it possible to combine both operations (centrifuge and dryer) in one machine. The machines have a hermetically sealed product chamber suitable for sterilizing and inerting. There is no contact with the product during the ongoing process. Supplemental rotary eddy shock drying significantly reduces drying times.
The process application spectrum for membrane technology has broadened significantly in recent years. Membrane processes are used to increase the concentration of extra-cellular enzymes and other proteins before they are solubilized further. As a result of advances in organic and inorganic membrane materials that can be used under difficult process conditions, membranes will continue to play an important role in the future. They have the advantage that they can be used on a very individualized basis. Membrane techniques can be specifically adapted to the particular chemical or physical properties of a product (size, charge, etc.).
The end of the line for
viruses and bacteria
Viruses and bacteria represent a constant threat to products and processes. Unwanted microorganisms can be introduced during the production of biological and bio-therapeutic compounds, destroying recombinant products worth thousands of euros. Routine processing and purification methods offer a variety of ways of removing viruses from biologically produced medicines and other products. A number of methods that are used primarily for purification of proteins are also effective in removing viruses, including precipitation, ion exchange, gel filtration, hydrophobic interaction, affinity and mixed-mode exchange chromatography and low pH buffer elution. Filtration based on size exclusion has a relatively low dependency on the product and on process conditions. It is regarded as being relatively robust, because its effectiveness does not depend on varying production parameters. Because the biological integrity of a product is not degraded, there are fewer undesirable biological and immunological reactions. Filtration based on size exclusion does not require the use of stabilizers or chemical substances (which have to be removed later on in the process).
Pall Life Sciences offers several virus filtration systems. One is the Ultipor VF GradeDV50, a virus retentive membrane filter that was specially developed for removal of viruses through size exclusion from fluids such as bio-pharmaceuticals, plasma derivatives, diagnostic reagents, cell culture media and buffers. A folded filter made of modified polyvinylidenefluoride exhibits an extremely tight pore size distribution and particularly low protein bonding characteristics. Millipore, another manufacturer, supplies the “Viresolve” which is designed to remove viruses during processing of monoclonal antibodies. The product line includes Viresolve NFP capsules and cartridges and NFR, an asymmetrical, pore-free membrane designed for higher throughput and faster processing. No matter which treatment method a user in the pharmaceutical industry decides to use, he or she will often combine a number of methods rather than restricting himself to just one. Combining different membrane techniques or combining membranes with centrifuges or chromatography is not at all unusual