SARTORIUS AG The conference presented both the upstream and downstream facets of current biologics production, with presentations by academics and industry representatives. Whereas a decade ago, there was concern that cell production facilities for would not be adequate to meet the growing demands of the pharma industry, this prediction was not fulfilled. As discussed at the conference, the rise of disposable culturing systems and the improvement in grams per liter production rates provided sufficient capability to avoid a worldwide shortage of biologics. In addition, whereas some biologics are required in very large volumes going up to tons of product, in most cases small quantities are satisfactory to fulfill the needs of rare diseases. Finally, the path to FDA approval was much more rocky than had been envisioned, so that rates of approval were well below forecasts.
In fact the bottleneck reversed itself, as downstream processing did not develop improvements as rapidly as the upstream end. Thus a number of presentations discussed advances in downprocessing which have greatly speeded the entire train.
The large production facilities built a decade ago are underutilized today, in some cases at only 40% capacity. Since these are billion dollar investments, it strains a company's resources if these plants are largely vacant and full depreciation become difficult to achieve.
The transition to fully electronic records, adoption of completely disposable trains and movement toward greater and greater levels of automation are all changing the face of the industry. These dramatic improvements can accelerate the process development phase of drug development, in some cases as much as from 12 months to 3 months.
These improvements work to eliminate human error, meaning that products are more reliable and can be produced more economically.
Disposables are more and more widely employed. Efficiency, ease of validation and savings in water utilization are all key factors. At the upstream end, taking down a disposable unit after production requires much less time, usually 15 minutes to remove a cell culture bag, whereas cleaning and resterilizing a large stainless steel vessel will require an entire day.
There is frustration over the pace of drug development; recent data records 5000 possible molecules discovered with only 250 making the cut for possible candidates. We need to move to a new generation of drug development that will circumvent long, laborious and fruitless early exploration of new compounds.
Among existing challenges is the difficulty of producing drug delivery systems that are acceptable to patients, who demand small needles, subcutaneous injection in a total of 2 ml. volume. Because of the tremendous viscosity of such highly concentrated protein solutions, the industry is a long ways from a delivery method that will be fully acceptable to patients, meaning that individuals receiving biologics will continue to face long hours of infusion protocols.
Several participants stated that the biotech industry is much more open today than in the past and there is a more free exchange of information, which allows for better communication and overall savings through avoidance of repetitive experimental protocols.
Mab processing may involve the use of a CMO, yet companies are not enthusiastic about this strategy, because there may be a loss of control.
Tangential flow filtration is receiving a lot of attention at the downstream end, since it can be a much more efficient method than conventional dead end filtration. There is less clogging of membranes, and it is less damaging to molecules. It remains the technique of choice for concentrating biomolecules.
Viral safety was considered; it always comes with risks attached, since one can never state that a preparation is virus free, only that the possible level of contamination is below some threshold of detection. The consequences of failure can be catastrophic as Genzyme learned when a siege of viral contamination forced closure of their facility in order to clean it from top to bottom. However, current methodology appears to be successful, as there has never been an instance in the industry in which a contaminated product reached the public and inflicted harm.
Advances in the bioprocessing industry are enabling faster, cleaner and more effective processing, allowing safer and more economical biologics to reach the public.
About the Author
K. John Morrow, Jr., PhD is a molecular biologist, consultant and author of over 290 peer-reviewed papers and articles. He has worked in both the academic and private sector and is presently Chair of Meridian Bioscience's Institutional Biosafety Committee as well as President of Newport Biotechnology.
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