What are the key challenges - and advances - in fermentation and cell culture technology that industry faces over the next five years? To gain some insight, BioPharm International turned to six industry professionals for their forecasts: David A. Dodd is president, chief executive officer, and director of Serologicals Corporation; Sean Eicher is a product manager at New Brunswick Scientific Company, Inc.; William R. Tolbert, Ph.D, a BioPharm International editorial advisory board member, is president of WR Tolbert & Associates, LLC; Tim Ward is director of cell culture for The Automation Partnership; Larry West is director of sales and marketing for Broadley-James Corporation; and Frank Wicks is president of fine chemicals for Sigma-Aldrich Corporation.
BPI: What are the most difficult challenges facing the fermentation and cell culture sector during 2004 and within the next five years? How do you think the challenges will be met?
Currently, the manufacturing technology for commercial scale production of therapeutic recombinant proteins - including monoclonal antibodies - has matured to the extent that this technology (that is, large, stirred-tank bioreactors in many thousands of liters using batch, fed- batch, or perfusion methodology) is no longer a major hurdle in the development of these biopharmaceutical products. Development of well growing cell substrates; high-yield recombinant expression systems; animal product-free media; and efficient bioreactors has led to the economically feasible manufacture of hundreds of kilograms annually.
With the large number of potential, new biopharmaceutical products, the availability of suitable mammalian cell manufacturing plants has become a problem for the next few years. This is a problem, however, of capital investment timing and plant construction planning, rather than of production technology. Future technological advances for these production systems likely will be incremental and focused on streamlining and increased efficiency, rather than on fundamental new approaches.
The transfer of regulation for recombinant proteins and monoclonal antibodies from FDA's Center for Biologics Evaluation and Research (CBER) to the Center for Drug Evaluation and Research (CDER) may cause some disruption in the short term as companies adjust to the different regulatory polices and philosophies of CDER, but this should not be a long-term problem and may become an advantage.
The equipment used to produce compounds from microbial or cell culture batches must adhere to numerous manufacturing and processing regulations. To meet these regulations, the required documentation can range from basic material certification with test reports to full boroscopic examinations of all welds within the sterile envelope.
Since the level of system validation is often unknown at the project onset, manufacturers need to accommodate the defined needs as well as anticipate additional requirements yet to be determined. One method to accomplish this is with a modular line of fermentation equipment that can be modified to incorporate components - that can be validated - into the system after delivery. This design would allow end-users to compensate for system features not defined in the original system specifications and further optimize their process with additional controls that could result in higher yields from the same equipment.
Many industry insiders are predicting a capacity shortfall in the next few years. With this in mind, scientists will need to venture from traditional protocols and investigate novel approaches to increase yields and efficiencies. Doing so could allow the scientist to use their current equipment to meet the increasing demand for certain compounds. Approaches such as fed and continuous batches in fermentation or perfusion with packed beds of non-woven polyester fiber disks in cell culture have shown promise in many applications. In some instances, employing a non-traditional approach has increased the production capability of a reactor tenfold compared to batch runs.
In addition to these unique methods to increase yields, manufacturers will be pushed to deliver units with shorter lead times. The market is demanding that the current lead times of six to 12 months be cut by one half or one quarter to meet their needs. This will result in fewer custom-designed systems being sold and lead to more pre-packaged systems - which have already been tested and designed - emerging in the marketplace.