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
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?
Tolbert: In the early to middle 1960s, the earliest large-scale (50 liters to 1,000 liters) suspension culture of mammalian cells
was accomplished. Then, during the 1970s, large-scale systems were further developed in Europe for biopharmaceutical production.
Microcarrier technology for large-scale production of anchorage dependent cells was introduced in 1967 and later used for
vaccine production in the Netherlands.
William R. Tolbert, Ph.D.
FDA, however, prevented any use of "continuous cell lines" (that is, non-diploid, long-life cells that were suitable for scale-up)
as substrates for human-use biologicals, until the middle to late 1980s. The first FDA-approved biological product - using
the continuous Chinese hamster ovary (CHO) cell line as substarate - was Genentech's Activase (recombinant tissue plasminogen
activator). This product has been produced both in the United States and Europe using bioreactors greater than 10,000 liters.
During the 1990s and early 2000s, many more biopharmaceuticals have been approved using large-scale mammalian cell culture
as the manufacturing technology.
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
Eicher: The three greatest challenges to be faced by the cell culture and fermentation sector in the next five years will be navigating
the governmental regulations concerning the development of products used for human consumption; dealing with the capacity
shortage for larger-scale systems; and gathering and maintaining process data.
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.