What are the key challenges - and advances - in fermentation and cell culture technology that industry faces over the next five years?
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?
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 an advantage.
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.
With the increase in regulatory constraints concerning the generation and storage of electronic records and signatures, the integrity and availability of process data is becoming paramount in its importance. As a result, the data from the supplied systems will be required to be simply integrated into the end users' existing supervisory control and data acquisition (SCADA) or laboratory information mangement (LIM) system, without the need for custom drivers. This feature will allow scientists to use a software package they are already familiar with for data analysis and process optimization. In order to accomplish this, it is believed that proprietary control packages, as well as system components, will become obsolete, being replaced with industry standard components and controls. This will not only provide scientists with the open architecture they require but give them the reliability their process deserves.
West: The most difficult challenges all have the same origin: technology. In 2004 the availability of technology allowing sensors to monitor their own performance and predict failure will redefine the expectations on research, process development, and metrology as it relates to productivity. In addition, the availability of technology that allows on-line instruments to communicate with off-line instruments will put more information in the hands of operators. And the effective use of this information, its interpretation and documentation, could increase the initial workload of supervisors and validation.
But technology - such as that already mentioned - will also alleviate its associated burden. The use of wireless communications, tablet PCs, remote interfaces, and the like will enable unprecedented multitasking by operators and supervisors alike. For example, a second shift operator in the United States could use his company's Intranet to contact a supervisor just getting into work in the UK to discuss a process alarm or unique cell activity.
My recommendation to face these challenges is to embrace the technology that is becoming available, while ensuring optimum implementation.
Dodd: The challenges facing the fermentation and cell culture industry include meeting the capacity for production of new, approved antibody-based therapeutic products; consistent assurance of viral clearance; and adequate quality systems throughout the entire development and manufacturing chain. Due to the continued industry-wide shortage in manufacturing capacity for approved antibody and recombinant protein therapeutic products, an increased number of contract manufacturing organizations (CMOs) can be expected to expand capacity.
Wicks: One challenge the biopharmaceutical industry faces is the replacement of animal-derived components. Industry increasingly will choose to outsource to medium development companies for medium optimization studies, spent medium analysis, and microarray analysis - to name a few - and also increase outsourcing to manufacturers of novel medium components. Another challenge is increasing productivity of fed-batch culture systems. This can be achieved by the use of bioreactor feeds or novel feed strategies in the production process and through protein expression in novel engineered cell types. In general, the biopharmaceutical industry is looking to increase the cost effectiveness of its processes at phase 2 and this helps drive outsourcing choices where cost-favorable.
Small and medium industry players also seek manufacturing capacity for preclinical recombinant proteins for purposes like toxicology studies. They can do this by outsourcing to nontraditional, non-CMO sources such as medium development companies with bioreactor capacity and this production capability.
Other notable trends include the use of disposables to enable multiproduct manufacturing strategies, implementation of design controls, and antibody engineering to reduce the therapeutic dose required.
Ward: The challenge facing the fermentation and cell culture sector during 2004 and within the next five years is delivering large quantities of cells consistently and on time.
BPI: What are the top technological advances industry will see in the fermentation and cell culture sector during 2004 and over the next five years?
Ward: Cell culture will become a precise operation. The demands upon in-house cell culture teams will be to produce cells-to-order and just-in-time. Alternatively, companies will be investing in cell storage systems from which cells prepared in advance may be drawn. The significance of just-in-time delivery should not be underestimated, as it will place demands upon the suppliers of automation to provide machines that are capable of unattended operation 24 hours a day, seven days a week.
In the next five years technological advances include more built-in intelligence, for example automatic cell life cycle management, and built-in QC functionality.
West: In 2004 and continuing throughout the course of the next five years, industry will see three significant technological advances related to on-line and off-line measurement and control in fermentation and cell culture applications. The first is the ability of sensors to monitor their own health and, in doing so, predict their own failure. The second is the ability of stand-alone instrumentation to communicate information to a single controlling device in the suite which will tie together control and data collection. Finally, the third is the ability of process monitoring and control to be portable through the use of wireless communications. All these will have the effect of reducing costs and improving reliability and repeatability.
Dodd: The industry will see advances in productivity from specialty supplements targeted toward specific cell lines; an increase in regulatory focus on the validated manufacturing processes relative to viral clearance objectives; and increased regulatory oversight of cell culture manufacturing to conform to tighter standards relative to viral clearance and quality systems.
Wicks: Innovations for 2004 will include increased speed in development of animal component–free and defined media through the use of analytical methods, design of experiment techniques, and the use of microarrays. We'll see this because new tools are available to speed the process. Novel raw materials have been created through chemical synthesis and, in some cases, with transgenic proteins to replace animal-derived components.
Within the next five years, the creation of new, engineered production cell lines to compete with the CHO cell line will be achieved, leading to increases in productivity while maintaining normal mammalian post-translation modifications.
Tolbert: New and novel cell-based medical advances are likely to come in the area of gene and cell therapy modalities. Recombinant viral vectors that are directly injected into patients (in vivo gene therapy) may be produced in the same - or similar - bioreactors used for therapeutic protein production. The scale-up requirement for these products is directly proportional to the vector expression level and the required patient dose. These parameters vary widely for different products and vector and cell substrate systems. Annual production requirements for a commercial operation may range from a few hundred liters to many thousands of liters. Future development of new cell substrates, new viral vectors, and new media all will be important to the economic feasibility of these products. The technology for viral vector products is at a stage similar to where therapeutic proteins were in the early 1980s.
Ex vivo gene therapy, where cells are removed from a patient, genetically modified in culture, and then returned to the same patient, shares problems with patient-specific cell therapies (such as adult stem cells and activated dendritic cells). Here, aseptic manufacturing controls must be in place for every process step, as it is not possible to sterilize or final filter the live cell containing product, and the production process is very labor intensive with one product lot per patient instead of thousands of patient doses per product lot.
However, academic research (at the preclinical and phase 1 and 2 clinical trial stages) has increased dramatically over the last few years, and there is the potential for substantial therapeutic advances, which may not be achievable by conventional pharmaceutical or biopharmaceutical drugs. It will be a major challenge to make any of these advances economically or commercially feasible for the hundreds of thousands of patients who might benefit from their use. In this field, innovative production technologies and novel manufacturing processes will be required to address the "one-patient-at-a-time" constraint and to effectively bring any of these therapies to the market. In order to properly address the regulatory issues associated with these new medical technologies, FDA raised the former Division of Cellular and Gene Therapies to office level within CBER. BPI