November 1, 2005 (Vol. 25, No. 19)
Design Innovations and Cost Concerns Drive Trend Toward Compactness
The biopharmaceutical industry has experienced tremendous growth over the last ten years as a result of genetic engineering. The global market for biopharmaceuticals, valued at $48 billion in 2004, has been growing at a healthy compounding rate of 20% over the last three years (Table 1).
Development of new biologic therapies, particularly for the treatment of cancer, is likely to fuel the most significant growth in the upcoming years.
There are more than 300 biotechnology-related drug products and vaccines currently in clinical trials, targeting more than 200 diseases,1 fueling biotechnology’s growth in the global pharmaceutical market (Table 2). It is forecasted that by 2010, nearly 50% of all new approved pharmaceuticals will originate from a biotechnology company.
As the biopharmaceutical industry matures, it is facing fierce competition and constant pressure to increase efficiency, reduce production costs, and speed time to market. The industry will experience growing pains as it transitions from science- and technology-based to manufacturing-based.
The paradigm shift from research to manufacturing has forced R&D groups to focus not only on new molecule and clinical development, but also on manufacturing efficiency in regard to production titer and yield, alternate platforms, and new technologies.
Cost containment concerns continue to drive innovative facility and equipment design. Progress has been made, and biomanufacturing facilities run leaner and more efficiently while maintaining consistency, quality, efficacy, and profitability.
R&D and Technology-based Trends
As biopharmaceutical companies move toward a manufacturing-based business model, much of their R&D efforts have been devoted to improving overall process efficiency and robustness. Biopharmaceutical companies have made breakthrough achievements developing common platforms with improved vectors and robust host cells.
High throughput screening methods have rapid isolation of potential high-production clones possible. Media formulation and optimization have also had a huge impact on the manufacturing process.
Process analytical technology is another tool used to speed up technology transfer to manufacturing. Additionally, the last few years have seen significant progress in the productivity of recombinant cell lines.
In the early 90s, cells typically reached a maximal density of about 25×106 cells/mL. The expression titer was 100300 mg/L. Now, it is not uncommon to see cells grown to a density of more than 1×107 cells/mL, with a production titer of 210 g/L. The high yields obtained in today’s processes are the result of years of R&D that has led to a better understanding of gene expression, metabolism, growth, and apoptosis delay in mammalian cells.
The biopharmaceutical industry used to measure biomanufacturing facility capacity by fermentor or bioreactor capacity. The global manufacturing capacity of biopharmaceuticals was around 2.27 million L in 20042.
It has been a constant struggle to balance capacity supply and demand due to product uncertainty. A capacity crunch was predicted as a result of Enbrel and Betaseron shortages in the late 1990s and early 2000s.
The latest prediction is that the production capacity for biomanufacturing will expand by 48% over the next five years3. Technology breakthroughs will continue to determine the future of biomanufacturing facility design.
High expression cell lines will significantly reduce the upstream reactor size, while putting more focus on downstream purification. More capacity does not necessarily mean more liters of fermentor and larger facilities.
For example, at a 200 mg/L production titer level, it will take a 25,000-L fermentor 40 batches to make a total of 200 kg of final bulk at a recovery rate of 70%. When the cell production level increases from 200 mg/L to 4 g/L, the same amount of bulk drug material can be produced in a 1,0000-L fermentor at the same run rate.
Reduction in upstream fermentor and bioreactor size will also trigger size reductions for supporting equipment, such as media preparation, harvest, CIP, and utilities.
The upstream fermentation/cell culture area used to represent nearly 40% of overall facility space and cost. It is likely that in the future the biomanufacturing facility will become more compact with additional focus on the downstream area.
Mammalian cells have become the dominant system for the production of recombinant proteins because of their capacity for proper protein folding, assembly, and post-translational modification.
Cost considerations will force most biopharmaceutical companies to look into more robust and efficient host cell systems. It is known that microbial expression systems, such as E. coli, provide fast-turn around time and high production levels.
Recent technology breakthroughs have made it possible to produce larger proteins, which require folding and post-translational modification.
Microbial host systems will continue to represent a significant market share in the global biopharmaceutical industry. Efforts have also been made to use lower eukaryotic systems, such as yeast, to produce complex glycosylated therapeutic proteins.
Other trends include the use of continuous culture technology, such as perfusion technology, at the production scale. Continuous cell culture technology provides steady-state growth conditions, continuous culture harvest, and a lower turn around time. It also significantly reduces the reactor size required for a given product. Continuous culture technology, however, still faces design and operational challenges such as system/equipment complexity related to sterility, as well as concerns about cell line stability.
Transgenics as an alternative biomanufacturing technology will continue to gain market share for vaccines and therapeutic proteins. Using animals or plants as the production source eliminates the upstream fermentation and cell culture process from the traditional biomanufacturing facility and results in significant space and equipment saving.
Facility/Equipment Design and Trend
The design, construction, and validation of a GMP biomanufacturing facility is a highly complex undertaking. Challenges include reducing capital expenditures, minimizing the project timeline (which is typically three to five years), and increasing operational flexibility while minimizing operational cost.
The need for faster processing time, increased productivity, and cost effectiveness has driven biopharmaceutical companies to entertain all available options in facility and equipment design and operation.
Design innovations have challenged traditional biopharmaceutical facility/equipment design and operation. The industry has seen design trends move toward equipment and facility size reduction, stressing overall operational cost containment while maintaining flexibility, safety and reliability.
Traditionally, it is assumed that most biopharmaceutical operations, especially in the downstream area, are open operations. This has led to the placement of large process equipment in a classified clean room area.
As a result of innovative equipment design and acceptance by regulatory bodies, the functional closed operation and grey space design concept significantly reduced the high cost of the clean area by moving a majority of the equipment into grey space (Figure 3).
Equipment design innovations include the use of ring headers with automated valves or multi-port valve assemblies (Figure 4) to replace the traditional transfer panel design, which requires make-and-break connections. New sampling devices also make it possible to sample in a controlled closed operation. A foreseeable trend is a small classified core area surrounded by large nonclassified space . The resulting reduction of cleanroom space has considerable cost saving implications.
Large sterile disposable systems and accessories are another trend. There are a number of economic advantages that can be realized with single-use systems. Disposable technology has found a role beyond buffer and media storage and into applications such as bioreactors, and membrane filtration and chromatography systems.
Disposable bag sizes of 1,500 L to 2,500 L are commercially available, and 10,000 L bags have been reported (Figure 5). Replacing large stainless steel tanks with disposable bags will not only lower facility capital equipment cost but also reduce manufacturing space requirements.
Another trend is the use of buffer concentrates and in-line dilution technology. Capital equipment represents about 4050% of the cost of a new biomanufacturing facility and a large percentage of that equipment is dedicated to the preparation and storage of buffers.
A typical biotech purification process requires, on average, 10 to 30 different buffers. Buffer volume ranges from 50100,000 L, depending on the scale. Most of the buffers used in the purification process are of low-salt concentration, which can be easily concentrated by 100-fold.
Use of buffer concentrate and in-line dilution technology will reduce the buffer hold and preparation tank size and result in space/equipment size reduction in both process and utility areas.
Buffer concentrates, coupled with disposable systems, can increase capital and operational savings. Care must be taken to ensure successful implementation of in-line dilution technology. It is important to understand pH, conductivity, and temperature shift during buffer dilution.
Process robustness related to the accuracy of buffer concentration must be carefully examined as well. Potential corrosion impact associated with the use of concentrated buffer can not be overlooked.
Powerful technology innovation, capitalization on the human genome project, and deep product pipelines will continue to fuel the growth of the biopharmaceutical industry. With advancements in manufacturing focused on R&D aimed at higher titer and yield, additional capacity demand does not necessary mean bigger fermentor and larger manufacturing facility.
Innovation in facility and equipment design will also lead to a much more compact and flexible facility, better able to meet increased capacity demand.