Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications
Single-use bioreactors are changing the biomolecular production landscape.
Biologic drugs including monoclonal antibodies, therapeutic proteins, immunotherapies, and vaccines have transformed the treatment of many diseases. Given their therapeutic and commercial success, the pharmaceutical industry has invested heavily in these molecules, and, by all estimates, markets for current and novel therapeutic proteins will continue to increase.
In a report published in 2005, disposable bag technologies, used for media storage, process development, seed inoculum, and as the actual bioreactor vessel itself, were predicted to develop into important tools in therapeutic protein manufacturers’ quest for ever increasing efficiencies. Multiple factors have driven this quest for efficiency, particularly the realization that cost savings in manufacturing biologics would drive their adoption and acceptance globally.
Biologics sales are set to reach about $166 billion by 2014, with the global market for monoclonal antibodies alone expected to rise at a compound annual growth rate (CAGR) of 5.3% to nearly $58 billion in 2016. The U.S. market remains the largest single market for therapeutic monoclonal antibodies, rising from nearly $19.8 billion in 2010 to reach $20.1 billion by 2011. It is further projected to grow to $27.4 billion by 2016, a CAGR of 6.4%.
Historically, biopharmaceutical production has relied on space-consuming, hard-piped equipment including fixed, large stirred-tank stainless steel bioreactors and tanks to hold product intermediates and buffers. But their inherent inflexibility as well as the requirement for large capital expenditures for these systems has diminished their utility both in response to volume demand, and in meeting changing market conditions.
For example, biopharma manufacturers need to maintain production capacity for large volume protein therapeutics needed in large doses over long periods of time such as monoclonal antibodies.
At the same time, new personalized protein therapies targeting fewer patients will require small batch production. Newer protein medicine may also be much more potent, reducing requirements for large batch production. Further, national security needs for systems that can easily and rapidly respond to biological attacks or rapid vaccine production from fast-moving epidemics and pandemics will further drive the need for campaign-based production schemes.
Biopharmaceutical manufacturers have met the demand for greatly increased volumes of protein therapeutics by improving conventional technology process productivity. Commercial products have expression levels in the range of 0.2–3.0 g/L with the highest titers seen for monoclonal antibody products. These technologies, including higher expression levels, improved and optimized media, and enhanced bioreactor conditions, have greatly increased biotherapeutic production without sacrifices in quality.
But facilities struggle to keep up with demand for existing product and match downstream capacity with bioreactor output. Technologies enabling higher bioreactor titers have created downstream processing (DSP) bottlenecks and limitations on equipment throughput.
And the inevitable development and introduction of biosimilar molecules will add to these pressures. CellTrion and Hospira submitted biosimilar antibody approval applications to the EMA in 2012, with the expectation that those products will be launched in the European Union in 2014. By 2023, it is predicted that biosimilar monoclonal antibodies and insulin products will account for 57% of the global biosimilars market.
The cost and complexity of developing and manufacturing biosimilars also suggests that, realistically, product pricing reductions will be 20% to 30%, compared to the 80% typical for small molecule drugs. These relatively low margins, combined with pressure from healthcare systems on end-user pricing, will require less costly manufacturing alternatives than the big tank approaches now widely in use.
The need for multiproduct facilities, with increased flexibility, reduces the requirements for expensive critical utilities such as water for injection and clean steam, decrease requirements for equipment cleaning and cleaning validation, lower capital investments, and shorten facility construction times.
All of these realities have caused biopharma manufacturers to incorporate disposable or single-use process technologies into their product manufacturing. These systems offer a smaller footprint, flexibility, scalability, and mobility without compromising product quality.
Compared with conventional bioreactor systems, single-use solutions have other advantages, including reduced cleaning and sterilization demands, with some estimates tallying cost savings of more than 60% with these disposable systems compared to fixed asset stainless steel bioreactors.
In pharmaceutical production, single-use bioreactors simplify complex qualification and validation procedures. Use of single-use bioreactors reduces the risk of cross contamination and enhances biological and process safety. Single-use applications are especially suitable for any kind of biopharmaceutical product.
Large protein therapeutic contract manufacturers have adopted the technology to produce biologics. For example, Laureate says it uses disposable components and single-use bioreactor systems to provide a number of quality, operational, and economic advantages. The company says that because system components arrive precleaned and sterilized, the need for cleaning and sterilization process steps is eliminated.
The reduced operating costs, smaller footprint, increased productivity, and rapid turn-around time associated with disposables are some of the major benefits that are pushing Laureate and others in the biopharmaceutical industry toward single-use technology in manufacturing
While the technology remains relatively new, manufacturers that use disposable bioreactors across the manufacturing process have steadily increased, including Lonza’s use of GE Healthcare’s Wave bioreactors in the inoculum train for large-scale production bioreactors and Shire’s use of single-use bioreactors and other disposable technologies in the upstream portion of its ATLAS commercial manufacturing facility.
Companies are now considering facility designs that incorporate disposables at all stages of manufacturing. DSM has introduced its XD® Technology and is opening a single-use bioreactor based facility in Brisbane, Australia, to support very high-density mammalian processes where, it says, increased bioreactor output and yield per volume can be increased 5–15 fold.
Several factors have driven this adoption, including technology improvements such as those provided by Xcellerex (now part of GE Healthcare Life Sciences), Thermo Scientific HyClone, and Sartorius Stedim Biotech. These platforms consist of a fixed support containing process-control software that is installed in a production facility. The disposable bioreactor consists of a single-use bag that can be inserted into that support structure, with agitation provided by a disposable impeller that attaches to a motor in the support structure. Feeding, pH, and dissolved oxygen are controlled through installed ports and probes.
Key the development of disposable reactors was cell culture in a plastic bag mounted within a cylindrical frame to support the bag. Hyclone was the first market entrant with its Single Use Bioreactor (SUB) system, which used a top-driven impeller for mixing and agitation. Xcellerex introduced its XDR disposable stirred tank bioreactors featuring magnetically coupled bottom-driven agitators.
Recently, DSM introduced its XD® continuous feed technology that allows a current maximum cell density of 242 million cell/mL, with a bioreactor output and yield per volume of 12 g/L for proteins and 27 g/L for antibodies. This system also continuously removes metabolites during cell culture.
Both cell culture processes and product quality, several studies have shown, are comparable in single-use bioreactors and same-sized stainless steel reactors.
Due to their advantages, adoption of single-use bioreactors will continue to increase. Facility optimization for multipurpose product manufacturing including personalized cellular therapies (T-cell expansion), recombinant “replacement” enzymes, unique mAbs requiring smaller batch sizes, and the evolution of cell-based vaccine production (whether in adherent cells or on microcarriers or cells in suspension), will necessitate further employment of single-use bioreactors.
In summary, market forces will push protein therapeutic manufacturers to adopt disposable technologies across the biomanufacturing process. Experts predict that by using local manufacturing facilities, modern, state-of-the-art manufacturing technologies, and efficient manufacturing approaches including single-use technologies, the international biopharmaceutical industry can meet these challenges and improve healthcare options worldwide.
Patricia Fitzpatrick Dimond, Ph.D. ([email protected]), is technical editor at Genetic Engineering & Biotechnology News.