Small-scale single-use platforms can be scaled directly to commercial manufacturing, significantly shortening the timeline to market commercialization.
Around 90 percent of biomanufacturing facilities utilize single-use technologies in clinical manufacturing1 and many have begun to explore its potential for commercial manufacturing.
The benefits of single-use technology have been widely discussed. They include the potential for a reduction in capital outlays, reduction in overall COG’s of drug product, reduced risk of product contaminations, and increased flexibility2.
Furthermore, a proven point that is often not taken into consideration in end-user decision making is that implementation of end-to-end single-use processes ensures a more sustainable facility3. Yet for the commercial supply of biologics, companies are continuing to invest in large-scale stainless steel facilities.
In February 2017, Lonza and Sanofi announced a joint venture to invest $288 million in a large-scale mammalian cell culture facility in Visp, Switzerland, similar to three facilities Lonza has built in the U.S. and Singapore4.
This is not an isolated case.
In December 2015, Boehringer Ingelheim announced that it would make a significant investment into large-scale capacity at its site in Vienna, Austria5. CSL Behring and Biogen have made announcements regarding the expansion of stainless steel capacity6,7.
Scale-Up to Large, Multi-Use Facilities
These stainless steel plants allow manufacturers to produce biologics in large volumes and can meet a significant amount of the market demand from a single or small number of production sites.
At a basic level, large-volume production is more cost efficient than multiple small plants because of economies of scale. Companies like Lonza have experience in designing, commissioning, and operating cell culture facilities containing 20,000 L stainless steel bioreactors and the industry considers multi-use technology proven for commercial manufacturing.
If facility utilization rates are consistently high, which is often the case when campaigns are long, large stainless steel plants can make economic sense and provide the lowest cost of goods despite the high initial capital expenditure required for their construction.
Not all companies, however, have the expertise to allow them to ramp up production to such large scales. Moving processes between smaller scales is a relatively common occurrence, yet across the industry bioprocess engineers have less experience of scale-up to 15,000 or 20,000 L bioreactors.
There are risks to transferring processes into very large facilities and the success of these transfers cannot be guaranteed.
Committing to enormous financial investments in production facilities when the success in the clinic or in the market has yet to be verified carries additional risks.
Firms can be left with surplus capacity that they have financed if products fail in development or the expected market demand does not materialize. The inflexible nature of stainless steel capacity means it is not easy to re-engineer processes for other products in the pipeline or function as a multi-product facility if the pipeline is diverse.
Those making this investment decision often seek to partner with companies to whom they can outsource additional available capacity in order to offset this risk.
Perhaps the biggest concern, however, beyond the financial risk, is the dependency of so many patients on a single location for the supply of life-saving medicines. If there is a disruption to production at the centralized manufacturing location, then a company will struggle to deliver upon their commitments to healthcare providers and patients around the globe.
Disruptions could range from severe contaminations, to labor disputes or unpredictable environmental events such as flooding or seismic shocks.
Scale-Out to Smaller Single-Use Facilities
Could firms adopt an alternative production strategy, capable of meeting the market demand for biologics while mitigating the risks associated with these very large-scale facilities?
In certain situations, firms could consider a ‘scale-out’ rather than a ‘scale-up’ model in which they operate multiple, small-scale facilities, located in different territories across the world.
This becomes an increasingly realistic proposition as process intensification efforts increase the throughputs that are possible at the 2,000-L scale and allow increases to the productivity of smaller-scale facilities.
Operating single-use bioreactors in perfusion or concentrated fed-batch mode enables higher titers and could compensate for losses in economies of scale that might occur. These different production scenarios are reflected in the Biophorum Operation Group Technology Roadmap8 for the biomanufacturing industry.
By implementing a scale-out model, companies could benefit from being able to expand capacity only when they have a clear indication they need it. Applying single-use technologies would allow them to implement these smaller facilities rapidly. Such a scale-out model could improve both the flexibility and agility of a biopharmaceutical company’s production network.
Using a network of small production sites will reduce scale-up risks but most significantly will minimize the probability of drug supply disruptions that occur unexpectedly. If there is a problem at one facility, a company could increase throughput at its other locations.
The challenge lies in identifying those scenarios in which six-pack facilities are required and those where an alternative approach with a network of smaller, more flexible facilities will provide supply chain responsiveness and security.
Using Single-Use Technology for Commercial Manufacture
In our experience at Sartorius Integrated Solutions, biomanufacturers have concerns about the predictability of their future operating costs when they are reliant on suppliers of single-use consumables. Process modeling during early stage process development is allowing engineers to understand their likely cost of goods (COGs) per batch.
By exploring different scenarios based on demand forecasts, suppliers of single-use technologies can agree upon medium to long-term pricing commitments. Furthermore, suppliers can provide open single-use technology platforms that allow customers to develop second supplier procurement strategies during process development and design.
From a technological perspective, what does the industry need to consider if it is to make this scale-out model a viable alternative to the traditional large-scale stainless steel approach?
Biomanufacturers are concerned about the security of the single-use supply chain. Single-use suppliers must ensure this is taken into consideration when designing their consumable products. These can be established by putting in place long-term supplier and quality agreements with key vendors. This ensures the necessary level of quality and change controls required for commercial manufacturing.
Suppliers that install redundant consumable production capacity across multiple continents can enhance the robustness of their supply chains and reduce the risk of supply chain shocks.
Suppliers must adequately demonstrate the physical, operational, and chemical robustness of their products to alleviate the concerns of biomanufacturers.
They should have characterized the extractables and particles that could enter the process from the materials used to construct single-use consumables and support their clients with training packages that educate operators on how to handle their products correctly to avoid damage from manual manipulations.
The careful selection of the appropriate components is necessary during the design of smaller scale, single-use facilities for commercial manufacture. These considerations range from the pressure rating of tubing, to the accuracy of flowmeters, sensor diameters, and pump sizing. Clients are increasingly demanding the full integration of single-use automation into their facilities’ distributed control systems.
It is our belief that to execute commercial manufacturing in single-use facilities, firms need to have this objective in mind from the outset of process development. It becomes more difficult to implement single-use in commercial manufacturing if scientists have developed bioprocesses with traditional engineering approaches in mind.
Biomanufacturers pursuing this path need to consider the manufacturability of their products within disposable facilities.
A more holistic approach during early process development by joining upstream and downstream processing in an integrated single-use platform will significantly impact the development of biological products and facilitate commercial manufacturing in single-use systems.
Small-scale single-use platforms can be scaled directly to commercial manufacturing, significantly shortening the timeline to market commercialization. Process development consultants should work hand-in-hand with clients in early phase development to develop the right process strategy, analyzing the optimum process design and technology options to ensure highest productivity and lowest cost of goods for the given molecule in development.
By taking this approach, we believe that the widespread adoption of completely single-use processes for the commercial manufacture of biopharmaceuticals can be facilitated.
About the Authors
At Sartorius Stedim Biotech, Dr. Nick Hutchinson serves as Technical Content Marketing Manager (Bioprocess Solutions); Dr. Christian Manzke is Director Integrated Solutions Europe; Miriam Monge is Director of Marketing Integrated Solutions; and Priyanka Gupta serves as Global Senior Bioprocess Modeling Consultant, Integrated Solutions Marketing.
1 Walker, N. (2016) Single-Use Technology Integral to Advancing Biomanufacturing. Contract Pharma. March 3, 2016.
2 Geipel-Kern, A. (2009) Single-Use Technologies in Biomanufacturing. Process Worldwide. November 2009.
3 An environmental study of single-use process technology offers an examination of environmental impacts across the full process train using lifecycle assessment. March 1, 2014, BioPharm International,Volume 27, Issue 3.
4 GEN News Highlights (2017) Lonza, Sanofi Pledge $288M to Build Large-Scale Biologics Plant in Switzerland. February 27, 2017.
5 Boehringer Ingelheim Company Website (2015) Boehringer Ingelheim Invests in Europe: Pharma Compnay Expands Biopharmaceutical Production at Vienna Site. December 22, 2015.
6 CSL Behring Company Website (2017) Projektseite Lengnau. The project.
7 Keshaven, M. (2016) Biogen breaks ground on $1.4B Switzerland plant. January 30, 2016.
8 Jones, S. (2017) BioPhorum Operations Group, Technology Roadmapping, Part 2: Efficiency, Modularity, and Flexibility As Hallmarks for Future Key Technologies. Bioprocess International February 2017.