The Changing Single-Use Landscape
The landscape for equipment in the bioprocessing industry has changed dramatically in recent years. Once considered inferior to fixed, reusable equipment made of stainless steel and glass, single-use technology has since made great inroads into the market. While it may seem counterintuitive, moving from fixed reactors to those that are used once is actually more cost effective. This is especially the case for a new facility where the investment in processing equipment has not already been made.
Single-use technology first penetrated the market in the form of storage containers where they were used for buffers, reagents, media and even final products. Over the last decade, there has been a gradual shift toward the design of increasingly complex vessels in disposable form. Innovations from vessel manufacturers have moved the market from bags to mixers, from simple mixers to mixers with sensors, from mixers with sensors to bioreactors, and now there is a real desire among biopharmaceutical manufacturers to integrate one unit with another. Single use technology is no longer restricted to stop-gap solutions for fluids handling. It has graduated into a full-scale turnkey manufacturing option.
Alongside these increases in the complexity of the technology, there have been advances in both production efficiency and quality standards. End-users tend to report that regardless of which company is supplying their single-use bags, they are generally happy with the quality and not concerned about potential risks. Only a few years ago, the number of improperly constructed bags was significantly higher than it is now. Indeed, at ATMI we get almost zero reports of bag failure, and the majority of the rare cases we do see are a result of customer mishandling.
Advantages Drive Adoption
The initial driver for moving away from fixed vessels towards single use was the dramatic reduction in validation requirements. The bags arrive from the supplier in guaranteed sterile condition, and can simply be plugged into the customer’s production process without the need for any further testing. The time it takes to validate a facility is greatly reduced, as is the time to turn it around between production runs. In addition, the risks of inadvertent microbial contamination of the batch, or cross-contamination from one run to the next, are negligible, thanks to the unused vessel’s sterility, and the fact that it has not been used before.
Over time, further advantages of single use have become evident. Time-savings are made in facility planning and process engineering. The speed at which a staff of experienced single-use operators can configure an entire new production scheme and scale the manufacturing process up is reduced – to the extent that, for a new product, it can be cut to just a few weeks or months. This continues to be a driver today, and there are few large-scale biologic manufacturers who do not have dedicated internal teams using single-use technologies on their products.
Considerations and Uses
In terms of market demand, there is an inflection point happening right now – the adoption of single-use technologies in the development and early clinical trials stages. At the much smaller volumes required for early lab development, there is a growing emphasis on developing bench-top reactors with scalability planned in as a primary requirement from the outset. Even in big facilities that rely on 20,000-liter cell culture reactors, down the hallway there will often be process improvement trials under way, which tend to be using single-use reactors.
There will always be a need for fixed reactors on the very large scale; single use is unlikely to be a viable option for volumes higher than about 3,000 liters. Up to that cut-off point, however, single-use is becoming the preferred choice. But even with a process that starts with a cell culture in a 20,000-liter vessel, once the culturing process is completed, the product is very quickly concentrated and clarified down to smaller volumes. Single-use vessels soon become appropriate for downstream steps in the manufacturing process.
Single use is particularly appropriate for emerging cell therapy treatments, if not essential in the case of personalized, autologous cell therapies where every batch is different. Suppliers like ATMI are working hard on improving the process efficiency of single-use bioreactors, whether this is by optimizing the microenvironment of the cells through altering shear force or improving the mass transfer of oxygen, or by shrinking the footprint of the bioreactor thanks to increases in efficiency and clever engineering design.
In terms of regulatory requirements, the agencies need to be confident that what a manufacturer is doing is both logical and safe. The FDA, EMA and other regulatory authorities are looking for compelling data that make it clear that the process is safe and reproducible – and that means condensed, reliable data rather than reams of data that needs to be interpreted. They need to be assured that the drug product will be the same from one lot to the next, and thus they need to be confident that the leachables and extractables profile for the plastic used to construct the vessels is not only within the prescribed limits, but also remains the same from one vessel to the next, so there will be no impact on the product itself.
For biopharmaceutical manufacturers wishing to move into single-use technology, it is important to partner closely with the vessel supplier. The overwhelming issue becomes one of absolute trust, based on the fact that they will be dependent on that vendor to supply what they need, when they need it. The customer must be certain that the quality and quantity of products they require to meet their own strategic plan will be available. When selecting a vendor, find out if the supplier has the necessary capacity, is there a back-up supply, and will the film used to make the bags remain identical throughout the biopharmaceutical’s entire product lifecycle.
The Case for Standardization
There is, however, one area where great improvements still need to be made, and that is standardization. There are many different suppliers of single-use technology, all with their own take on how things should be. But the customer benefits of standardization across suppliers are clear, as evidenced by the success of other industries where common standards have been adopted, such as microelectronics, the automobile industry, and even the food sector. Customers want, for example, to be able to buy the best bioreactor for their particular process, combine it with their own preferred technologies for mixing and downstream clarification, and not worry if it is possible to connect them together.
Standards evolve over time, but suppliers need to reach a consensus, and that is not going to be easy. The best way to move ahead will almost certainly be via industry user groups, where technology providers and end-users can discuss and agree what they need, what is practical, and what has to be done to achieve a set of usable standards.
The standardization of leachables and extractables is well under way. Safety standards like these are already on the horizons of the suppliers, but what the industry - including consumers, customers and manufacturers - is really looking for is engineering compatibility, something that will be much more difficult to achieve without consultation and cooperation. But this type of open architecture will enable them to integrate equipment from different suppliers into their manufacturing train, and greatly facilitate the expansion of the overall market for single-use technologies.
The single-use industry is still in its early stages, but gaining traction. Further improvements are still required and are happening all the time. There has been a lot of discussion and activity in the area of single-use probes, for example, but there is still room for a good deal of innovation in that space. In the meantime, the advantages of single-use technologies have been proven and it is projected that market penetration will continue to rise. Add to that the continued development of newer, better, more efficient single-use vessels, components and bioreactors, and it is clear that single-use systems and components have a bright future ahead.
For more information on ATMI visit www.atmi-lifesciences.com.