Does size really matter in single-use applications?

By Barb Paldus, Finesse Solutions, LLC

Today, there is a great deal of marketing noise touting the 5000 L single-use bioreactor. The direction of single-use vendors (in increasing vessel size) appears to be in direct contrast with the evolution of market needs.

“Focusing on large therapeutic areas such as cancer, but acquiring approvals for multiple related orphan indications, has proven to be a good strategy for many drugs”
-Barb Paldus

Consider that the landscape of biotechnology-based drugs is evolving from a small number of high-volume blockbuster cancer drugs to larger numbers of more targeted drugs for smaller populations. Focusing on large therapeutic areas such as cancer, but acquiring approvals for multiple related orphan indications, has proven to be a good strategy for many drugs. The result of this diversification in monoclonal antibody drugs is a need for flexible manufacturing facilities capable of rapid product changeover at smaller volumes, as opposed to high-volume, capital-intensive facilities focused on the high-volume production of a single drug.

Similarly, facilities built to develop and manufacture biosimilars can benefit from high-yielding, robust new cell lines, and therefore do not require the same production volumes. Moreover, biosimilar product facilities must minimize capital expenditure, and diversify the risk with multi-product capability. These drivers, namely multi-product capability, rapid scale-up and capital efficiency, have driven the adoption of single-use systems by the cell culture community.

Because single-use bioreactors are still a relatively 'new' area, vessel design continues to evolve, as do new processes such as perfusion. Furthermore, single-use automation systems are designed to be flexible in both hardware and software for easy product changeover, so that they naturally lend themselves to the incorporation of new sensors, new types of vessels, new control algorithms, and new cell culture methods. It is precisely this flexibility and ease of use that is expected to propel single-use system adoption in the future.

The recent proliferation of single-use bioreactor designs has focused primarily on aeration methods, as well as optimizing the uniformity of mixing and temperature. This becomes more and more difficult to achieve in volumes of 2000 L or more, whereas it is relatively straightforward and low risk in smaller size vessels.

The advent of new sensors will allow additional data about the bio-process to be obtained and new algorithms to be developed for improved control and titer. In contrast to electrochemical sensors that vary up to four times in length depending on vessel size, the same optical pH and dissolved oxygen sensors can be used in 1 L or 2000 L single-use vessels using a clever port design.

Moreover, single-use optical sensors such as Finesse's TruFluor pH and DO sensors can be manufactured to a well-defined set of tolerances that assure reproducible and predictable performance parameters. As a result, all measured values are obtained using the same sensor and the same performance specifications, so that the bio-process engineer can be assured that the measured process values in scale-up and scale-down studies are completely consistent, and any variations between the processes are a result of fluid mechanics in different sizes of vessels. In this case, literally, size won't matter.

Additionally, because single-use bags allow easy modifications and additions of new ports, it is much easier to introduce new measurement technologies in the process as they become available in the market. As a result, it is anticipated that the process analytical technologies (PAT) initiative will be much more useful for single-use technologies than for traditional stainless steel platforms. Because the measurement technologies will be independent of reactor type and size, their testing and validation should actually become much easier, with greater repeatability of results and consistency in measurement during scale-up and scale down.

Finally, owing to more robust cell lines, whose productivity can yield tens of grams of product per liter, bioreactor size of single-use vessels for the production of most biologicals is not expected to exceed 2000 L. Most single-use production systems today are a 1000 L stirred tank configuration that mimics a stainless steel reactor in geometry, but can be designed to have a more homogeneous cell culture environment. This size of reactor allows manageable handling of the bioprocess bags, while matching (with the increased titer) the capacity of a typical production Protein A chromatography column. Realistically, handling bags larger than 2000 L carries significant risks to both the product and personnel involved.

In the end, size will matter. What will matter is that the bioreactor is 'just right'. To that end, with further increases in titer and the downstream bottleneck in chromatography, the industry may indeed find that 'small is beautiful'.

Barb Paldus was most recently the CTO of Picarro, a company she founded in 1998. At Picarro, she was responsible for technology strategy, research and business development, which led to a solid-state Cyan laser product in 2003 and cavity ring-down spectroscopy products in 2004. Paldus is currently a partner at Skymoon Ventures. She received both her PhD (1998) and MSEE (1994) degrees in electrical engineering from Stanford University, and her BS (1993) in electrical engineering/applied mathematics from the University of Waterloo.