Limits and Successes Define Large-Scale SUBs Path

Successful performance of large-scale single-use bioreactors (SUBs) depends in part on defining their limitations and working around them or discovering solutions to overcome them. A main concern, for instance, centers around the increased separation of scale with respect to the scale-down models and large-scale reactors, says Brian Follstad, scientific fellow, Upstream Process Development, Catalent Biologics, Madison. This increased separation makes it more difficult to qualify scale-down models, which Follstad says are crucial to establishing and characterizing process design space and robustness. In Catalent’s case, the implementation of their Ambr high-throughput bioreactor systems closed this gap significantly. “They have been routinely used in the industry to qualify scale-down models, effectively making process characterization easier and improving throughput,” Follstad asserts.

Yasser Kehail, Biomanufacturing Business Development leader at Cytiva states that high pressure, increased agitation rates, and aeration requirements will continue to challenge single-use bags because these increased forces may cause leaks, pin holes, or defects. “This is one of the major engineering challenges for large-scale SUBs,” Kehail states.

“In addition, single use bags need to be transported using special packaging to reduce any sort of rubbing that could cause damage to the film, tubes, and chamber. Hence, when you scale to larger than 2000 L, the robustness of the bag becomes a huge risk, the packaging will be larger, and the risk of failure and damage increases,” Kehail cautions.

It is also technically important to ensure that the process can deliver the requisite mixing and gassing at 2000 L, providing a truly scalable process, states Adrian Mazzone, director, Process Development, Pharma Services, Thermo Fisher Scientific. He points out that, logistically, the SUB packing is significantly larger for single-use SUBs greater than 2000 L. As the whole package comes partially inflated, it must be de-boxed prior to entering the cleanroom and managed through wipe-down through to its final destination in the production suite, Mazzone explains. In addition, effective pre-use visual inspection is difficult for such a large SUB, so a robust leak test is required following installation. “Lastly, from an engineering perspective, the 5000 L bioreactor needs to be installed in a production suite with high ceilings and must be bolted to the floor,” he says.

Making a SUB very large is an engineering challenge, adds Alex Chatel, product manager at Univercells Technologies, partly because the surface area of the vessel does not increase linearly with its volume (m vs. m3). Because of this, efficient heat transfer, gas transfer, and mixing must be considered carefully. Chatel explains that there is a theoretical limit above which making large vessels results in difficult trade-off in terms of operation performance. “This can be highlighted by the difficulty in providing adequate mixing in large-scale bioreactors while limiting shear rates at the impeller tip, which can be damaging to cell health. In this light, process intensification, which instead reduces the volumes of bioreactors for an equivalent throughput, is an interesting approach as the low volumes mean that engineering challenges are more easily resolved and scale-up is made simpler,” Chatel states.

Jorge Garcia, senior manufacturing sciences engineer, Catalent Biologics, Bloomington, emphasizes that currently installed 1000-L SUBs have proven success in efficient gassing and carbon dioxide-stripping of mammalian cell cultures, which reduces the creation of foaming in the reactors. This is a significant benefit because excess foaming can cause operational issues and affect metabolism of the culture. “The successes in controlling foaming through efficient gassing/carbon dioxide-stripping at these smaller scales suggest that this challenge can be overcome in larger-scale single-use bioreactors as well,” Garcia points out.

Kehail affirms that the 2000-L size SUB has also demonstrated its success, namely as 2000-L SUBs have been used in multiple approved protein therapeutics, including COVID-19 vaccines. “Its value proposition of being first or fastest to market has been proven,” Kehail says. “In addition, more clinical trial materials are being produced at GMP scale for different phases; and finally, the low initial CapEx [capital expenditure] required has been a catalyst to constructing more and more green field facilities than ever before,” he states.

For its part, Thermo Fisher Scientific has been seeing significant interest from SUB users since the launch of its large SUBs in March 2021, says Kevin Mullen, director of Product Management, BioProduction, at Thermo Fisher Scientific. “Thermo Fisher has made a significant investment to acquire inventory of these units so that these large-scale SUBs can be delivered in short lead times. There is considerable interest in the high productivity, low-risk scalability, small footprint, attractive GMP price-point and short lead time of SUBs,” Mullen states.

About the author

Feliza Mirasol is the science editor for BioPharm International.

Article Details

BioPharm International
ol. 34, No. 10
October 2021
Pages: 26

Citation

When referring to this article, please cite it as F. Mirasol, “Limits and Successes Define Large-Scale SUBs Path,” BioPharm International 34 (10) 26 (2021).