Moderator Dan Stanton, with Weichang Zhou, Jenifer Wheat, Roger Lias, and Jim Vogel
Single-use technologies (SUTs) are now prevalent within bioprocessing, but does this spell the end of industry’s historic reliance on stainless steel and fixed facilities? This roundtable was formed to discuss the wealth of investment in single-use (SU) equipment and flexible manufacturing solutions by contract development and manufacturing organizations (CDMOs) over the past few years, pitting that against what looks like a resurgence in fixed-cost stainless steel plants among some biomanufacturers.
In his introduction, Stanton noted that during the early part of this decade, mammalian cell culture contract manufacturing organizations (CMOs) were dominated by three companies: Lonza, Boehringer Ingelheim, and to a lesser extent Celltrion. According to reports from BioPlan Associates, those three companies held more than 76% of the outsourcing capacity, mainly in fixed, large stainless-steel tanks.
Today, the demand for third-party biomanufacturing has increased, and those three CMOs have increased their capacities further, joined by a growing number of others that have entered the commercial biologics space through adopting SU equipment and modular and flexible facility designs.
An Enabling Technology
Stanton asked Jim Vogel how SU equipment has enabled more companies to enter the biomanufacturing space as a service. Vogel explained that the key consideration is the lower initial investment for SU materials, which allows a company to get started faster. Scales also have gone down because of improved cell culture titers, so biomanufacturing platforms also benefit from the ability to produce drugs in smaller containers. But saving on the up-front investment is key relative to purchasing stainless steel equipment and maintaining (and validating) utilities and facilities space to support it.
Because WuXi has been expanding its operations using only SUT, Stanton asked Zhou how that environment allows the company to be such a large player.
Zhou pointed to issues of flexibility and the modest initial investment in SUTs but emphasized the advantage of speed in building a facility based on those technologies. That gives his company more time to develop a process for commercialization. A second significant advantage of SUT is in minimizing scale-up risk. WuXi’s SU “scale-out” strategy uses the same size of bioreactor for all product phases, including commercialization. That enables global expansion of the company’s capabilities using SUTs. He highlighted the importance of SUTs to effect process intensification now that a company can manufacture 5–15 g/L.
CDMO Perspectives: Stanton asked Jenifer Wheat to comment on the points about process intensification as a representative of a CDMO with large amounts of stainless steel capacity.
She replied that Lonza is not all stainless steel and that the company also appreciates the need to manufacture flexibly for smaller patient populations and multiple indications. It has everything from SU bioreactors and stainless steel at small, medium, and large scales. In some of its newer facilities, SU downstream combines with some stainless steel facilities at mid scale to handle much higher titers than previously possible. Lonza sees a great need for large-volume manufacturing of antibodies and other products, but it also tries to meet small-scale demands at earlier stages.
She elaborated on the importance of flexibility. “You can start with us at small scale and delay decisions and multiplexing until you hit a certain point. And then you can choose to go commercial with multiplexing of single use. Or you could choose to go midscale or large scale. Some clients may choose to move from SU multiplex to commercial, but they can delay that move until they achieve phase 3 success, reducing their cost of goods.
With a modular approach, a prebuilt shell can cut down a significant amount of the time required to build facilities. As Wheat said, “Every product, every business case needs something different, so the key is flexibility and reliability.”
Stanton asked how Lonza views the influx of CDMO competitors entering the space from a business perspective. Wheat answered that “it’s good to support the industry because there are still a large number of products that need smaller volumes and need to scale up quickly. And SU is a lower investment. If you’re going to build your own facility as an innovator, it makes a lot of sense. And there’s definitely a need for manufacturing capabilities across the CMO industry.”
Scale-Up As Horizontal Rather Than Vertical: Stanton asked Lias how Avid works with both stainless steel and single use. Lias explained that his company has a legacy stainless steel facility that goes up to a 1,000-L working volume, which is relatively small for stainless steel. That facility has been approved by the FDA and EMA for 15 years. He sees fewer opportunities for large-scale stainless steel facilities, although he noted that a large-volume therapy such as Humira might make sense to transition into large-scale stainless steel. Avid operates a new multiproduct facility with multiple 2,000-L SU tanks and views scale-up as a horizontal rather than vertical process.
In addition to improvements in specific productivity of the cell lines, the industry also is using higher culture densities. Lias reminded the audience that tremendous advances are happening on the downstream side as well, including technologies for filtration and chromatography. That is where he thinks the industry will see the biggest advances in the next five to 10 years. He believes that most current opportunities can be handled at the 2,000-L scale and agreed with Wheat’s comments that with higher productivities, different classes of products can be made in SU for smaller, niche markets. But ultimately, implementing disposable technologies lowers some of the high fixed costs for maintaining highly compliant environments.
Stanton asked Zhou whether any customers have reported limitations with having only SU capabilities.
Zhou described WuXi as an enabler, helping its clients to meet set needs. Using multiple SU bioreactors in combination with larger columns could meet the needs of both cost and capacity. So far, even though some customers have asked for a dollar-pergram calculation, his company has found that SU meets the challenge.
Stanton asked Vogel to comment on whether SU presents limitations to process intensification. Vogel pointed to things that get overlooked when comparing the benefits of SU with conventional processes. “One example is filtration. Usually you need some pressure to perform filtration, and in some cases single-user may not withstand the pressures that people need. When your filtration isn’t as efficient as it might have been at lower cell densities, sometimes operators and/or process development chemists don’t understand how to manipulate single use through that challenge.”
He agrees with Lias that novel technologies are coming into play on the downstream side, and those developments are further supported by regulatory agencies urging development of continuous processing. Such demands and lessons learned from other industries using continuous operations may point to increased opportunities for hybrid approaches. He concluded that “single use does have some limitations, but with the proper design and considerations, a company usually can get around them.”
In response to Stanton’s question about limitations of stainless steel, Vogel drew on his experience with the ASME Bioprocess Equipment Standard to agree that even stainless steel does not last forever. He mentioned flexibility limitations in cleanability of gaskets and clean-inplace sterilization that can present a greater risk than with SU equipment. Lias and Wheat both agreed that many variables factor into the choice of manufacturing decisions. Legacy stainless steel processes involve dealing with rouging and cleaning concerns, but bags can suffer from cholesterol absorption onto plastics. Technical issues are encountered with both types of technologies. SUTs continue to advance — especially downstream — but Lias still sees a lot of complex products, even newer ones, that need handling in large-volume stainless steel over the long term.
Transfer and Standardization
Stanton asked whether SU that enables internal manufacturing might be a threat to outsourcing. The general opinion of the panelists was that SU manufacturing is more an enabler than a threat. It allows companies to do more work themselves at earlier stages, but they’re still likely to outsource a good portion of that work, perhaps at later stages. But one focus of discussion was the difficulty of technology transfer given the different types of bioreactors on the market, the need to store bags, and complexities of supply chains. So lack of bag standardization and other components such as connectors adds complexity overall. Lias agreed, noting that warehousing SU components might be complex for CMOs that have to store “cargo boxes everywhere full of disposable equipment” to handle customer projects.
Zhou said that his company manages well with different types of bioreactors, but that he discourages companies from implementing more and different types of bioreactors, if only to prevent inventory problems. Lias added, “It’s important to remember that these bioreactors are not all the same. They have built-in ports, and it’s not a one-size-fits-all issue. Transferring between one supplier’s SU bioreactor and another’s is not an insignificant challenge.”
Stanton brought back an earlier point about a trend of vendors buying CMOs — e.g., Thermo Fisher buying Patheon — and how that leads to a competitive advantage. Vogel responded that it might reduce flexibility if a client brought in a different system. “Almost every vendor has to buy components from the other ones, because if a process is validated on a certain filter, you’re probably not going to do a resubmission to change out that filter to the one that you’re using. And so brand X filter can be on brand Y assembly, and same thing goes for the connectors. If you’re starting from zero as a brand new company, you may want to choose one system, but that also may remove some flexibility if performance issues occur.” Changing to a different filter, for example, might provide a more competitive advantage.
Advantages of Vendor Consolidation on Standardization: Stanton asked whether vendor consolidation would make processes easier. Lias acknowledged that consolidation is happening, but that “some of those companies have been acquired by or merged with others with different operating systems, software, and control systems. So it’s then quite difficult to transition to running truly one operation at one company. A number of merged businesses still run as several separate entities. They’re not really very standardized yet. It’s a huge challenge.”
Zhou said, “I don’t think consolidation is the answer: I think it’s standardization. Undoubtedly there will be many products made by many companies, both technology providers and users. Standardizing to some extent would help the whole industry.” He sees that, over the years, technologies tend to become more standardized. But that it takes time.
Vogel suggested that the key might be alignment rather than standardization, such as agreeing to use one type of filter. But developing protocols for change management, such as those developed by BPSA and BPOG, might be a more practical way to help biotechnology companies try to normalize changes in vendors and equipment. Wheat agrees that although some standardization is happening as the industry matures, “standardization is going to be a challenge for some time. “
Market Considerations in the Postblockbuster Era
Stanton returned to the topic of capacity, speaking of investments by CDMOs such as Samsung Biologics. “They’ve suddenly jumped up from nowhere by investing in thousands of liters of stainless-steel capacity. At the same time Lonza and Boehringer Ingelheim also have increased their capacity through stainless steel.” He asked where demand for such huge capacity is coming from.
“People are getting smarter about how they perform their trials and what their applications are,” Wheat pointed out. “You see them choosing products with multiple indications or combinations.” Future blockbuster products, such as those to treat widespread diseases such as Alzheimer’s, still may be around the corner. She said it is a misconception that large companies are making only biosimilars. “A lot of other products need large volume, just as a lot of products need 2,000-L or 5,000-L processing. It’s not either/or.”
Zhou noted that capacity management will be a critical issue going forward. He believes that building flexible facilities is critical for adapting to market forces. Vogel expects capacity needs to continue: “The work’s out there, and the demands are there. And I think it will just morph into other types of products. But he emphasized the importance of keeping an eye on scale as more personalized products enter the market. Lias directed attention to new markets opening around the world, with the biopharmaceutical industry still young and growing. The current customer base eventually will need manufacturing space. But scaling out with disposables can allow flexibility to balance future demand on a tactical level. Wheat agreed that the industry needs the capacity to serve different needs and said that the market corrects itself based on need like any other market in any other industry.
Watch the full interviews online at www.bioprocessintl.com/BIO-Theater-2018.