By James Netterwald, Ph.D.
There has been widespread acceptance of disposable technologies in the biopharmaceutical industry but not in the larger pharmaceutical industry. Several reasons could account for this trend, ranging from cost concerns to technical challenges. Some might call this trend an adoption, while others have a different idea.
According to Christian Julien, business development manager at Meissner Filtration Products, there has not been a slow adoption of disposables by the industry. “Although the industry has adopted single-use technologies at an initial rate of 25% to 35%, I think the current adoption rate is closer to 10% to 20%, depending on what it is that is being adopted [e.g., disposable bags have a greater adoption rate than disposable chromatography columns],” says Julien. He adds that although there are some adopters who wish to go fully single-use, this approach appeals more to people who are starting new facilities from scratch because then they are not so burdened by the lack of efficiency and existing economic models that are characteristic of the more traditional stainless steel manufacturing equipment.
“The single-use technology adoption story started, for the most part, in membrane filtration, followed by cell culture media and buffer prep,” says Julien. “What has happened in the last 10 years is the continued adoption of single-use unit operations like bioreactors, mixers, etc.” However, some disposable technologies, such as those for centrifuges and process chromatography, have not yet seen the same level of adoption. Because of cost considerations, many companies do not have the option of using a disposable column for an industrial process and then throwing away the resin after one use.
Another reason for the seemingly low adoption rate of single-use technology is that adoption itself “is inherently a conversion predicated on technical feasibility,” says Julien. As well, he adds, “Many companies that already have a drug on the market have no incentive to change their validated processes; the technology for them has to be absolutely proven because they want tangible results, data, and assurances because they are risk-averse.”
According to Eric Grund, Ph.D., senior director of biopharma applications at GE Healthcare in Uppsala, Sweden, “There are a number of obvious situations where they have converted.” One area in which single-use technology has been completely adopted is small-scale manufacturing under GMP conditions for clinical trials. “Companies have retrofitted disposables where it was very straightforward to do so, and bags for storage of buffers are the most frequently used disposable products implemented, where appropriate,” says Grund.
The conversion that Julien and Grund refer to is one from a stainless steel manufacturing infrastructure to one entirely made of disposable manufacturing technologies. For example, single-use expert Jeff Craig, global director of marketing and business development at ATMI LifeSciences, estimates there is somewhere between 1.1 million and 1.2 million liters of excess capacity in stainless steel cell culture and fermentation, the majority of which is represented by reactors exceeding 2,000 liters. “ATMI went into the single-use bioprocessing business with the idea that we would not replace existing facilities for approved products or very large-scale processes,” says Craig. “We’re targeting development labs, clinical supply facilities, and mixing, bioreactor, collection, or formulation steps; we supply manufacturing equipment with volumes up to 2,000 liters for all of these environments and processes. Ironically, most of our technologies have a stainless steel component; we still make temperature-controlled jacketed tanks, for example, that support disposable liners.”
Guenter Jagschies, Ph.D., senior director for strategic customer relations at GE Healthcare, says, “Changes are made only to existing processes once people have experience and confidence in the technology.” He adds that these decisions can actually cost people their jobs. “To allow a new technology onto the production floor requires quite a lengthy review process and confidence that it does what the established technology does,” says Jagschies. The result of this decision-making process, he says, is that there is a long lag phase between technology introduction and acceptance for disposables, and it can take at least 10 years for acceptance and complete conversion to all disposables.
“To do a comparison of single-use versus stainless steel, you set up a cost model based on using one or the other, but in actuality, it is a combination of both,” says Julien. “Indeed, there are some companies that use only single-use technologies and others that use only stainless steel. But, if you talk with most end users what you’ll find is that many of the manufacturing facilities — the real-world systems — are actually hybrids.”
FACTORS IMPACTING USE OF DISPOSABLES
Companies have to weigh a lot of issues when making decisions regarding their use of disposable technologies, some of which are economical, while others are technical or regulatory in nature. Faced with these issues, the engineers who implement new technologies at biopharmaceutical manufacturing companies often face pushback from corporate management. There are technical reasons why companies have not opted to implement disposable technologies, such as when manufacturing solutions are available for mammalian cell culture. “Disposable bags are not practical if you are using Escherichia coli or yeast because the biomass levels are so high that mixing, oxygenating, etc. is not easy with current disposable technology,” says Grund. There are also limitations with disposable centrifuges for harvesting the product after fermentation. Customers generally implement new technologies after they are truly tested and well-proven.
Another technical issue that can delay the acceptance of disposable solutions is scale. “Many of these disposable solutions cannot be scaled up to the very largest scale that the manufacturers want. So, when growing mammalian cell cultures in our WAVE bags, the maximum scale is 500 liters, which is fine, but if you want to scale up to 2,000 L or 10,000 L, you will have to invest in much more hardware," says Grund. “For example, some bag solutions for bioreactors combine all the advantages — being both ready-to-use and readily disposable. They use a rocking table for mixing and require very little handling and intervention. They are ideal when you want to make a process really lean in terms of logisitics, installation, preparation, lack of cleaning, dismantling, turnaround, etc. As far as I know (and this is certainly a dynamic area in terms of available products and might change tomorrow), bag solutions at larger scale (up to 2000 L) require more hardware and handling, such as a supportive bag-holders, internal mixers, and other components, making the whole system more complex and less plug and play or unplug and throw away. You lose the level of containment and you have a lot more handling — introducing risks and being less amenable to lean approaches.” However, for many applications, smaller scales are enough, and bags offer speed and flexibility beyond what steel can deliver.
Smaller companies find single-use technologies attractive because they can be set up quickly with reduced capital requirements and operated in a relatively inexpensive lab space to produce a drug under GMP conditions. “Single-use technologies are powerful strategic tools for smaller companies who need to advance their early-stage drugs to Phase 2 or even Phase 3 clinical trials before partnering for market approval and commercial manufacturing. It would be a shame for an innovator to give up a great development program because it can’t manufacture another 500 grams for clinical studies. Single-use technologies allow promising new drug candidates to move through the approval process quickly and at reduced expense when compared to building new stainless steel facilities,” says Craig. “One trend that we expect will drive implementation of single-use technologies is the rise of specific drugs for smaller patient populations and personalized medicines. When you combine this with the trend for higher upstream yields of an unpurified drug, a 2,000 liter bioreactor could easily become the manufacturing tool of choice. In this way, single-use technologies are closing the gap between development, clinical trials, and commercial scale manufacturing.”
In summary, as in many areas of pharmaceutical processing, there is more than one way to skin a cat, so to speak. So, whether a company is completely dedicated to using a disposable technology, all stainless steel, or some kind of hybrid technology, at the end of the day, the name of the game for a pharmaceutical manufacturer is to produce large quantities of high-quality drug product in the most cost-effective and efficient manner.