By Bernard Tulsi
Buoyed by the inherent diminution of cleaning requirements and more favorable cost and technical onsiderations, the adoption of single-use or disposable bioprocessing components is on a growth trajectory. Still, key peripheral technologies, especially sensors, seem somewhat out of sync and remain an area
in need of innovation.
From a production facility perspective, the areas in which single-use systems have made the most inroads include storage, mixing, and harvest bags. It was relatively easy to ship media or additives in these single-use plastic bags; use them once, and throw them out. “As sophistication increased, mixers were included, and once those were up and running, it was realized that a similar product could serve as a bioreactor,” says Barbara Paldus, CEO of Finesse, which supplies sensors, hardware, and software solutions for bioprocessing operations.
Single-use bioreactors and mixing bags for buffers are now typically made of plastic. Once, all of these systems were based around reusable stainless steel containers, which required considerable cleaning after use. Cleaning is an unattractive process that consumes large quantities of water and energy, as well as chemicals, which require safe disposal.
To be sure, there are still important hurdles to overcome. Almost anywhere in the spectrum, the required electrochemical sensors, whether glass or stainless steel, are not well-matched to single-use biocomponents.
“There is poor matching basically anywhere there is conversion to single use,” says Mark Selker, CTO at Finesse.
Paldus explains that as mixers and bioreactors started to become more integrated, it was soon realized that the current crop of available sensors was completely mismatched to the plastic mixers and bioreactors. “So there has been a huge outcry for single-use sensors on the upstream side,” she says. “On the downstream side, there was already considerable use of columns and HPLC [high-performance liquid chromatography] separators and filters that were more or less disposable, though very expensive.” For the downstream side to go fully singleuse, there will be a need for new, cheaper materials — otherwise that will be a very expensive proposition, Paldus says.
In addition, single-use systems are not suited for the production of large quantities of material with a low yield of active ingredients. In such situations, such as the high-volume production of vaccines, large stainless steel systems are still the best option. Focusing on sensors, Paldus points out that in stainless steel tanks, the control systems are unique and are customized for the requirements of individual tanks. As a result, any product or process changes require remaking the control system from scratch. By contrast, in a single-use system, once a bag is used and thrown out, a completely new process can be initiated, enhancing overall production flexibility.
THE ADVANTAGES OF SINGLE-USE SYSTEMS
Inherent in these differences are advantages for single-use systems. Time to market is much shorter — six months to get a single-use system up and running versus about two years for a stainless steel bioreactor. The custom automation requirements for stainless steel systems also make it impossible to transfer process recipes.
Addressing the suggestion that discarding and replacing processing units and components on an ongoing basis may actually incur greater costs and create environmental issues, Paldus says, that while at first glance that may appear to be the case, “Studies have shown that the incineration of plastic components is safe, and that the process can generate energy, though, at the moment, the components generally end up in landfills. On the other hand, stainless steel plants generate a large amount of wastewater and chemicals. Neither is ideal, but one is not really worse than the other.”
Gamma sterilization methods used with the disposable systems are more environmentally friendly because radiation provides a guaranteed kill of the organic matter. It is a potent way to sterilize and does not create any waste. With stainless steel systems, there is a need to clean with water and chemicals on both the front and back ends.
SINGLE-USE AT A BIOTECH COMPANY
Privately held biotech company Merrimack Pharmaceuticals is among the growing ranks of companies using single-use solutions. Merrimack’s Senior Process Engineer Washington Alves says, “Our goal was to develop and move our new oncology products to the clinic as quickly as possible. We wanted to move fast while conserving our capital as well.”
Washington says Merrimack considered three options. One was to take the project to a contract manufacturing organization (CMO), which would develop the process and make the product for clinical trials. Another was to build a small bioprocessing plant using traditional stainless steel systems. “We decided to go the disposable route. Originally, we thought we wouldn’t because we did not have a lot of experience with these technologies. But, when we looked at the overall cost as well as the time frame to go the CMO route or build and validate a stainless steel platform, we realized those time and cost models would not fit our overall goals for these products,” says Washington.
A closer look at a single-use system showed that it would cost less to build a facility using disposable technology, require fewer personnel to operate, and validation would be simpler. “We would also be able to do it all in-house and in the process, develop the capabilities to support other products in our pipeline,” he says.
After starting out with WAVE bioreactors, Merrimack now uses HyClone single-use bioreactors in its operations. HyClone makes the vessels and the disposable bags but not the controllers or the sensors. “So we acquired the vessels from HyClone and engaged Finesse to build the processing control systems,” says Washington. “Finesse provides us with control systems, integration of the software, hardware pieces for the controllers, as well as some of our sensors.”
SAVING 50% ON THE TIME TO BRING A PLANT ONLINE
Finesse also helped Shire Pharmaceuticals address some of its laboratory needs. Pilot operations are an intermediary area between the small-scale process development and the manufacturing group. Christopher Adams, associate director of pilot operations with Shire, says his shop works in process development primarily for enzyme replacement and specializes in genetic therapies. “We work on severe orphan diseases, that is, small populations of people with genetic disorders,” he explains.
In the past, Shire used glass vessels for small-scale work (1 to 10 liter bioreactor vessels). When the company would scale up to anything above 25 to 40 liters, it used stainless steel bioreactors, which required a lot of supporting infrastructure for manual cleaning and autoclaving.
“We first used disposables with the WAVE bioreactor system about seven years ago,” says Adams. “While we still run both single-use and reusable systems, at the large-scale development pilot plant, which I supervise, we use fully disposable systems.”
Adams says the decision to go single-use was easy for them: substantially reduced timelines and cost savings. “You save about 50% on time to bring a plant with fully disposable components online versus a traditional plant,” he says. “Furthermore, one of the best aspects of this technology, especially for a company like Shire, is the quick turnover and product change time,” he says.
He explains that Shire has a number of different products and its production needs do not include very large-scale production equipment. “With our products, we can do a few batches at perhaps 1,000 liters each, and that could meet our demands for a year or two — so quick changeover is important for us, and it’s where disposable technology is a plus.”