Conservative attitudes tend to dominate the pharmaceutical and biopharmaceutical industries, which have traditionally resulted in slow adoption of newer manufacturing technologies. The movement away from the blockbuster drug model to more targeted therapeutics, however, is driving the need for drug manufacturers to avoid costly investments in traditionally large, stainless steel equipment (1).
Companies with a longer history of using single-use systems are the ones who are more likely to embrace newer technologies as well as to invest in them, but companies who hesitate or are reluctant to invest are those that remain uncertain about how to implement a disposable biomanufacturing system in their network (1).
There is a move toward smaller, more efficient biomanufacturing facilities, however, compared to 20 years ago. The ability to manufacture a comparable amount of biologic product due to process optimization means a smaller facility with single-use equipment can be a preferable solution to a traditional stainless-steel facility.
“It is far more common today that biopharma manufacturers are building small economical facilities with several 2000-L single-use bioreactors--20 years ago, the companies were building a facility with the same number of 20,000-L stainless steel bioreactors, but because the process intensification has taken a major step, the output is the same,” says Nigel Darby, advisor, Cytiva.
“However, if you look at the total industry capacity, the portion of single-use technologies is still relatively small, at most 10%, but in the new installations the portion of single-use technologies is already between 25% and 50%, and the market growth has been reported to be around 20% in the past three years,” adds Parrish Galliher, chief technology officer of Upstream BioProcess at Cytiva’s Life Sciences division.
Cost and time savings
To date, has single-use manufacturing technology thus far fulfilled the promise of saving time and cost? “With the modern technologies that we have in place, we can build manufacturing capacity a lot quicker than before: it is estimated that single-use manufacturing technologies can help reduce capex [capital expenditure] costs by up to 50% (2) and water and energy use by up to 80% (3) compared to a traditional facility,” Galliher says.
“The saved time allows the biopharma companies to build their capacity at a later stage in the clinical cycle, where there is more certainty that a therapeutic will reach the market. The capacity can be expanded in steps if the demand increases,” he adds. “The single-use technologies have also [had] a key role in process intensification--the financial benefits are great when the output is maximized from a smallest possible facility.”
One of the costliest aspects in biomanufacturing is the cost of sterile-fluid transfer, such as product and reagents, through the different process steps that are typically located in different parts of the facility. Sterile-fluid transfer has traditionally been conducted through product piping, stainless-steel vessels, routing manifolds, and valves--all of which requires cleaning and sterilization. In addition, equipment validation is required before re-use (4).
To put the time consideration into perspective, a typical clean-in-place cycle for vessels between 100 L to 1000 L can run between one-and-a-half to two-and-a-half hours long. Furthermore, if the bioprocess is classified as totally sterile, then vessels need to undergo an additional steam-in-place cycle, which can run another three hours or longer. The time used to prepare and validate equipment for sterile-fluid handling is therefore time consuming, and this translates to time that production capacity is not being optimized (4).
In comparison, disposable single-use bioreactor bag systems, which range from 50 mL to 3000 L and are intended to replace the glass bottles or stainless-steel vessels traditionally used for sterile-fluid handling, are designed to save space and provide ease of maneuverability around the facility (4). Because they are disposable, they do not require cleaning cycles. In addition, validation for disposable technology takes less time than for traditional equipment.
Company investment in single-use technology
Investments in single-use technology include Cytiva’s portfolio. “Cytiva has developed and made a number of investments over the years in single-use manufacturing technologies. Now we have a complete portfolio of single-use upstream and downstream systems for bioprocessing, including rocking and stirred tank bioreactors, sensors, smart mixers, filtration pump skids, virus inactivation systems, chromatography systems, single-use connectors, welders and ready-to-use tubing assemblies (ready circuits),” Galliher says.
One of the company’s most important investments was the 2012 acquisition of Xcellerex, a supplier of manufacturing technologies, including FlexFactory for biologics, a centrally automated, flexible biomanufacturing platform based on single-use technologies, that allows for GMP manufacturing. The acquisition complemented Cytiva’s portfolio with production-scale bioreactors.
Additionally, in 2016, the company announced a $7-million expansion project in Westborough, MA (5), where a range of single-use products, including cell growth bags, will be manufactured. Other recent investments include $5 million in an extractable and leachable testing lab for on-going support of single-use product development, according to Galliher.
“We have also launched a high-performance single-use microbial fermentor at the 500-L scale. In addition, we have also launched a single-use ÄKTA ReadyFlux ultrafiltration/defiltration system,” he says.
Evolving capacity needs
As the capacity needs of biologic drugs in development change (e.g., going from high volume product to smaller-volume high potency volumes), single-use technologies can expect to evolve. “Small-scale, single-use systems are already in widespread use for process development and small-scale expansion of cell cultures and downstream processing. Therefore, we expect evolutionary, not revolutionary, changes in single-use technologies for small volume highly potent drugs,” says Galliher. Examples of this evolution include the development of more closed systems, novel film chemistries, smart sensors, and automation for small-scale single-use systems, he adds.
One example of how modular manufacturing is evolving to fit capacity needs is Cytiva’s deal in January 2018 to equip a cell therapy manufacturing facility with the FlexFactory platform, which the company will design to speed up manufacturing timelines for cell therapy clinical trials and commercial launch (6). The facility in the plans is Cellular Biomedicine Group’s (CBMG) Shanghai, China, cell therapy manufacturing facility. CBMG is a clinical-stage biopharmaceutical company focused on immunotherapies for cancer.
Gaps exists in manufacturing cell therapies to meet demand, according to Cytiva. Scalable integrated solutions to support the transition from clinical trials to commercial manufacturing have also been limited. Many of the multiple steps in the cell therapy manufacturing process remain largely unintegrated and require manual labor, and open transfers between steps increase the risk of contamination (6).
CBMG will be the first company to install the FlexFactory platform for the manufacture of cell therapies and anticipates that the platform will be operational by the end of 2018.
In a similar move, Sartorius Stedim Biotech entered into a deal in January 2018 to equip Abzena’s two integrated contract development and manufacturing organization (CDMO) facilities in Bristol, PA, and San Diego, CA, with single-use manufacturing systems (7). Abzena, a CDMO, conducts development and GMP manufacture of antibody drug conjugates at its Bristol facility and conducts development and GMP manufacture of monoclonal antibodies and other recombinant proteins at its San Diego facility.
Under their agreement, Sartorius Stedim will equip Abzena’s San Diego process development lab with industry technologies that enable fast scale-up to 500 L initially and later to the 2000-L scale single-use bioreactor at Abzena’s center of excellence for clinical manufacturing.
The role of modular manufacturing
Modular manufacturing, a design concept that typically involves the use of self-contained, maneuverable units (or modules) of equipment in a “ballroom” concept (8)—a large manufacturing space with no fixed equipment—is another aspect of single-use manufacturing systems; it plays a role in the adoption of single-use technologies.
“Modular manufacturing solutions are making a comeback, enabled by single-use technologies, because modular systems based on single-use are less complex and costly to manufacture and operate,” Galliher notes, “For example, Cytiva has already installed over 20 FlexFactory biomanufacturing platforms globally that are based on single-use technologies.”
Modular technologies are not new and have been around for many decades, Galliher states. They have been rediscovered, however, due to the simplification and lower costs afforded by single-use manufacturing technology, he notes.
1. PharmaIQ, “Investment Trends in Single Use Systems ,” accessed Jan. 18, 2018.
2. Cytiva, “Biologic Manufacturing Capacity Expansion with Single-Use Technologies: Key Variables to Consider ,” accessed Jan. 22, 2018.
3. Singapore Economic Development Board, “Amgen Unveils Next-Generation Biomanufacturing Facility in Singapore ,” accessed Jan. 22, 2018.
4. A. Sinclair and M. Monge, “Quantitative Economic Evaluation of Single Use Disposables in Bioprocessing ,” Pharmaceutical Engineering. 22: 20-34 (2002).
5. Cytiva, “Cytiva Enhances Single-Use Manufacturing Capabilities with Facility Expansion and Automation ,” Press Release, Oct. 31, 2016.
6. Cytiva, “CBMG Accelerates Cell Therapy Manufacturing with Cytiva’s New Start-to-Finish Solution,” Press Release, Jan. 18, 2018.
7. Sartorius Stedim Biotech, “Abzena Selects Sartorius Stedim Biotech to Equip its US Based Development and Manufacturing Sites in San Diego and Bristol ,” Press Release, Jan. 4, 2018.
8. S. Riley, “Modular Manufacturing, ” Pharmaceutical Processing, accessed Jan. 22, 2018.