Vendors can attest to the increasing acceptance of single-use equipment in biopharmaceutical manufacturing. For instance, the Bioprocess Solutions Division of Sartorius Stedim Biotech, Goettingen, Germany has posted a double-digit increase in orders over the last nine months, largely due to demand for single-use products in such manufacturing. Meanwhile, GE Healthcare Life Sciences, Chalfont St. Giles, U.K., has gotten an order for the first plant to use its new modular approach for biopharmaceutical production.
The significant growth in the demand for single-use technology stems from the major advantages it offers over traditional stainless-steel solutions, says Christel Fenge, Sartorius Stedim Biotech's vice president, marketing and product management, fermentation technologies. "As cleaning in place is not required due to the fact that single-use bags or bioreactors are disposed of after use, significantly less steam and water is required. This, in turn, reduces the investment cost for new facilities, both in terms of the process equipment needed for these utilities but also the space. So overall you are saving cost, time, space and utilities," she contends.
Fenge also emphasizes the benefits in terms of speed of product changeovers: "With single-use technologies you can increase the number of campaigns by more than 25% with the same number of operators. A typical changeover takes just 3–4 hours, or even less, and decontamination procedures are obsolete as the bags used are disposed of or incinerated."
Single-use bioreactors also have played their role in this development, especially as biopharmaceutical companies are under significant cost pressures to generate pre-clinical and clinical materials such as monoclonal antibodies (MAbs) needed for trials.
One of Sartorius Stedim Biotech's latest innovations is the FlexAct family of standardized configurable disposables (Figure 1). These trolley-based units can be adapted to carry out a range of biopharmaceutical production steps, including buffer and media preparation, manifold bag filling, cell harvesting, ultrafiltration and diafiltration, and low pH virus inactivation. The trolley includes mixing tanks, filters, pumps, sensors and an integral control unit. "It is an important product because it replaces a lot of bespoke solutions put together by companies that often weren't very streamlined and which required a lot of labor to use and maintain. Because of its automation, it also frees up operators to do other tasks," says Fenge, who boasts, "in terms of the development of single-use technology, bags were the first wave, bioreactors the second and FlexAct the third."
The cumulative effect of all this single-use development is that the concept of a "process in a box'" has become a reality, she notes. "I prefer to call 'process in a box' 'industrialized pre-clinical and clinical supplies,' but a number of companies have already established very standardized processing concepts — notably with antibody development where, as with drug development, you are dealing with lots of leads and need to select the right cell lines. So speed is crucial here, as is the ability to make as many different candidates as possible. You might also use this concept when using protein engineering to improve the potency of a drug."
She cites WuXi, Shanghai, China, as one company that operates single-use-only processes. At the end of October, WuXi announced the completion of a cell-culture capacity expansion, including two 2,000-L disposable bioreactors that are ready for cGMP manufacturing. The company says its new plant is the largest disposable bioreactor facility in the world that is able to support phase-III clinical manufacturing and initial commercial launches of therapeutic antibody and recombinant protein drugs.
Fenge also points to a veterinary vaccine supplier in France that operates a single-use-only facility. "There are many other customers, both in the U.S. and Europe, which are using legacy stainless steel plants, but also investing into entirely single-use facilities for MAb [monoclonal antibody] manufacture. Most companies looking at single-use today are making MAbs, recominbant proteins and vaccines," she adds.
Sartorius Stedim Biotech now is turning its attention to process analytical technologies — using intelligent bags with single-use sensors to further automate production or support the development of better, more robust processes, or to add additional information that today comes from an offline measurement. "For example, single-use biomass measurement might be used to control a nutrient feed rate, while single-use pressure and flow sensors could be used in downstream unit operations such as cross flow."
In late September, GE Healthcare Life Sciences announced that it will build the inaugural plant using its KUBio modular approach to biopharmaceutical manufacturing — for contract manufacturer JHL Biotech, Wuhan, China. The plant will manufacture MAbs initially, although the equipment could make other products in due course. Single-use technology underpins KUBio and enables delivering a fully functional facility in only14–18 months (Figure 2).
The project is an important moment for GE. "It's tying all the technical expertise together from around the company, including bioprocess manufacturing technology, process development, automation and GMP manufacturing — all in a showcase plant," says Amersham Place, U.K.-based Daria Donati, head of strategy and offerings.
"We decided to bring an OTS [off-the-shelf] solution for MAbs to the market first because we wanted a process that is fairly straightforward and one that can be fully disposable. So for the first-ever KUBio project we wanted a facility that contained every aspect of disposable technology," she adds. GE also intends to introduce modules for production of other key biopharmaceuticals.
After completion in 16 months' time, the JHL Biotech facility will have a floor space of approximately 2,400 m2. It will contain a number of GE Healthcare's 2,000-L single-use bioreactors and will boast a manufacturing capacity of 100–110 kg/yr.
According to Donati, the extensive use of single-use technology throughout the plant offers manufacturing flexibility as well as lower validation costs. "Being able to shorten the time to market from the classic 2–3 years to 18 months at max provides a great advantage," she concludes.
Eppendorf, Hamburg, Germany, says its new BioBLU 0.3f is the first fully-instrumented single-use bioreactor designed specifically for microbial applications (Figure 3). The BioBLU 0.3f joins the BioBLU 0.3c, which launched last year for cultivation of animal and human cells. Both work with the company's compact DASbox system that allows parallel operation of four, eight or more mini-bioreactors for process screening and development applications.
The rigid-wall bioreactor features working volumes of 65–250 mL and includes two Rushton impellers that achieve oxygen intake levels comparable to industrial glass and stainless-steel units. All critical parameters, such as temperature, pH and dissolved oxygen, can be monitored and regulated using industry-standard sensors.
"We're pleased to be taking a new direction in single-use bioreactor technologies," explains Matthias Arnold, managing director of DASGIP Information and Process Technology, which became part of Eppendorf last year. "The physical requirements placed on single-use systems for microbial applications are much higher than the demands that are placed on cell culture processes — the conventional field of application for disposable bioreactors. By working together with the polymer experts at Eppendorf, we managed to overcome these hurdles, and as a result were able to optimally match material, design and functionality at the highest level of quality."
Meanwhile, Thermo Scientific, Waltham, Mass., has introduced technology to improve cell culture performance in its HyPerforma single-use bioreactors. Cell growth depends upon the availability of the right amount of oxygen in the bioprocess, which in turn hinges on sparging of air to create the optimal environment. Its new dual-sparger design consists of a micro- and a macro-sparger and is engineered to produce a consistent bubble size for predictable scaleup and performance from the company's 50-L to 2,000-L single-use bioreactors.
The micro-sparger features a porous frit design that produces bubble sizes in the range of 20–40µm diameter, creating a higher surface area and better oxygen transfer. The new macro-sparger, known as a drilled hole sparger (DHS), is a film-based sparging disc with laser-drilled pores — the specific size and quantity of the pores is tailored for each single-use bioreactor volume. The larger air bubbles of the DHS support the micro-sparger with oxygen transfer and improve the removal of carbon dioxide.
"This next-generation design sets a new standard of performance, flexibility and ease of use during scaleup for all cell culture applications," claims Millie Ullah, senior product manager for single-use systems.
Applikon Biotechnology, Tewkesbury, U.K., has launched micro-Matrix, which it describes as the next generation in micro-bioreactors. Containing 24 independent bioreactors in a simple microtiter plate footprint, micro-Matrix affords separate control — e.g., of pH, temperature, dissolved oxygen, individual liquid additions and up to four separate gas additions — of each bioreactor. Users can implement advanced strategies such as cascade controls (up to five actuators per process variable), time-based setpoint changes, and event-triggered liquid feeds. Liquid feeding can occur via a variety of addition profiles, too.
The micro-Matrix's software offers an easy way to operate 24 bioreactors in parallel, plus simple comparisons of large numbers of experimental cultures, says the company. Using an instinctive left-to-right progression, the interface guides operators through experimental setup, instrument configuration, control strategy definition and data visualization. All data can be exported from the instrument during or after the experiment.
NEW WEBSITE FOCUSES ON SINGLE-USE-SYSTEM DOCUMENTS
The AdvantaPure division of NewAge Industries, Southampton, Pa., has launched SUSdocs.org, a searchable directory of online documents related to single use systems (SUS) in the pharmaceutical, biopharmaceutical, and bioprocess industries. A number of organizations — BPSA (BioProcess Systems Alliance), ASME-BPE (American Society of Mechanical Engineers-Bioprocessing Equipment), PDA (Parenteral Drug Association), ASTM International and ISPE (International Society of Pharmaceutical Engineers) — provide information for the website.
SUSdocs.org was developed following a summer industry meeting on single-use systems where attendees, including many from associations and equipment manufacturing companies, commented that having data regarding single-use systems in one place would be helpful.
Examples of documents and articles found on SUSdocs.org include: "BPSA Extractables and Leachables Guide," "Designing the Ideal Bioreactor with Single-Use Technology," "PDA Technical Report No. 22 (Revised 2011), Process Simulation for Aseptically Filled Products" and "The Maturation of Single-Use Applications."
Seán Ottewell is Chemical Processing's Editor at Large. You can e-mail him at firstname.lastname@example.org.