Disposable bioreactor use grows in commercial production

A disposable future

04 March 2008 00:00  [Source: ICB]

Biologics manufacturers are already using disposable technology for its inherent practicality and argue that it is a commercially viable means of production

Feliza Mirasol/New York

 

PHARMACEUTICAL AND biotechnology companies appear to be on the cusp of accepting stirred tank disposable bioreactors for biologics manufacturing.

"We are already selling our technology to companies that are planning to use our system for commercial production within a couple of years or less," says Parrish Galliher, founder, president and chief technology officer of Xcellerex, a Marlborough, Massachusetts, US-based company that develops single-use stirred tank manufacturing technology for biomolecules.

"It's going to happen very quickly. The economics and advantages are so compelling for companies, and the FDA [Food and Drug Administration] has already accepted INDs [Investigational New Drug Applications] for drugs manufactured with this technology," says Galliher.

Xcellerex has large-scale reactors in the 40 liter to 2,000 liter working volume range in use in good manufacturing practice (GMP) production, says Galliher.

"Those are the sizes we're selling right now." Galliher explains that Xcellerex deals in "working" volumes, "meaning the actual volume you can grow a culture in."

"We are highly likely to see the spread of disposable bioreactors but this will be within a certain volume range. Vendors are currently looking at scales up to around 2,000 liters. Beyond this scale, stainless steel bioreactors would tend to be the option chosen," says Dominik Werner, media relations representative for Switzerland-based Lonza, a leading biologics contract manufacturer.

"There are a number of products like vaccines or cell therapy products in the clinic now for which it is the intention to keep producing them in smaller-scale, disposable bioreactors once they go commercial," he says.

One of the primary advantages of using disposable technology in biologics manufacturing is the compelling cost advantage.

"The first main advantage is that the fully installed capital cost (including utilities) is much lower. It's about half the capital cost to put in a single-use system than a hard-pipe stainless steel system," says Galliher.

CLEANS UP NICELY

Installing a single-use system is much quicker, taking about one-third of the time to order the reactor and install steel pipes. And what's more, the cleanup is much simpler and faster.

"By using disposables, you eliminate the need for cleaning validation, which helps lower cost and can also improve changeover in a multiproduct facility," says Howard Levine, founder and president of BioProcess Technology Consultants.

"The use of disposable equipment allows you to avoid cleaning steps of fixed equipment, such as tanks, so the time it takes to do the cleaning and bring it back on line for use in the next batch is eliminated. You don't lose that time anymore," adds Tom Ransohoff, vice president and senior consultant at BioProcess Technology Consultants.

"The main difference [between disposable and fixed bioreactors] is that the disposable reactor is ready to use. Stainless steel reactors need hours and volumes of water and cleaning agents to be set up. Additionally, these need to be steamed or autoclaved. All the setup time delays production time, which will be avoided by using disposable reactors," says Maik Jornitz, group vice president, marketing and product management, filtration/fermentation technologies for France-based equipment supplier Sartorius Stedim Biotech.

Equally comforting is the notion that these disposable components don't require a separate disposal.

GREATER FLEXIBILITY

Using disposables also provides increased flexibility. A manufacturer can reconfigure production processes or a plant more easily.

"You don't have fixed tanks installed in your facility that are maybe hard-piped to one another. If you can't make a change in your process equipment, it makes it more difficult to make changes overall," says Levine.

In addition, eliminating the need for cleaning and conducting extensive product changeovers, in a multiproduct plant, offers the possibility of increased output for a plant.

"If, instead of taking 10 days between each batch, you can shrink that time to five days, for example, then over the course of one year those extra five days can add up to an extra production run. And so for the same capital investment - the same facility - you're getting one more batch per year," says Levine.

"That could be an incentive to use disposables, because distribution of your fixed costs over one more batch will lower overall cost of goods," adds Ransohoff.

One concern is whether the increased output of waste, in the form of plastic bags, will have a greater environmental impact.

"Consideration also needs to be given to the increase in the quantity of waste that subsequently needs to be removed from the facility and appropriately disposed of," notes Werner.

However, Levine argues that this is not a major drawback. "[There is] the potential concern that if you have to switch to more and more disposables, the trash output from the facility goes up, and what is the environmental impact of that," he says. "But we believe that this is a manageable concern."

Another advantage important to biologics manufacturers is the significant reduction in cross contamination. A manufacturer can use the disposable option in multiproduct processes without fear of this happening.

The use of disposable components and disposable bioreactors is being driven by several factors, the main one being the increasingly smaller volumes of biologics drugs coming through the pipeline.

These drugs are significantly more potent than traditional biopharmaceuticals already on the market. As a result of this increased potency, lower doses are needed.

"Many low-potency, high-dose biopharmaceuticals need to be produced at larger scales (10,000-20,000 liters) in order to reach commercial quantities. However, it turns out that many new drugs coming through the pipeline are very potent and their volumes are small enough that they can be produced with today's 2,000 liter disposable bioreactors," says Galliher.

"We see this trend continuing, and by that I mean greater and greater percentages of drugs that reach the market will be produced in single-use systems, including in disposable, stirred-tank bioreactors. The new drugs we see coming through the pipeline from research organizations, companies and universities are much more potent," he adds.

Another factor driving this high-potency, low-dose drug trend includes the productivity of the manufacturing processes.

"The amount of drug produced is increasing from each cell in the reactor because we're learning better how to produce these compounds," says Galliher.

Furthermore, the markets for these drugs are shrinking. "These drugs are more closely tailored to a narrower segment of patient populations," he adds. "They are more tailored to specific responders with specific receptors."

A classic example where this shrinking niche market trend is happening is in the use of receptor-based clinical diagnostics. The drug is only given to patients who show evidence of containing the receptor for the drug.

"Instead of just giving the drug to just any breast cancer patient and seeing how they'd do with it, you're screening for patients who are responders. At the end of that process, you end up reducing the number of patients who are actually qualified to get the drug. Personalized medicine is going in this direction full bore," explains Galliher.

"In five to 10 years, the workhorse bioreactor scale for this industry will be around 2,000 liters - not 10,000-20,000 liters. Processes are becoming much more productive, drugs are more potent and niche markets are much smaller," he adds.

"I think disposables fit perfectly with those trends of niche drugs and personalized medicines, because these areas lead into smaller batches of more products. Disposable reactors are really ideal in the small to medium scale," says Levine.

"So if the industry's requirements shift from 20,000 liter production runs to make an antibody that is a blockbuster product, to 1,000 liter production runs of multiple antibodies, then it will be much more cost-effective to do this in disposable bioreactors," Ransohoff adds.

Disposable technology would thus make drug development in niche markets much more economical. One of the hurdles in developing these small-market, niche products lies in the fact that demand for any one product is often so small that it makes it difficult for a manufacturer to justify an investment in making such a product, let alone developing one.

"Now with disposable technology you can say: If I can lower the overall cost because I'm making lots of different batches in a smaller facility, then perhaps it becomes more feasible," says Levine.

ROADBLOCKS AHEAD?

Although there wouldn't seem to be any roadblocks ahead for the commercial use of disposable technology, some kinks still exist in its practical application. The main preventative factor would be scale.

"When the disposable bioreactor becomes too large there will be physical limitations and stability issues. We believe the maximum range will be 1,000 liters, maybe 2,000 liters. For this reason, we believe that there will always be a stainless steel option. The other hindrances are agitation and overpressure needs related to some applications," says Jornitz.

"There are also technical issues," says Ransohoff. "Since these disposable reactors are generally made of plastics with potential for leachables and extractables, manufacturers and their suppliers need to invest in assessing the potential impact of these leachables and extractables. It is also important to understand the origin of the disposable components as some plastics are produced using animal-derived components."

There may also be process limitations. Some disposable bioreactors are not built with an impeller, and even in larger, more conventionally designed ones, the impeller is not as efficient as that of a fixed reactor.

"You have limitations in oxygen transfer. Now if you're doing a mammalian cell culture, this is less of an issue, but if you're doing microbial fermentation where the demand for oxygen is much higher, since the cells grow faster into higher densities, then you may have difficulty providing enough dissolved oxygen," says Levine.

Galliher says: "There's nothing to prevent disposable bioreactors from being used in commercial-scale production. Disposable bioreactors are being used in commercial production in inoculum seed expansion, but it is for small-scale products. The larger-scale products we are going to be making in the next couple of years for the market will be at the 1,000-2,000 liter scale, and there's nothing to prevent their use as long as they are validated for GMP use and are licensed by the FDA."

Galliher says that Xcellerex already makes clinical trial material of these new proprietary compounds for its partners. If approved for market, the company will make the drugs on a commercial scale.

"The FDA has already accepted INDs for drugs manufactured using these disposable bioreactors. Other companies have already used them for commercial production in inoculum seed trains, but, again, at the small scale end for very small volume products," says Galliher.

"Lonza has been using disposable elements in their manufacturing plant in Slough, UK, for some five to six years. We routinely use disposable cell bags for our inoculum scale fermentations and single-use bags for preparing medium and feeds. Similarly, buffers for purification operations are stored in disposable bags," says Werner.

More recently, Lonza introduced disposable bags for sampling its bioreactors, disposable filter systems for primary recovery operations and disposable mixing systems for use in downstream operations.

UNDER THE SPOTLIGHT

So the burningquestions are:

Who builds this technology and what is on the market today?

The growing use of disposable, or single-use bioreactor systems in the biopharmaceutical arena signals an upcoming technology shift.

Some firms with single-use bioreactor systems on the market now, include France-based Sartorius Stedim Biotech, UK-based Cellexus Biosystems, Netherlands-based CELLution BioTech, and US-based Xcellerex , GE Healthcare, and HyNetics.

One of the more popular designs on the market is called The WAVE design, which consists of a presterile plastic bag that sits on top of a rocking platform. The rocking motion induces waves in the culture inside the bag.

GE Healthcare, through its acquisition of Somerset, New Jersey-based Wave Biotech in April 2007, sells the WAVE Bioreactor. This system provides mixing and oxygen transfer that can easily support over 10 x 106 cells/ml and has been used for monoclonal antibodies, anchorage-dependent cells, virus production and insect cell/baculovirus culture.

The WAVE Bioreactor is also in used in current Good Manufacturing Practice applications for production of inoculum for large, conventional stainless steel bioreactors and is also used in clinical and commercial production of human therapeutics.

Meanwhile, Sartorius Stedim Biotech also supplies disposable bioreactors in the WAVE design that range from 1-200 liters.

"There are three options: basic without sensor optical with disposable sensors measuring O2 and pH and perfusion," says Maik Jornitz, group vice president, marketing and product management, filtration/fermentation technologies at Sartorius Stedim Biotech. "In the very near future, we will launch cylindrical disposable bioreactors with different agitation technologies with various volume ranges. The first one will be 200 liters."

Other components that can be found in disposable manufacturing systems are filter capsules, cross-flow, valves, pressure transducers, piping, connectors, holding tanks, mixing tanks, and, soon, pump heads, Jornitz says.

Switzerland's Lonza, one of the world's leading biologics manufacturers, signed a strategic partnership in February with CELLution Biotech. Under the agreement, Lonza will launch a new two-dimensional system called CELL-tainer.

"The CELL-tainer, which Lonza will launch, is a patented bioreactor bag with separable compartments. The bag is mounted on the rocking platform of the CELL-tainer," says Lonza media representative Dominik Werner.

"The patented two-dimensional movement of the bioreactor bag results in an increased mass transfer. Gas exchange properties are superior to what is achieved in the conventional single-use bioreactors and even in stirred-tank reactors as applied in cell cultures," he adds.

The CELL-tainer technology offers the biopharmaceutical sector the benefits of higher cell densities and higher productivity with mammalian cell cultures. Further, the linear scalability of this new system shortens the process development time significantly.

"Due to the increased mass transfer rates, the CELL-tainer also is suited for microbial cultures such as Pichia pastoris, E coli and others," says Werner.

Xcellerex's technology differs in that its stirred-tank disposable bioreactors mimic conventional stainless steel tanks. Xcellerex's bioreactors have the same shape, mix the same way and are controlled the same way as conventional stainless steel fixed bioreactors.

The company decided to go that route because of the status of conventional stainless steel fixed reactors as being an already established technology with the US' Food and Drug Aministration for manufacturing biologics and other drugs. Hence, it is a predictable technology in terms of process scale-up. Xcellerex has these stirred-tank disposable bioreactors in the 10-2,000 liter ranges.

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