Disposable equipment earns lasting role

Improvements in materials and processing know-how have led to a steady increase in the use of single-use or disposable equipment.

By Seán Ottewell, contributing editor

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Single-use or disposable equipment first appeared in small laboratory-scale applications decades ago. Improvements in materials and processing know-how since then have led to a steady progression up the process stream — and to increasing reliance on such units by manufacturers in sectors such as pharmaceuticals.

That’s not surprising because disposables offer several important advantages. Single-use units boast lower capital outlay, better return on investment, plus reduced expenditure on clean-in-place (CIP) procedures, autoclaving and validation, say their proponents. Such units avoid delays due to fabrication and commissioning common with some types of conventional equipment — thus enabling faster batch or product changeover times and lower contamination rates. By avoiding the need for CIP, disposables reduce utility costs, generate less waste and require use and storage of fewer hazardous fluids. Overall, disposables can serve as a key tool in speeding a product’s time to market, backers stress.

Small wonder then that the Bio-Process Systems Alliance, founded just last year under the auspices of the Society of the Plastics Industry, Washington, D.C., has grown to more than 40 members. One of its aims is to increase the worldwide market for single-use components and systems. And, judging by all the action — technical and commercial — now underway, that’ll be a cinch.

Joe Dallapiazza, global director single use systems for Pall Corp., East Hills, N.Y., undoubtedly speaks for many when he voices confidence about business growth. For instance, he points to an increasing role at contract manufacturing organizations and vaccine producers for whom productivity and quality are key drivers.

“I think the market will keep growing. Their scale is getting bigger, so the demand is for bigger bags, bigger tubes and bigger connectors. At the same time, however, batch sizes are getting smaller because there are fewer blockbusters in the pipeline and [the] drugs industry is getting much more personalized. So contract manufacturers might be doing 20 or more different product lines each week and it’s a huge advantage not to have to clean from batch to batch.”

Speedier turnarounds made possible by avoiding CIP procedures, etc., also certainly appeal to many pharmaceutical manufacturers such as Eli Lilly & Co., Indianapolis. “This is a big issue for us,” explains senior research scientist Mark Bailey. “Today, with disposables, we can change the equipment set for making a batch of one material to making a batch of a completely different material in a matter of hours. Years ago, it could have taken days to turn the equipment around between batches.”

No mix-up

 

The increasing progress of disposables certainly is evident in mixing and materials handling. For instance, Millipore Corp., Billerica, Mass., has just added a new disposable mixer to a range of bioprocess hardware that already includes filters, container valves, connectors and other mixers. Its modular Mobius MIX200 disposable mixing system is designed for biopharmaceutical manufacturers, especially those involved in pharmaceutical ingredient mixing and cell culture media preparation (Figure 1).
Figure 1. Modular unit is the first to benefit from expertise of recently acquired companies. Source: Millipore.
Figure 1. Modular unit is the first to benefit from expertise of recently acquired companies. Source: Millipore.

                                                                                              It’s the first product to combine Millipore’s capabilities with the biopharmaceutical expertise of two recent acquisitions. NovAseptic, Gothenburg, Sweden, which was acquired in August 2005, provides a range of aseptic products, including high-performance mixers. Newport Biosystems, Anderson, Calif., which became part of Millipore in April last year, specializes in disposable process containers.

“With our expanded footprint, we can help our customers reduce their risk, increase their speed and gain an edge in the marketplace,” says Jean-Paul Mangeolle, president of Millipore’s Bioprocess Division.

Processing speed also is at the heart of the latest offering — the PureFeed AP-300 auger feeder — from Schenck AccuRate, Whitewater, Wis. To maximize material handling versatility, the feeder features a flexible hopper and programmable, external dual-arm agitation system. It also pioneers the use of flexible EPA-accepted ethylene propylene diene monomer (EPDM) feed-hoppers that are both disposable and recyclable. The result is simpler, shorter cleaning cycles with virtually no chance of cross-contamination when moving from one material to another, says the company.

PureFeed comes in both volumetric and gravimetric configurations for pharmaceutical, nutraceutical and cosmetic applications that involve feed rates from 500 g/hr up to 150 kg/hr. Such applications, the company says, include jet milling, continuous blending, medical-grade plastics compounding, packaging, coating and ingredient weighing.

Many companies also market disposable mixers. For example, LevTech Inc., Lexington, Ky., offers a range of units including the WandMixer, which comes in a 5–50-L benchtop model and a 50–200-L mobile model, and the Magnetic Mixer with a 50–3,000-L capacity.

Figure 2. Devices such as these ensure quick and easy connections between system components. Source: Colder.
Figure 2. Devices such as these ensure quick and easy connections between system components. Source: Colder.

HyNetics, Logan, Utah, a 50/50 joint venture of Alfa Laval Biokinetics and the Fisher Scientific company HyClone, offers a family of mixing systems ranging from 20 L up to 10,000 L. The modular skid-based hardware allows the integration of completely disposable mixing systems. In other words, all product-contact surfaces are single-use, permitting their disposal after each batch and their replacement with a new system.

Of course mixers — and other single-use equipment — need to be connected with each other and with the rest of the process. Ensuring the sterility of this step was once a major headache for disposables’ suppliers. Now, however, such integration is routine thanks to developments in connection hardware. Take, for example, the latest additions to the Steam-Thru series from Colder, St. Paul, Minn. An innovative design allows quick and easy sterile connection between biopharmaceutical processing equipment and disposable bag and tube assemblies. Media can be safely transferred without the cleaning and validation concerns associated with reusable components (Figure 2).

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Combine the ability to link single-use equipment in a safe and efficient manner with takeovers that expand process know-how at vendors and you begin to wonder how far away we are from a whole disposable process. This isn’t a pipedream.

A process-in-a-box?

 

Pall has been in the disposables business for ages, and its recent product introductions and business expansion plans clearly are pointing in one direction: the process-in-a-box.

Already this year the company has launched its SupraCap 100 depth filter capsule, marketing it as the only intermediate-scale depth filter to be offered in a range of sizes, styles and configurations (Figure 3).

Figure 3. This low-hold-up-volume filter comes in a wide variety of sizes, styles and configurations. Source: Pall.
Figure 3. This low-hold-up-volume filter comes in a wide variety of sizes, styles and configurations. Source: Pall.

The capsule provides the usual features of disposables, but also a lower hold-up volume than standard module housings. This both speeds up and increases product recovery in the 5–100-Lr applications that are typical of pilot-scale operations as well as clinical batches and personalized medicines.

In an important hint at the shape of things to come, these capsules can be manifolded together or connected upstream of the company’s KleenPak Nova filters as a fully-integrated disposable system that reportedly offers higher performance in a smaller footprint and increased production with minimal revalidation (Figure 4).

“This new intermediate-scale capsule complements Pall’s line of SupraCap depth filters and provides a critical scale-up path for process developers,” says Scott Anderson, global product manager for Pall Life Sciences. “Providing a critical link between discovery and production processes, the SupraCap 100 depth filter capsule enables process developers to begin testing at the earliest development stage to maximize their investment.”

This year the company also introduced an innovation in biocontainers, which are an integral component of single-use processing for collecting and transporting process solutions, product intermediates and cell culture media. It launched Allegro Biocontainers, a comprehensive, integrated, disposable system that comes gamma-irradiated and ready-for-use. The new units are manufactured from an advanced film that reduces extractables and leachables to a very low level, and provides broad chemical resistance and an effective oxygen barrier. The system’s novel design significantly improves its robustness for more efficient drainage and process flow, claims the company.

Figure 4. Connection technology enables a fully integrated disposable system. Source: Pall.
Figure 4. Connection technology enables a fully integrated disposable system. Source: Pall.

Available in capacities ranging from 50 ml to 50 L, such units enable quick start up or rapid scale up, speeding implementation and time-to-market. Importantly, these are the sorts of advantages that multiply as single-use technologies expand from standalone devices to multi-component system assemblies.

Dallapiazza says these two new products highlight the way the market is developing. “There was definitely an issue with disposables to begin with, one of the big hurdles being leachables. This made us look at all our core products, for example the biocontainer. Now we find that disposables are being adopted more and more. The market itself is driving developments. Manufacturers gain big advantages if they aren’t having to do cleaning and validation, for example. This means you get products to market faster and don’t have such large up-front capital costs.”

The company is tapping into its years of experience on the stainless steel side of the business and leveraging this for the disposables group. “We don’t just want to be an integrator. We try to understand the whole process stream. Our steel people have that expertise and it’s a huge benefit to us that we have that applications knowledge,” he notes.

The logical extension of the increasing integration of disposable modules is an entire disposable process. “We are seriously considering offering the entire bioprocess manufacturing stream,” he acknowledges. “We’re looking to gain this, achieve this through using our own R&D capability together with external companies — perhaps involving alliances, partnerships and exclusive distribution arrangements.”

“This market is crazy, dynamic and with a lot of consolidation,” he concludes. Crazy the market might be, but Pall is not alone in looking to a whole disposable process.

Acquiring an interest

 

The “industrialization” of disposables technology also is a driving force at GE Healthcare’s BioProcess business, Chalfont St. Giles, U.K. “GE came into biopharma three years ago with the acquisition of Amersham. The business is really made up of this and other acquisitions, including filter businesses and businesses that create carriers for cell-based vaccines. We want to industrialize our vision, make the whole process disposable. This will make pharma companies faster to market, with more reliable production and improved efficiency,” explains Ann O’Hara, general manager.

This was the thinking behind April’s acquisition of Wave Biotech, Somerset, N.J. That firm develops and manufactures novel bioreactors that are designed to replace traditional and more-expensive stainless steel tanks and piping while providing rapid installation and the other advantages of disposable units. The equipment is already in use in more than 300 companies worldwide (Figure 5).

Figure 5. Rocking of this reactor subjects its contents to a wave-like motion. Source: GE Healthcare.

In its drive to move from mainly downstream processing into the whole process stream, GE Healthcare intends to carry out ongoing development of Wave Biotech’s stable of products. At the moment, for example, the largest biowave reactor available is 500 L but a larger model now is being trialed, O’Hara confirms. “We are also developing a new mixing system which will not necessarily involve the current rocking technology,” she adds.

Wave Biotech’s Wave Mixer and Tuber Fuser technology also figure in this holistic strategy. “The Wave Mixer is a very important product. One of the things that takes up real estate is buffer solution, so this needs less room on the factory floor.

“Vaccine manufacturers want rapid deployment of product so the development cycle is very much shorter here. They are the force that is really pushing for the fully disposable process plant,” says O’Hara. She also emphasizes that an out-of-the-box process should appeal to smaller players, “not least because it makes them a more attractive takeover target after successful phase one trials — not having to re-do all the process work again for validation.”

Another company clearly envisioning disposable processes is Sartorius, Goettingen, Germany. In January, it took over Toha Plast, also of Goettingen, a specialist in plastic processing.

“For our further dynamic growth with disposables, plastics technology has a high strategic significance,” notes Sartorius CEO Joachim Kreuzberg. In the summer, it completed the acquisition of Stedim Biosystems, Aubagne, France, a global leader in disposable bags, and merged it with the existing Sartorius Biotech Division. “This transaction significantly accelerates our strategy to offer customers fully integrated solutions for next generation biopharmaceutical manufacturing,” he says.

The new company, Sartorius Stedim Biotech offers fluid management, purification, filtration (Figure 6) and fermentation— in fact the sort of comprehensive range of biotechnologies and services needed for future entirely disposable processes.

Figure 6. This biopharmaceutical production operation relies on disposable products. Source: Sartorius.

A user’s perspective

 

Clearly single-use equipment is gaining increasing acceptance. Lilly provides an illuminating example of a leading manufacturer’s approach to disposables. The company uses disposable bioreactors, buffers/medias, sample bags and connectors, plus more specialized disposable technology such as tangential flow filtration (TFF) and nanofiltration.

“In terms of the suppliers, our big issue is delivery time,” explains Bailey. “When we need something, we usually need it very quickly. For example, we might be making product ‘A’ today, but things change and we need to move to product ‘B’ very quickly. Therefore lead times are the biggest issue.”

Lilly encountererd what Bailey describes as “one of the growing pains of using disposables.” At one point, he urgently needed a very specific tubing set. While two suppliers had the tubing in stock, the disposable connectors required would take 12 weeks to arrive from its manufacturer. “We have now worked this through with our suppliers to identify the longer-term supply items and make sure that they always have them in stock for us.”

This close working with the suppliers also is important to Lilly in terms of technological innovation. For example, when the company first attempted to source a disposable TFF unit, no supplier could help. However, Millipore later came on board and together the companies developed the required unit. “Working with suppliers has proved to be the way forward and we are now working with a number of vendors in order to get exactly what we need,” says Bailey.

While Bailey can understand the process-in-a-box vision of some suppliers, he points to an ongoing challenge — purification . “In terms of the future, one issue for Lilly is membrane adsorbers. We are working in a consortium to understand exactly how they work because membrane adsorbers have the potential to become a key part of our purification process. Also, it would be great is someone could really figure out a method of making disposable on/off chromatography possible,” he concludes.

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