Mixer Developments Create a Stir

The technology is used extensively in fermentation processes -- including for production of monoclonal antibodies and viruses, insect cell culture and cGMP manufacturing. Scales range from bench-top systems as small as 100-ml to production-scale units of 500-l working volume.

However, the bag is quite complex due to the need for aeration, inoculation, sampling and acid/base addition. So GE now has launched a simpler single-use bag for basic liquid mixing applications. The M Bag does away with the need for a mixing tank or a conventional mixer and, like the Wave Bioreactor, also obviates cleaning, sterilization and validation. The bags, which range in size from 20-l to 600-l, come with a large screw-cap port for the easy addition of powders and other solids, as well as fill and sample lines. They also can be customized to suit an end user's individual processes. If larger-scale more-aggressive mixing is required, GE offers versions with a built-in impeller.

Demand also is growing for more sensing technologies.The company already offers dissolved oxygen, pH, carbon dioxide and oxygen sensors via miniature fiber-optic microprobes. "The ultimate goal here would be to integrate every probe that you might want in the bag to give all the required data in real-time. Going forward, there is a lot of interest in RFID too, as the wireless format makes everything much easier for operators," says Rich Ferraro, senior product manager.

While originally developed to avoid cleaning and validation issues, today the technology has evolved into a route for flexible manufacturing. "Remember that it avoids large capex [capital expenditure] and the hardware is generally off-the-shelf, too," he notes.

Ferraro believes that some innovations developed for use by bioprocessing and pharmaceutical companies eventually will find their way into mainstream chemical processing as the focus there also shifts to more flexible manufacturing techniques.

"In chemicals processing you run into issues that you don't see in bioprocessing -- for example, the different fluid viscosities and solids loadings as seen in slurries. There is only so much shear force or energy input that a disposable impeller or Wave format can do in these situations before you run into performance issues," he admits. "We'll need a more elegant yet cost-effective solution going forward for the fine chemical or small molecule industries and some companies are already working on this."

He cites GE's collaboration with ILC Dover, Frederica, Del., which has developed a novel mixing technology based on an internal perforated septum moving through the bulk fluid. This creates fluid jets capable of mixing solutions with viscosities up to 100,000 cP. Single-use units are in the offing. "This type of technology may find a home in the fine chemical and pharmaceutical industries in the near future," he adds.

Meanwhile, business developments are stirring up the disposables sector. Merck, Darmstadt, Germany, in late February announced its acquisition of Millipore, Billerica, Mass., for $7.2 billion.

Like GE, Millipore has a strong focus on the single-use market and its Mobius family of mixing systems delivers advanced technology for mixing pharmaceutical ingredients from intermediate to final drug products and for preparation of process solutions such as buffers and media.

Described by the company as the only single-use mixers that are part of an integrated solution, Mobius MIX100, MIX200 and MIX500 systems include, respectively, a 100-l, 200-l or 500-l container with a magnetically driven impeller and an electronic drive unit (Figure 2). A variety of filter, connector and tubing options enable tailoring to a specific application and environment, including sterile interfaces, from fermentation to final fill. The single-use mixing systems also are available with stainless-steel carriers with and without external-heat exchange jackets.

Enduring Solutions
Disposables aren't the answer for all mixing chores requiring sterility, however. Some services call for capabilities that only can be provided by heavier-duty equipment. Innovations are emerging here, too. Indeed, future success in pharmaceutical processing depends on adopting such new technology, believes Peter Matthews, technical manager of Silverson Machines, Chesham, U.K. and East Longmeadow, Mass. He cites his firm's UHLS ultrahygienic in-line mixers and Flashblend mixing system as examples.

One veterinary vaccine maker links two vessels side-by-side with a UHLS in-line mixer, which is used to pass product back and forth to achieve the required level of mixing. "Remember that for some customers it is essential to know exactly how much shear a product has been subject to -- something which can be very costly in terms of time and equipment to establish," he notes.

Another long-term challenge is preventing loss of a powder's sterility when it's being added to a mixing vessel. With the Flashblend mixing system, the company has focused on eradicating dead areas, crevices and any other hindrance that might lead to contamination. "We've gone down to the nth degree on this one -- with the result that there is no horizontal pipework anywhere on the units."

A recent application at a U.S. pharmaceutical company that manufactures a product containing a particularly toxic ingredient underscores the system's value, he says. "While degowning, operators were still at risk of coming into contact with the toxic powder. The solution here was to put the powder into a containment unit -- a bag -- which is then introduced into the Flashblend via a total containment valve. So the operator is completely divorced from the ingredient and the product. More and more [companies] are now actively looking for solutions like this, both to apply health and safety regulations and to handle raw materials and products more effectively."

In the future, the location where mixing occurs could change as the size of cleanrooms will be drastically reduced, he believes. "The cost to build a cleanroom is phenomenal, so if you can minimize the size of it, for example, by external mixing, you can reduce the capex. And we are beginning to see some technologies go this way. For example, we are just opening a cleanroom for a company in France. It's very small and the operator passes the powder direct to the vessel from outside the area. In another example, an operator has a 5,000-l vessel in the technical area, with the clean room on the floor above for access."

Rotating jet nozzles are prominent in the efforts of Alfa Laval, Lund, Sweden, and Richmond, Va. It offers mixers with two or four such nozzles positioned under the liquid surface at the top of a tank. A variable speed pump circulates liquid to be mixed through the tank in a closed-loop system. The resulting flow drives a gearing system in the rotary jet mixer that causes the nozzles to rotate around both the horizontal and vertical axes (Figure 3).

This double rotation produces mixing action throughout the entire tank volume, reportedly resulting in fast and efficient mixing of the injected liquid, gas or powder. The rotary jet mixer also may be used for cleaning the tank by feeding cleaning fluids through the nozzles.

For Ekato Mixing Technology, Lörrach, Germany, and Ramsey, N.J., a long-term focus has been on viscous systems. The company's latest equipment is the modular Paravisc system that can handle viscosities from 1 mPas to 1 million mPas. In addition, it can be combined with baffles, wall scrapers or independently driven additional mixers (coaxial or with excentric two-shaft systems) as necessary.

Meanwhile, APV, a unit of SPX, Charlotte, N.C., is working to keep air from entering as powders are added to liquid in a mixing tank. The air can can pose problems in processing foods and beverages, among other products, by causing foaming, clogging and lumps, and hindering full dissolution of powders. The company combats the problem with a surprisingly simple solution. The Flex-Mix Instant inline batch mixer uses vacuum to draw powder under the liquid, minimizing the amount of air that enters the mix.

For its part, Chemineer, Dayton, Ohio, which offers a diverse range of impeller technology for sanitary applications, places an emphasis on cleanability. The company evaluates all components in its mixing systems, from welds to impellers, to ensure mixing surfaces promote free draining of liquids.

Seán Ottewell is Chemical Processing's Editor at Large. You can e-mail him at [email protected].