Liquid Mixing: Solid Challenges

For consistency and success, there’s no substitute for experience and power.

By Angelo De Palma, Ph.D., Contributing Editor

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Liquid mixing and blending would seem to be among the most straightforward of pharmaceutical manufacturing unit operations. Mechanical process mixers have been on the market for more than 100 years, and not much separates mixers for drug making from those used in food and chemical industries.

“Sanitary features are the only distinguishing characteristic of pharmaceutical-grade mixers,” says Kevin McNamara of MixMor (Los Angeles). In business for more than half a century, MixMor serves the gamut of process industries but custom-designs most of its pharmaceutical-grade liquid mixer/blenders. Customers pay a premium — between $1,000 and $5,000 — for smooth vessel and impeller designs and all-stainless construction.

Many liquid mixing/blending operations are indeed straightforward — those involving two similar liquids, for example. They get complicated with very dissimilar fluids, such as oil and water, or whenever solids are involved. For very thick slurries, manufacturers begin to worry about uniformity, time-to-blend, and the horsepower of mechanical blending units. And for additives that may crystallize or combine with water, one must be on the lookout for the ultimate disaster of a blend: solidifying to rock-hard consistency, right in that brand-new, $100,000 stainless steel reactor.

In the GEA Diessel Continuous In-Line Blending System, ingredients are received directly from plastic totes provided by suppliers. Courtesy of GEA Diessel.
Like all pharmaceutical manufacturing operations, liquid blending is changing as companies warm to the idea of in-process monitoring and more formal process analytic technology. “Companies are now blending and mixing on the fly, unafraid of multivariant parameters,” says Tim Hoover, business development manager for GEA Liquid Processing (Columbia, Md.). “Instead of blending through a series of large stainless steel batch tanks, processors can take raw materials, blend them continuously, and send the result directly to the filler. We’re moving away from the stainless steel tank and batch mentality.”

The advantage of all this is lower capital costs for “tank farms,” less processing floor space, lower facility costs, and elimination of much of the cleaning and cleaning validation associated with large-scale processing.

Borrowing technology from parent company GEA Diessel, GEA developed continuous blending/mixing equipment that de-aerates liquid components and assures that meters are continuously calibrated to the process stream. GEA is working with instrument vendors to include downstream, on-the-fly monitoring of component concentrations. “It’s a question of marrying instrumentation technology with our mechanical metering systems,” Hoover notes.

Blending for consistency

Bioprocess chromatography is considered a high-risk operation because of variability in columns, chromatography resins and packing, and buffer flow and composition. TechniKrom, Inc. (Evanston, Ill.) has developed modular process skids which, through an innovative mix-and-measure scheme, minimize buffer variability. The idea: eliminating controllable variability (buffer composition) allows greater vigilance, and feedback, over more intractable sources of error.

Premixed bioprocess buffers prepared in large tanks may vary in composition by 3% to 10%. This variation principally results from mixing anomalies, temperature and concentration gradients within the tank, difficulty in measuring component feed, feedstock quality variability, mixing inefficiencies, and human error.

Observing that a great deal of variability disappears when mixing in small volumes, TechniKrom developed a buffer dilution/blending system that manages composition variables in a relatively small volume at a time, monitoring and controlling feedstocks at millisecond intervals, only delivering to the process when the blend is perfect. The sequence of mix, measure, control and deliver repeats, continuously and rapidly, until the desired volume is reached, thus nearly eliminating aggregate variability from all sources on the fly, before delivering the buffer to the next process step. TechniKrom claims blend accuracies as low as 0.1%, and has demonstrated its approach at flow rates ranging from 25 ml to 250 liters per minute, regardless of gradient type.

By contrast, conventional buffers are blended by addition of volumes of pre-mixed components. These systems use accurate flowmeter feedback but lack monitoring of the actual blend composition. Since premixed input components vary significantly by composition, the result is variable blends: Lack of quality in, lack of quality out.

“We learned very early to focus on accurate, low variability blending, since in LC applications such as protein separations a very small change in the mobile phase has a big impact on quality,” says John Walker, VP of Engineering. “Only when the controllable variability elements have been driven out of a process can a developer clearly determine the underlying effects of the remaining parameters, and then design the appropriate process controls to guarantee quality by design.”

Since the technology is modular, it may be deployed for almost any process requiring buffer, for example integration into a chromatography skid, as an add-on upgrade, or as a free-standing buffer dilution skid.

TechniKrom has specialized in process-scale liquid chromatography equipment for some time. The company’s offerings include custom-configured, modular, PLC- and HMI-controlled process skids featuring highly accurate delivery of liquid components for ultrafiltration and process/chromatography buffer solutions.

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