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Product Focus: Freeze Dryers

Demand for reliable methods of preparing and storing high-value samples has rejuvenated the market for freeze dryers, also known as lyophilizers.

Angelo DePalma, PhD

Angelo DePalma is a freelance writer living in Newton, New Jersey. You can reach him at

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Advanced Control Tops Rich Feature Options

Demand for reliable methods of preparing and storing high-value samples has rejuvenated the market for freeze-dryers, also known as lyophilizers. In response, vendors have transformed freeze-dryers from clunky, homemade agglomerations of pumps, flasks, and cold traps to precision instruments under strict computer control. Freeze-drying removes close to 100 percent of the water from a sample, leaving behind the “bones”—either the structural framework of plant or animal tissues or powdery chemicals, proteins, or residues.

One of the most significant trends in freeze-drying instrumentation has been the integration of lyophilization’s three steps (freezing, primary drying, and secondary drying) into a single, miniaturized instrument. The Triad lyophilizer from Labconco (Kansas City, MO) is one such instrument.

Freeze-drying is hard on vacuum pumps, which is why Labconco includes a moisture detector in the drain lines of some units. The sensor prevents the pump from turning on in the presence of significant moisture. “The last thing you want is to ruin your pump by having it suck in a liter of melted ice,” notes Labconco product manager Jenny Sprung. Pumps can also be ruined, albeit more slowly, by units with coils that cannot handle the volume of sublimate.

Two interesting controller add-ons

Freeze-drying is a dynamic process that requires close control over freezing rate, drying temperature, and pressure in order to prevent product melt-back, which occurs when the product temperature rises above its critical point.

Product temperature is controlled by adjusting the shelf temperature. It may still vary significantly, however, depending on its thickness, the solids content, the thickness of the dry layer during primary drying, and the equipment’s condensing rate and heat transfer dynamics.

Historically, drying temperature is adjusted by trial and error until a suitable freeze-drying process is established for a particular quantity of a specific product. Subsequent runs are conducted according to that protocol, without in-process temperature monitoring.

This empirical approach requires numerous trial runs, which may be unreasonable to perform at scale with very high-value products. “So the goal should be to achieve an acceptable freeze-drying protocol in a single test run,” says T.N. Thompson, president of Millrock Technology (Kingston, NY). Millrock has championed a technique, Auto-Dry, to assist in achieving rapid optimization.

Auto-Dry is a lyophilization optimization strategy that generates a baseline protocol based upon user input. It consists of a software algorithm and a PLC (programmable logic controller) that can replace the existing controller.

Once the baseline protocol is established, the freeze-dryer automatically adjusts the shelf temperature to minimize freeze-drying time while keeping the product well below its critical temperature.

Auto-Dry automatically detects the end of primary drying and advances to secondary drying using either a conservative or an aggressive profile.

With conventional freeze-drying the operator needs to monitor product temperature and manually adjust shelf temperature over the entire course of the lyophilization. The result is typically a long, conservative cycle. But as Mr. Thompson notes, “Reducing lyophilization time is critical for keeping operating costs to a minimum.”

Millrock offers a second interesting control-oriented technology, called “instant nucleation,” which promotes uniform nucleation— the initial process in the formation of ice crystals. According to Millrock, uniformity is critical for achieving consistency, shorter lyophilization cycles, and reduced product losses.

Like Auto-Dry, instant nucleation is a software/control add-on that is adaptable to most advanced laboratory (and production) lyophilizers. Some freeze-drying models may require one of these modifications, either in the field or at Millrock’s facility. “The nucleation technology is scalable, doesn’t require an ASME pressure-rated vessel, keeps sterilizable systems intact, and is relatively inexpensive,” says Mr. Thompson. “Pressure-rated vessels are costly and may not be adaptable to standard lyophilizers.”

Not just for liquid samples

Sergey Mareninov, staff research associate at the UCLA school of medicine (Los Angeles, CA), uses a lyophilizer from Labconco to prepare and preserve brain tumor tissues for translational medicine. Human tissues are good candidates for lyophilization because they consist of 85 to 90 percent water.

Mareninov’s methods are a bit unusual for pathology labs, where freezing or chemical preservation are the methods of choice. Conventional sample preparation has the advantages of preserving DNA and RNA. On the downside, these methods require a time investment and, in the case of freezing, an appropriate sample freezer must be maintained.

“With freeze-drying you don’t need a freezer, which in the long term is more environmentally friendly,” says Mr. Mareninov. “And preservation is on par with freezing except for nucleic acids [RNA and DNA], which degrade.” Mr. Mareninov is currently conducting a study to compare formally the advantages and disadvantages of freeze-drying versus standard tissue preservation methods.

Freeze-dried samples may be stored at room temperature, with all anatomical features preserved. Pathologists find lyophilized tumor tissue easy to work with, according to Mr. Mareninov.

What to look for

Lyophilizers come in a variety of configurations with a dizzying array of features. When considering the purchase of a freeze-dryer, Mr. Thompson suggests that all but the most experienced users consult with an expert to determine which features best fit the user’s needs.

Considerations should include contact materials (304 L or 316 L stainless steel), internal or external condenser, condensing rate (liters per 24 hours), condenser temperature (-50°C to -85°C, condenser size (4 liters minimum, to 1,000 L), shelf style (bulk or stoppering), shelf spacing (2 inches to 10 inches), shelf freezing temperature: -45°C or -70°C, shelf area (1 sq ft to 1,000 sq ft), vacuum sensor (Pirani, capacitance manometer, or both), door material (acrylic or stainless steel), and vacuum/pressure rating (vacuum or ASME pressure-rated).

Additional features might include an isolation valve, clean room capabilities, cleaning (clean-in-place, steam, hydrogen peroxide gas), validation and documentation, 21 CFR Part11 software capability, redundant compressors or pumps, and control system (from Allen Bradley, Siemens, etc.).

Angelo DePalma holds a Ph.D. in organic chemistry and has worked in the pharmaceutical industry. You can reach him at