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Foods, pharmaceuticals, and even whole animals for museums are examples of freeze-dried products. The largest

At the end of primary drying, the dew point drops (see the chart on the next page). This indicates the last drop of water

Adding Precision to a Difficult Measurement

freeze dryer market for process moisture analyzers is the pharmaceutical industry. Its products are the most costly and has sublimed and been drawn off by the vacuum pump. Now the shelf temperature can be raised to allow the product to

Freeze Drying End Point Monitoring

have the highest potential for loss if a process is not totally under control. A specific formulation can be tested and approved by the FDA, but marketing the product can be a problem if it has a short shelf life. Freeze drying solves this problem in many products, such as injectable drugs, allowing these medications to be more readily available. As the name implies, the basic function of freeze drying is to remove a solvent (generally water) from a product. While the benefits of freeze drying have been recognized for 50 years, until now the process control has been mainly a manual system. As companies move toward automation, this process will require new methods for determining product parameters. The most critical of these is to determine when the product is dry. An analyzer that shows precisely when the last traces of solvent are gone would be very important for maximizing the throughput of a freeze dryer because it would determine when the process is complete. When the product is a water-based material, General Easterns trace moisture analyzers are able to provide the data necessary to give end point determination. Even if the material requires removal of a mixture of organic solvents and water, our analyzers may provide a relative process reference point to indicate when the solvent is removed. In this Application Note, we'll assume the solvent being removed is water. Extending the shelf life of a product often translates into maintaining some physical or chemical property of a product while removing its moisture. Thus, the first step in the process is to freeze the product to stabilize its structure. The material is loaded on shelves in a vacuum chamber. Coolant is pumped through coils in these shelves to freeze the material. Because the various chemical components in the product may have different freezing, or eutectic, points, the product temperature must be driven lower than the lowest freezing point before the drying phase can begin. Once that point is reached, the vacuum pump is started. As the vacuum is drawn down to roughly 0.1 torr, the ice begins to sublime. The water vapor is drawn off through the vacuum pump and collected on a condensing surface near the product at a temperature of -40. This phase, called primary drying, can last from several hours to several days. Throughout this phase, moisture continues to evolve from the material at a steady rate. This will be indicated on our moisture analyzers as a steady dew point temperature (usually between -31F and -85F (-35C and -65C dew point)). warm up without suffering damage. At this time, the process can move ahead to secondary drying or, if the freeze drying is complete, the container is sealed and the load is removed from the chamber. The moisture analyzer may be able to successfully monitor this secondary drying phase, but it depends on the specific product and how repeatable the results are for that formulation. In the past, it was thought that moisture sensors were too fragile to be of any use in freeze drying measurement. Various pressure and temperature sensors have been used, but all have drawbacks. These weaknesses translate into longer drying times and can mean considerable losses due to ruined product. Temperature and pressure sensors can allow some process control but proponents of using moisture sensors persisted. Research proved that the sensor would work to show the end point more reliably. Then the work to apply this technique to real world production processes began.

The chart at right indicates the sensitivity of the moisture sensor method for detection of vials with incomplete sublimation drying. Product temperature curves F and L represent, respectively, the first and last of the product containers to show dryness by the temperature response criterion. Product temperatures of the overfilled containers is given by the curve labeled O. Point B marks the proposed moisture sensor criterion for the end of primary drying.

Chart reproduced with permission from the Journal of Parenteral Science & Technology, Vol. 43, No. 2, March-April 1989, p. 64.

Using a moisture analyzer to monitor the freeze drying process may seem straightforward, but a special adapter is usually required to get our probes to function successfully throughout the entire process cycle. This is due to the many segments of the process. First, the chamber often must be steam sterilized after each batch. We must use trace moisture probes to detect the moisture in the chamber, however exposure to steam temperatures and moisture content will ruin the probes. Our solution is to isolate the probe with a special fixture. Second, because the entire environment must be sterile, we've included a biological barrier that can be sterilized within the fixture. Finally, since the sensor is only needed to determine when the process is finished,

it is not exposed to the process chamber conditions until the last third of the process. This reduces the exposure to corrosive components contained in some of the solvents used in the manufacturing process. Once the end point is determined and the sensor has done its job, it is isolated by the valve until the next batch. General Eastern has been working with scientists at Eli Lilly for years to perfect this approach to freeze drying process control. We can supply the fixture (see the illustration on the next page) and all components to bolt onto almost any size port available in the chamber. The ideal location, however, is as far away from the vacuum source as possible.

General Eastern Instruments, Inc 20 Commerce Way Woburn, MA 01801 Tel 781-938-7070 Fax 781-938-1071 www.geinet.com