1118 MONITORING DEVICESTIME, TEMPERATURE, AND HUMIDITY
This chapter provides background on the science and technology of temperature and humidity monitoring. It describes the available technologies and their performance characteristics, and it provides recommendations for verification and validation of performance. The shelf life of a drug is a function of the temperature and humidity conditions under which it is stored and transported as well as the chemical and physical properties of the drug substance and preparation. For this reason, the ability to monitor those conditions is important in the shipping and storage of temperature- and humidity sensitive preparations. Historic geographic and seasonal trends may be used as a planning tool in selecting among the types of temperature and humidity monitoring devices. Meteorological forecasts are available for any pertinent location.
TEMPERATURE MEASUREMENT TECHNOLOGIES
The devices described in this section are those most commonly used to monitor temperature in the storage and distribution of drugs in North America. The measurement of temperature at extremes, such as close to absolute zero or above those reasonably expected to be experienced by drugs, is not addressed.
Alcohol or Mercury Thermometers These devices are based on the change in volume of a liquid as a function of temperature. Mercury thermometers are typically used in the ranges from 0 to 50 with a precision of about 0.1. [noteSome local regulations apply to mercury-based thermometers. Alcohol thermometers may have a precision as good as 0.01, but they must be quite large to measure temperatures in ranges of more than a few degrees. Both types of thermometers may be designed to indicate the maximum and minimum temperatures measured. See Thermometers 21.]
Chemical Device This is a device based on a phase change or chemical reaction that occurs as a function of temperature. Examples include liquid crystals, waxes, and lacquers that change phase, and thereby their appearance, as a function of temperature. Such materials represent the least expensive form of temperature measurement, but they may be difficult to interpret.
Other types of chemical sensors include systems in which a reaction rate or diffusion process is used to deduce a temperature equivalent integrated over time rather than the temperature at a specific moment in time such as a spike or critical threshold, for which a separate device may be preferred. Thus, chemical sensors provide a measure of accumulated heat rather than instantaneous temperature. It should be noted that these devices are generally irreversible; once a color change or diffusion process has taken place, exposure to low temperatures will not restore the device to its original state. Accuracy and precision vary widely among different types, to differentiate often limited by their ability or their ability to visually interpret diffusion distances.
Infrared Device This is a device based on measuring the IR radiation from the article whose temperature is being determined; the IR radiation varies as a function of the object's temperature. The advantage of the device is that the article may be at some distance from the IR sensor. However, IR devices are expensive compared to other temperature sensors.
Resistance Temperature Detector (RTD) This is a device based on the change in electrical resistance of a material as a function of temperature. Precision and accuracy depend on the quality of the electronics used to measure the resistance. Therefore, although RTDs are among the most stable and accurate temperature sensors, their accuracy may change with the age and temperature of the device as its electronic components are affected. A particular type of RTD uses platinum or platinum alloy wire as the sensor. These are referred to as platinum resistance temperature detectors (PRT or PRTD).
Solid State Device This is a device based on the effect of temperature on either an integrated circuit (see Thermistor below) or a micromechanical or microelectrical system. These devices can attain the highest precision available and also have the advantage of producing a digital output. Their accuracy is typically limited by the accuracy of the calibrating system employed.
Thermistor This is a semiconductor device whose resistance varies with temperature. Thermistors are able to detect very small changes in temperature. They are accurate over a broad range of temperatures.
Thermocouple This is a device based on the change in the junction potential of two dissimilar metals as a function of temperature. Many metal pairs may be used, with each pair providing a unique range, accuracy, and precision. Precision and accuracy depend on the quality of the electronics used to measure the voltage and the type of temperature reference used. Accuracy may be a function of temperature reference used. Thermocouples have relatively poor stability and low sensitivity, but are simple and cover a wide temperature range.
Thermomechanical Device This is a device based on the change in volume of a solid material as a function of temperature. For example, a mechanical spring, which expands or contracts as a function of temperature, thus opening and closing an electrical circuit or moving a chart pen, is such a device. Precision may be as good as 0.05, but in practice it is rarely better than 0.5. Accuracy is often in the range of ±1.0, but it may change with the age and temperature of the device.
Timetemperature integrators, commonly referred to as TTIs, change color or physical appearance as a result of exposure to a temperature above a specific threshold for a specific time duration, and thus accumulate heat. TTIs are typically single use, disposable devices that react irreversibly. Once the color changes, it will not revert to the original one even if the temperature returns to the acceptable, normal range. The four basic types of chemical-based TTIs are described below.
Table 1 lists the four types of chemical TTIs presently in use. The closer the activation energy of the TTI's color change to the activation energy of the degradation process of the drug being monitored, the more accurately the TTI will reflect the status of the drug. In actual practice, the activation energy for degradation of a particular drug is not known precisely enough to enable selection of a particular type of TTI. The range of possible activation energies of a TTI is given in the table to provide a sense of the flexibility of that particular technology. A TTI with a range of possible activation energies can be configured to cover a wider range of time and temperature thresholds.
Table 1. Characteristics of TTI Technologies
An important characteristic of chemical TTIs is the precision with which the endpoint can be determined. It is difficult to quantify an indication such as a gradual color change. Accuracy may also vary widely with the control and quality of the manufacturing process. As discussed below in Validation of Temperature and Humidity Monitoring Devices, it is not possible to calibrate an individual chemical TTI because the test is, by the nature of the device, necessarily destructive. Chemical timetemperature indicators are relatively inexpensive and may be customized for a wide range of applications.
ChemicalPhysical Based TTI This type of TTI is based on a temperature-dependent diffusion/chemical reaction process. It consists of a pressure-sensitive tape structure, which is composed of an indicator tape and an activator tape. The indicator tape contains a dye dispersed in a polymer carrier. The activator is incorporated into an adhesive on the activator tape. Laminating the activator tape over the indicator tape causes activation. A color change or readable message occurs as the activator migrates into the indicator as a function of temperature and time. These TTIs can be manufactured to provide a wide array of timetemperature configurations. Also, because they can be made using a printing process, they can be directly integrated into a product label or provided as a stand-alone label if required.
Chemical Polymerization Based TTI This type of TTI uses a polymerization process in which a color change occurs as a function of time and temperature. The color change happens when a small, colorless molecule polymerizes into a larger, colored molecule on exposure to temperatures above a specific threshold for a specified period of time. These TTIs can be applied as print process, permitting direct integration into a product label or stand-alone label. Since this type of TTI does not require activation, it must be shipped from the manufacturer on dry ice and stored at temperatures below freezing prior to use. Chemical polymerization based TTIs have somewhat limited selections of timetemperature threshold configurations.
Diffusion Based TTI This type of TTI is composed of a color-dyed fat, an ester that diffuses along a porous filter paper strip or wick once the temperature exceeds the melting point of the ester. The distance the colored fat migrates is a function of the time the TTI is exposed to temperatures above the melting point of the ester. Removing a barrier film that separates the dyed fat from the wick activates these devices. They can be modified for various applications by selecting esters of different melting points, and by changing the length of the wick. These TTIs are contained within their own packaging and have limited timetemperature threshold configurations.
Enzyme Based TTI This type of TTI uses an enzyme-catalyzed color generating reaction that occurs as a function of time and temperature. The color change is caused by esterase hydrolysis of a fatty substance, accompanied by a decrease in pH. The enzyme and the fatty substrate are in separate solutions in adjacent compartments. Breaking the barrier between the two compartments and mixing the two solutions activates the device. Enzymatic reactions provide a wide variety of timetemperature configurations.
ELECTRONIC TIMETEMPERATURE HISTORY RECORDERS
These devices, which may serve as an alternative to chemical-based TTIs, use one of the electronic temperature measurement technologies described above and create a record of the temperature history experienced by a device. Some are simple electronic devices that record and save temperature values representative of the cumulative temperature history over a period of time. These may be designated as electronic TTIs. They have the advantages of being able to calculate the Mean Kinetic Temperature (MKT) based on the measurements recorded and they can be calibrated.
Data Loggers A more capable device records the temperature at very short intervals and is able to download the temperature history record to a peripheral system, such as a personal computer. Such devices may be termed electronic temperature data loggers. In addition, data loggers may record the humidity using sensors described below. Data loggers may be permanently fixed within a storage facility or they may be portable and travel with a product. Data loggers equipped with transmitting devices (hard-wire or radio transmission) can be used to monitor temperature and humidity of a product while in transit, with the ability to download the recorded data when the data loggers arrive at a destination.
RELATIVE HUMIDITY MEASUREMENT TECHNOLOGIES
Relative humidity may be defined as the ratio of the observed partial pressure of water vapor in a volume of air to the saturation pressure at that temperature. In other words, the relative humidity is the amount of water vapor present divided by the theoretical amount of moisture that could be held by that volume of air at a given temperature. Extensive tables of data are available. Devices for measuring relative humidity are called hygrometers. Several different technologies exist for measuring relative humidity.
Sling Psychrometer The simplest type of hygrometer is based on the temperature difference observed between two identical thermometers, one ordinary, and one with a wet cloth wick over its bulb. The two thermometers are whirled at the end of a chain, and the evaporation of water from the wick cools the wet bulb thermometer. The temperature difference between the wet and dry thermometers is then compared to a table, specific to that psychrometer, based on dry bulb temperature, and the relative humidity is determined. The use of a sling psychrometer in a commercial setting is impractical.
Hair Hygrometer This type of device is based on the fact that the length of a synthetic or human hair increases as a function of the relative humidity. This change is used to move an indicator or affect a strain gauge. A hair hygrometer can be accurate to ±3%, but it is unable to respond to rapid changes in humidity and loses accuracy at very high or very low levels of relative humidity.
Infrared Hygrometer This type of hygrometer determines relative humidity by comparing the absorption of two different wavelengths of IR radiation through air. One wavelength is absorbed by water vapor and the other is not. This type of hygrometer can accurately measure relative humidity in large or small volumes of air. It is sensitive to rapid changes of humidity and can be integrated with an electronic data handling system.
Dew Point Hygrometer This type of device uses a chilled mirror to determine the dew point of an air sample. The dew point is the temperature at which water vapor in the air begins to condense, that is, the temperature at which the relative humidity is 100%. From this measurement and an accurate measurement of the ambient temperature, the relative humidity can be calculated. The dew point hygrometer is the standard against which most commercially available instruments are calibrated.
Capacitive Thin-Film Hygrometer The principle of this type of hygrometer is that the dielectric of a nonconductive polymer changes in direct proportion to the relative humidity. This change is measured as a change in capacitance. This type of hygrometer is accurate to ±3%.
Resistive Thin-Film Hygrometer This type of hygrometer is similar to the capacitive thin-film type in that it uses the effect of changing relative humidity on an electrical circuit. In the resistive thin-film hygrometer the sensor is an organic polymer whose electrical resistance changes in logarithmic proportion to the relative humidity. This type of hygrometer is accurate to ±5%.
VALIDATION OF TEMPERATURE AND HUMIDITY MONITORING DEVICES
Thermometers and hygrometers, used to provide data about the temperature and humidity exposure of a product, must be suitable for their intended use. Specifically, they must be appropriately validated. Validation is a process that assures the user of the monitoring device that the device has been tested prior to use either by the manufacturer or the user, to assess the measurement accuracy, measurement responsiveness, and time accuracy, where appropriate. Monitors used in manufacturing, storage, and transport of drugs should be properly qualified by their users to ensure that the monitors have been received and maintained in proper working order. Pharmacies and consumers may accept the validation performed by the manufacturer of the device.
Measurement Accuracy For temperature and humidity monitoring devices, measurement accuracy refers to the closeness of the value obtained with a particular device to the true value being measured. In practice, this is determined by comparison with a device that has been calibrated against a standard that is obtained from or traceable to the National Institute of Standards and Technology (NIST).
Measurement Responsiveness Any monitor takes time to respond to a change in the temperature or humidity. The more rapid the response, the clearer the picture of the environmental history of a monitored product will be. Measurement responsiveness may be defined as the time, t½, required for a device to read a value of (x + y)/2 after an instantaneous change in the property being measured from x to y. Measurement responsiveness is typically defined for the operating range of a device.
Different levels of responsiveness are needed for different monitoring applications. For devices used to monitor storage locations, where the temperature and humidity are unlikely to change rapidly, a t½ 15 minutes may be appropriate. For devices used to monitor transport, where more rapid changes are possible, a t½ 5 minutes may be needed.
Time Accuracy Most commonly, time accuracy is expressed as a ± percentage of total duration of the recording period. For pharmaceutical applications, a ±0.5% time accuracy is adequate.
Validation of Chemical-Based TTIs This type of device presents a problem for validation because testing the individual device causes its destruction. For this reason, calibration of individual chemical-based TTIs against an NIST traceable standard is not possible. Ideally, chemical-based TTIs would be made using Good Manufacturing Practices, and their use in connection with monitoring the storage and transport environment of drugs would be appropriately regulated. In the absence of those conditions, the performance of a batch of these devices may be assessed statistically by subjecting an appropriately sized sample to elevated temperature conditions for a set period of time and observing the results. Appropriate acceptance criteria should be adopted.
THE USE OF HISTORIC TEMPERATURE DATA
It is clear that the type of temperature monitoring needed is a function of the environmental conditions that can be expected. Therefore, climatic data are useful when selecting the most appropriate local storage conditions and monitoring methods. For example, an inexpensive limit detector may be all that is needed when there is a low probability that excessive temperatures will be experienced. Alternatively, a data logger may be preferred when it would be useful to demonstrate that exposure to the highest temperatures was very brief.
It should be noted, however, that outside temperatures are not necessarily reliable indicators of the temperatures experienced by different items in the distribution chain. For example, recent studies reported significant departures from ambient temperatures on summer days for mailboxes, trucks, and warehouses. Detailed historical temperature data are available from the National Oceanic and Atmospheric Administration showing the daily mean maximum and minimum temperature on any given day of the year in a geographical region of interest (e.g., http://www.cdc.noaa.gov/Usclimate/states.fast.html).