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AND HUMIDITY
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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 . [note—Some 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
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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.
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.
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.
TIME–TEMPERATURE INTEGRATORS
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Time–temperature 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
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not possible to calibrate an individual chemical TTI because the test is, by the nature of
the device, necessarily destructive. Chemical time–temperature indicators are relatively
inexpensive and may be customized for a wide range of applications.
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 time–
temperature 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
time–temperature 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 time–temperature configurations.
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
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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 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.
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.
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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%.
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.
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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.
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.asp).
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