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<1118> MONITORING
DEVICES-TIME,
TEMPERATURE, AND HUMIDITY-General Chapters
1118
MONITORING DEVICES—TIME, 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 temperatureand 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 . [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 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.
TIME–TEMPERATURE INTEGRATORS
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
Table 1. Characteristics of TTI Technologies
Type
Chemical–
Physical
Storage
Controlled room
temperature
Activation
Energy
(kcal/mol) Indication
13–80
Readable
message
or image
Placement
Activation
Primary label
or
primary
package
Placement of
activator
tape
over
Type
Storage
Activation
Energy
(kcal/mol) Indication
Placement
Activation
indicator
Polymerization
Diffusion
–44
Controlled room
temperature
21 or 37 Readable
message
or image
9.8
Progressive
color
diffusion
observed
through clear
window
Primary label
or
primary
package
Removal
from
frozen
environment
Primary
package
Removal of
barrier film
Primary
Breaking seal
8–30 Color change
Controlled room
package
to mix
observed
temperature;
liquids
through
cold for
clear window
extended
storage
lists the four types of chemical TTIs presently in use. The closer the activation energy
Enzymatic
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.
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
time–temperature indicators are relatively inexpensive and may be customized for a
wide range of applications.
Chemical–Physical Based TTI— This type of TTI is based on a temperaturedependent 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 time–temperature
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 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.
ELECTRONIC TIME–TEMPERATURE 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, a data logger may record the humidity using
sensors described below. A data logger may be permanently fixed within a storage
environment or it may be portable and travel with a product.
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).
Auxiliary Information— Staff Liaison : Desmond G. Hunt, Ph.D., Senior Scientific
Associate
Expert Committee : (PS05) Packaging and Storage 05
USP29–NF24 Page 2976
Pharmacopeial Forum : Volume No. 29(1) Page 206
Phone Number : 1-301-816-8341
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