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.

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.

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.

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.

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.

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.

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.

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).