Continuous temperature monitoring is the perfect way to ensure that the environment where medicinal products are stored meets the product requirements and reduce human interaction. All reporting can be done at the push of a button and the pharmacy team can focus on their patients.

In order to ensure that the temperature data loggers are located in the area that experience the extremes of fluctuations, an initial temperature mapping exercise should be carried out under representative conditions. Further to a risk assessment, the temperature mapping should be repeated on a regular basis.
The storage and distribution temperatures defined by the U.S. Pharmacopeia (USP) are the following:

• Liquid Nitrogen (submerged): -196°C.
• Liquid Nitrogen (vapor phase): -150°C.
• Dry Ice: -80°C.
• Frozen: -25°C…-10°C.
• Cold/Refrigerated: 2…8°C.
• Cool: 8…15°C.
• Controlled Room Temperature (CRT): 20…25°C.

The equipment used to monitor the environment where the medicinal products are stored should be calibrated at regular intervals, also defined by a risk assessment. The calibration should be traceable to a national or international standard.

The Rotronic Monitoring System (RMS) is a GAMP©5 category 4 software combined with category 1 hardware, helping users monitor their GxP compliant applications, looking into the critical quality attributes and monitoring critical process parameters, helping focus on patient safety, product quality and data integrity and compliant to EudraLex Annex 11 and FDA 21 CFR Part 11.

The USP 1118 Monitoring Devices – Time, temperature and humidity offers an overview of the measurement devices that can be used and explains the various technologies. Rotronic employs the following technologies for the wired or wireless electronic data loggers:

As a regular calibration is required, the reminder function within RMS will help define and remind when a device requires a new calibration.

Temperature sensors:

• Resistance Temperature Detectors (RTD): Pt100 and Pt1000's
• Thermistors: NTC's

Relative humidity sensors:

• Dew Point hygrometer
• Capacitive Thin-film hygrometer

RMS allows the user to configure each measuring points with a warning (pre-alarm) and an alarm. Both the warning and the alarm can be configured with a delay (for example for differential pressure) as well as a hysteresis. Notification repetitions can be setup to ensure that critical events are not forgotten, warnings and alarms can be sent via E-Mail, SMS and telephone call.

RMS will allow for specific users to adapt the various levels to ensure that optimal levels are maintained: all changes are documented within the audit trail, stating the user who made the changes, the time stamp and the values before and after the change.

All level excursions are easily and quickly visible within RMS. Each event can be acknowledged and commented so that in case of an audit all relevant information is available. RMS has been built up on a digital level, so any hardware changes will also be visible within the RMS audit trail.

RMS offers a range of additional calculations to help the users get the most out of their system.

The mean kinetic temperature is the total influence of temperature on an object or product over a certain period of time.

Extract from the ICH Topic Q 1 A (R2): Stability Testing of new Drug Substances and Products:

Mean kinetic temperature: a single derived temperature that, if maintained over a defined period of time, affords the same thermal challenge to a drug substance or drug product as would be experienced over a range of both higher and lower temperatures for an equivalent defined period. The mean kinetic temperature is higher than the arithmetic mean temperature and takes into account the Arrhenius equation.

When establishing the mean kinetic temperature for a defined period, the formula of J. D. Haynes (J. Pharm. Sci., 60:927-929, 1971) can be used.

TK is the mean kinetic temperature in kelvin.
ΔH is the activation energy (in kJ mol-1).
R is the gas constant (in J mol-1 K-1).
T1 to TN are the temperature at each of the sample points in kelvin.
t1 to tn are the time intervals at each of the sample points.

RMS offers a calibration management tool. On one side, all devices can be calibrated within RMS, offering a complete traceability to a national or international measurement standard. Calibration reports can also be generated and documented within RMS.

As a regular calibration is required, the reminder function within RMS will help define and remind when a device requires a new calibration.