Monitoring of storage and production environments has become an important issue within the Pharmaceutical Industry. The FDA and other regulatory bodies require not only accurate measurement and storage of room parameters but if the storage medium is electronic then the methods used must comply with 21 CFR Part 11.
Stability Monitoring of medicinal products is an area also addressed by the ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use) and the ICH final guidance (agreed Feb 2003), is now being adopted across Europe, Japan and the United States.
The FDA also states in its 21 CFR part 203 section that manufacturers, authorized distributors of drugs and their representatives shall store and handle all drug samples under conditions that will maintain their stability, integrity and effectiveness, and ensure that the drug samples are free of contamination, deterioration and adulteration.
With environmental chambers, temperature, humidity, particulate counts, differential pressure, lighting, gas levels and other environmental conditions can be controlled. This can be extended to equipment required to detect toxic gases and fume hood positions.
Regulatory bodies require that stability facilities have to meet the following criteria:
- Proper documentation, including SOPs and periodical reports
- Chambers and rooms have to be equipped with multiple sensors spread evenly throughout the controlled area
- Generous multilevel shelving providing orderly storage and proper exposure to the controlled environment
- Acceptable monitoring equipment (probes, recorders, etc.)
- Continuous recording of data and full traceability
- Corrective action taken when stability factors go outside the specifications
Alarms and Excursions
Detecting and announcing abnormal condition is a key requirement for the environmental monitoring systems.
Pharmaceutical companies have adopted various methods for capturing and announcing abnormal conditions. These include:
- Alarms if monitored values go outside a predefined value.
- Alarms on excursion conditions being breached (usually a set temperature or humidity for a particular time).
- Intelligent alarms (e.g. “alarm immediately if it is silent hours, after a period if it is during the day” or “delay the alarm if the room door is known to be open”).
- Alarms based on rolling yearly MKT.
- SMS or e-mail alerts triggered by alarms or events
Mean Kinetic Temperature (MKT)
Measurement and recording of temperatures is vital to the storage of perishable goods, but there is more than one way to record an average.
The ICH defines the mean kinetic temperature as being “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”.
MKT expresses the cumulative thermal stress experienced by a product at varying temperatures, during storage and distribution. It differs from other means (such as a simple numerical average or arithmetic mean) in that higher temperatures are given greater weight in computing the average, thus, recognizing the accelerated rate of thermal degradation of materials at higher temperatures.
The mean kinetic temperature is calculated as being:
Tk being the mean kinetic temperature in Kelvin
ÄH is the heat activation in kJoule per mole
R is the universal gas constant in kJoule per mole per Kelvin
T1 and Tn are the temperature samples for periods 1 and n, respectively
n is the total number of periods in the calculation
There are a number of interpretations of how this calculation is achieved using real samples:
- All sample values fed into formula
- Maximum/minimum samples fed into formula separately (recommended by the FDA)
- Arithmetic mean of maximum and minimum fed into formula (recommended in the US Pharmacopeia and by the UK MCA)
Eurotherm offers all the above methods with:
- A choice of stability testing period (hourly / daily / weekly)
- A choice of sampling frequency (from 1 minute to 1 hour)
- Option to remove individual probes from calculation (e.g. during a calibration process)
- Corrective action in case stability is out of specification
- Secure and low cost custom reporting
- Significant reduction of the cost of ownership