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David Trew

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STABILITY STUDIES ON PHARMACEUTICALS

PART 2

Using Mean Kinetic Temperature to Access the Impact of Storage Temperature Excursions

Stability studies carried out on drug substances and drug products are an essential component of all drug development programs. The samples used in stability studies must be stored under tightly controlled conditions of temperature and relative humidity. Typically, the allowed variations are ± 2 °C for temperature and ± 5 %RH for humidity. Stability samples are normally stored in incubators or stability chambers, which are able to maintain the conditions of temperature and humidity to within the required tolerances. The temperature and humidity inside stability storage incubators should also be continually monitored and recorded, and an alarm should be activated in the event one of the monitored parameters falls outside the specified range for more than a specified time period and appropriate corrective action should be taken.

However, incubator breakdowns and malfunctions can occur when the laboratory is closed, either overnight, at the weekend, on an extended weekend or during the extended Christmas holiday. When this happens the question that needs to be addressed is should a member of staff be on call out to come in to the laboratory to correct the malfunction or at least relocate samples to a properly functioning incubator. Such arrangements can be disruptive of employee’s family and social lives as they need to be readily contactable and be able to respond to a call out.

In Part 1 of this series of articles, I discussed how a single calculated Mean Kinetic Temperature (MKT) can be used to simulate the thermal effects of temperature variations over time. The Mean Kinetic Temperature calculation is derived from the Arrhenius equation and is an exponential function reflecting the exponential dependence of rate of chemical reactions on temperature. The Mean Kinetic Temperature is given by:

Where:

E = Activation Energy

R = Universal Gas Constant (8.314 J/°K mol)

t = Temperature

n = number of temperature time points  

In this article I will show how temperature excursions of differing magnitudes and duration impact the MKT and thus the thermal effect on the stability samples. I will do this using a series of thought experiments to investigate the effect of temperature excursions occurring during representative periods when a laboratory would be closed on the mean kinetic temperature.

Experimental Methodology

All thought experiments will use a total study period of four weeks (28 days); this is the usual shortest time period between stability test time points. There will be a total of 84 temperature time points, reflecting three temperature time points per day each time period is eight hours.

The representative duration of the temperature excursions will be 16, 64, 88, 112 or 232 hours, these represent closures of the laboratory overnight, a weekend, a three day weekend, the Easter weekend  and the Christmas holidays in England, respectively.

Results and Discussion

In the first scenario, the experiments simulate temperature excursions of 5, 10, 15 and 20 °C in a stability incubator set at 25 °C. In this set of experiments the baseline MKT was 24.9 °C simulating a normal operation of the incubator without any temperature excursions. The results for this series of experiments are presented in Table 1.

In the second scenario, the experiments simulate temperature excursions of 5, 10, 15, 20, 25, 30 and 35 °C in a stability incubator set at 40 °C. In this set of experiments the baseline MKT was 39.9 °C simulating a normal operation of the incubator without any temperature excursions. The results for this series of experiments are presented in Table 2.

The results show that the mean kinetic temperature is not greatly changed by the simulated temperature excursions investigated. Applying the usual tolerance of   ± 2 °C used in stability studies, of all of the scenarios investigated only an excursion of at least 10 °C lasting longer than five days will take the MKT outside the temperature acceptance criteria.

Conclusion

In conclusion, stability studies would not be affected by a temperature excursion of five days or less and consequently there is only any need to establish call out arrangements to respond to a stability chamber malfunction if the laboratory is to be closed for a period of longer than five days.    

MKT =

E/R

n

e-E/Rt1 + e-E/Rt2 +…..e-E/Rtn

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