By Dr. Scott Rudge
The ICH has established well known temperature and humidity standards for conducting stability studies that mimic the environments in various parts of the world. Zones I and II correspond to cold and temperate areas respectively, such as North America and Europe, while Zones III and IV correspond to hot and dry or hot and humid climates, like Equatorial Africa, Brazil and lower altitude South America and southern Asia including India. There are exceptions within these regions, to find out the zone for a specific country, you should reference ICH Q1F or WHO Technical Report Series No. 953, 2009. These stability conditions are for pharmaceuticals meant to be stored at room temperature. And it makes sense to consider relative humidity at room temperature, the amount of water in the air can be substantial. But recently, we’ve had clients specifying a relative humidity in refrigerated conditions. This is not an ICH requirement, but perhaps with very moisture sensitive products, it makes sense to specify this and control it.
Relative humidity is a fairly familiar concept. We know that when it’s humid out, it feels
hotter. Your clothes don’t dry, and
neither do you! As I’m sure all the
readers of these posts know, “relative” humidity is the amount of water vapor
in the air relative the air that is saturated with water. This is expressed most conveniently as the
measured partial pressure of the water vapor in the air divided by the vapor
pressure of water at the temperature of the “system”. The vapor pressure of water is a strong
function of temperature, as shown in the following graph:
As the temperature goes towards 0°C, the vapor pressure goes
to zero. It doesn’t reach zero, as ice
also has vapor pressure, but it gets close.
At 2°C, the vapor pressure is 5.2 mm Hg at 8°C, it is 8 mm Hg. So, in the case of a refrigerator, where you
might store pharmaceuticals, whatever humidity is in the refrigerator is
divided by a very small amount of humidity that represents saturation. In fact, you would predict that, at a
constant partial pressure of water, say 4 mm Hg, the relative humidity would
vary with an amplitude of 25% with a temperature range of 4 ± 2°C, as shown below.
We tested this in one of our refrigerators at RMC, and found the actual situation to be a little worse, an amplitude of about 40%. The amount of water in the air in our 13.75 ft3 refrigerator is 1.65 grams. That’s quite a bit of water in the air, but a relative humidity profile that seems more or less uncontrollable.
We tested this in one of our refrigerators at RMC, and found the actual situation to be a little worse, an amplitude of about 40%. The amount of water in the air in our 13.75 ft3 refrigerator is 1.65 grams. That’s quite a bit of water in the air, but a relative humidity profile that seems more or less uncontrollable.
So what’s the answer?
It doesn’t seem that specifying a relative humidity range for a
refrigerator is a great idea. On the
other hand, if you have water sensitive samples that are not otherwise
protected, you are probably playing with fire.
The use of a desiccant and vapor impermeable overwraps that have been
seal tested is probably a requirement.
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