Tuesday, May 1, 2012

Relative Humidity Specification at Refrigerated Conditions

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.
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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