THE FACTS ABOUT PHOTOSTABILITY ACCORDING TO ICH Q1B
In the pharmaceutical environment, photostability is the stability of drug substances and drug products to light exposure, and though seemingly a simple concept, is one of the most confusing and misunderstood techniques currently employed.
Photostability requirements are defined in the International Conference on Harmonization (ICH) Guideline Q1B entitled Guidance for Industry Q1B Photostability Testing on New Drug Substances and Products. In order to understand photostability as defined by Q1B, we must look at what Q1B actually requires.
There are three basic components of photostability that need to be examined. These are:
· Light sources
· Exposure
· Measurement of exposure
Light Sources - Q1B allows for one of two light sources.
Option 1:
"Any light source that is designed to produce an output similar to the D65/ID65 emission standard such as an artificial daylight fluorescent lamp containing visible and ultraviolet outputs, xenon or metal halide lamp."D65 is the internationally recognized standard for outdoor daylight as defined in ISO 10977 (1993)."
Option 2:
"A cool white fluorescent lamp designed to produce an output similar to that specified in ISO 10977 (1993); and"
"A near UV fluorescent bulb having a spectral distribution from 320 nm to 400 nm with maximum energy emission between 350 nm and 370 nm; a significant portion of UV should be in both bands or 320 nm to 360 nm and 360 nm to 400 nm."
Option 1 sounds nice, since it only requires exposure to a single bulb. Unfortunately a true D65 lamp doesn't really exist. That is why Option 1 specifies an output similar to that of a D65 emission standard. ISO 10977 is a standard that deals with color illuminants, i.e., illuminants that are used for evaluation of color. ISO 10977 has absolutely nothing to do with photostability. The D65 output is very complicated and cannot be exactly duplicated using a single lamp. D65 is short for D6500, which means that the color temperature of a D65 lamp is 6500 degrees Kelvin. D65 is meant to simulate a northern arctic light at noon, supposedly the light under which colors can be most accurately evaluated. A true D65 lamp should have a full white light spectrum plus UV-A between 320 and 400 nm in a single lamp.
All fluorescent lamps have a color temperature and a color rendering index (CRI). Natural sunlight is given a CRI value of 100. The closer a bulb's CRI is to 100, the better is its ability to show colors relative to natural sunlight. In the United States there are a number of fluorescent bulbs available. Among these are:
· Warm white: low CRI and color temperature of about 3000 degrees Kelvin
· Cool white: moderate CRI and a color temperature of about 4100 degrees Kelvin
· Full spectrum: Good CRI and a color temperature of about 5000-5500 degrees Kelvin (noon sunlight )
· Artificial daylight: Good CRI and a color temperature of about 6500 degrees Kelvin (arctic noon sunlight)
The artificial daylight lamps having a color temperature of 6500 degrees Kelvin would seem to fit the bill, however since UV-A phosphors are generally not included, the UV-A output is deficient. D65 lamps that meet Q1B Option 1 are available from Europe or Canada but to the best of my knowledge are not sold in the United States. In addition, these lamps are quite expensive.
D65 can also be simulated with metal halide lamps or Xenon lamps, but these are not recommended due to cost and safety considerations. Metal halide lamps for example can cost $200 and up per bulb, are at risk for explosion and generate a lot of heat.
Option 2 is much more practical since cool white and UV-A bulbs (black light bulbs) can be purchased locally and are readily available. In addition, the spectral power distribution curve for cool-white fluorescent lamps meets ISO 10977 requirements.
Exposure
Q1B specifies minimum exposures of 1.2 million lux-hours for white light and 200 watt-hours/meter squared for UV-A (about 360 nm). D65 lamps can supposedly accomplish both with a single lamp. Use of cool white lamps in combination with black lights is more desirable for several reasons such as cost, availability and control of exposure.
Measurement of Exposure
Traditional:
White light exposure is measured using a lux meter. One generally measures lux of exposure over time until an exposure of at least 1.2 million lux-hours has been achieved. UV-A exposure is measured using a radiometer fitted with a UV-A sensor. The watts per meter squared are measured over time until an exposure of 200 watt hours per meter squared has been achieved. For example a cool white light with a power of 10,000 lux at the point of sample exposure for an exposure time of 120 hours would produce 1.2 million lux-hours of exposure (light intensity at sample site will be a function of a lamps output, in lumens, and the distance of the sample from the lamp). Similarly, a UV-A source of 2 watts per meter squared at the point of sample exposure for an exposure time of 100 hours would produce 200 watt-hours per meter squared exposure.
The problem with light meters is that they must be calibrated, traceable and have associated standard operating procedures (SOPs) in place for use and recalibration.
A Better Alternative:
In addition to traditional light meters, Q1B also allows for the use of Quinine Chemical Actinometry to measure light exposure. This technique measures the increase in absorbance, over exposure time, of an aqueous 2% solution of quinine monohydrochloride dihydrate versus a portion of the solution that has not been exposed to light (dark control). For Option 1, at 400 nm, using a 1-cm path length, a change in absorbance of at least 0.9 must be ensured. For Option 2, at 400 nm, using a 1-cm path length, a change in absorbance of at least 0.5 must be ensured.
Once the photostability system has been initially validated and qualified, this system of measurement is relatively maintenance-free. Meter operation, calibrations or traceability are no longer needed. Quinine Chemical Actinometry is simple, compliant with Q1B and is highly recommended as a cost effective, trouble-free alternative to expensive light meters.
PHOTOSTABILITY APPLICATIONS:
Most pharmaceutical laboratories use photostability primarily in forced degradation studies as part of the analytical methods development process. The other obvious use, is the conducting of actual photostability studies. Photostability cabinets tend to be used intermittently as needed rather than continuously, and spend most of the time sitting unused on a laboratory bench.
PHOTOSTABILITY EQUIPMENT:
There are a number of companies that manufacture photostability cabinets with a lots of bells and whistles, almost all of which have pretty fancy price tags. It is hard to justify a cost outlay in excess of $30,000 for a piece of equipment that is only used occasionally. Many commercial units come with chart recorders, temperature and humidity controls, automatic cutoffs, and built in light meters. After the purchase, one still needs to perform installation and operational qualification (IQ/OQ), write SOPs and set up scheduled maintenance and calibrations, and may have to validate the equipment, all of which drive up cost. And don't forget about replacement of those D65 lamps and mapping of the cabinet's light exposure surface area.
WHAT DO WE REALLY NEED:
To achieve Q1B compliance at a reasonable cost, the following considerations are strongly recommended:
· Use Option 2 lighting (cool-white fluorescent plus UV-A bulbs)
· Use Quinine Chemical Actinometry for measurement of exposure.
· Forget about temperature and humidity control, as Q1B allows for dark controls in lieu of this. Simply place the photostability cabinet in an environment that has "normal" temperature and humidity, such as on a laboratory bench away from heat-generating equipment.
The goal is to use a simple light box that provides illumination, exposure time and measurement of exposure time the meets the Q1B Guidance and that will stand up to regulatory scrutiny. There are more sensibly priced, fully compliant (validated and mapped) units that are commercially available. The MB87X is such a unit.
