Approaches to Photostability Evaluation in Drug Development: Testing Conditions (Part 2 of a 3-Part Series)
By Mike Molloy, Director of Chemistry Lab, Boston Analytical
In the first installment of this blog series, I discussed environmental conditions that impact the outcomes of drug testing. In this segment, I address two major testing approaches.
To help guide investigation into the influence of light on drug quality, the International Conference on Harmonization (ICH) has published a guidance, Q1B, Photostability Testing for New Drug Substances and Products, that details how photostability studies should be approached. The guideline is a specialized subset of the guidance Q1A, Stability Testing of New Drug Substances and Products. It covers testing of drug substance and drug product, along with evaluating the impact of protective packaging on the drug product.
The guideline deals with two major testing approaches: Forced degradation and confirmatory testing.
Forced degradation looks to put enough stress on the molecule to force it to break down, and use that as a stepping stone to identifying what it breaks down into. It is helpful in developing stability indicating test methods that will be able to discern any degradation of products. Typically, tests are done for effects on the drug’s appearance, purity (assay), degradation, dissolution as a performance marker for solid oral dosage forms, or other relevant testing.
The approach is to expose the drug to light until a targeted level of degradation is achieved. This can be done by putting several sample preparations in the chamber and removing one after a specified time to see whether any degradation has occurred. Researchers use assays by chromatography or other techniques to evaluate the amount of drug present and see if the amount changes with exposure. Researchers will look for a targeted level of degradation, for example looking for a 10-20% reduction in the assay value, but the actual target value should be justified.
At this stage mass balance calculations may be considered, although a thorough understanding of the degradation products resulting from exposure goes a long way in helping achieve mass balance.
Once researchers have some idea of the damage that light can cause, methods can be developed and validated and a confirmatory study can be run. Confirmatory studies expose the drug to a predetermined level of UV and visible light exposure. This is usually done on a single registration batch if the results show the product to be clearly photostable or clearly photolabile. If the results are equivocal, further testing is warranted.
The best outcome is that the drug is not degraded by light and requires no special handling to protect from light; that is the drug is photostable. If the drug is photolabile, or degraded by light, consideration has to be given as to the best approach to avoid light damage. A common approach is to use packaging that is opaque so light never reaches the product. ICH Q1B doesn’t deal directly with the effects of light at the prescribed conditions of use, but patient behavior may also be considered. If a patient is likely to leave a product where it may be exposed, then it makes sense to develop a less light-sensitive formulation.
The ICH guideline has two options for sources exposing the samples to light, with option 2 the more prevalent. Option 1 uses light sources that meet a recognized standard for outdoor and indoor daylight that is laid out in ISO 10977, D65 and ID65. Any light source meeting the D65/ID65 standard is appropriate for option 1. If the source emits light below 320nm, it may be useful to apply a filter that eliminates contribution of those wavelengths.
Generally option 2 uses two light sources and option 1 uses a single source. Use of a single light source will result in overexposure to UV since the endpoint for UV exposure is ordinarily achieved sooner than the visible. Samples can be tested with two light sources in sequence to achieve the correct exposure levels, or can be exposed simultaneously.
Types of light sources used include Xenon lamps, fluorescent tubes some may target specific parts of the spectrum, and metal halide lamps. The choice of option 1 or 2 and the choice of lamps should be made to achieve the most appropriate conditions for testing.
There are two main ways of measuring the level of light impinging on the sample. One is to use a lux meter, or radiometer, an electronic device capable of measuring and recording the exposure level. This type of device is commonly associated with chambers specifically designed to run photostability studies. Modern photostability chambers can maintain temperature at the desired setpoint and can be programmed for a fixed exposure based on the light exposure measured at a lux meter that is placed in proximity to the samples. Some chambers have separate exposure chambers so that multiple studies can be run simultaneously, and most chambers generate data on exposure to include graphical representations.
The second means of establishing the level of exposure is chemical, using actinometric systems such as quinine, which give a measurable and predictable change in absorbance after a fixed exposure to light. It’s used to measure light in the UV range, specifically 300-400 nm. Chemical systems are dependent on appropriate handling of the quinine solutions used, with pH and temperature changes likely to introduce variability in the measurements.
In both approaches, Option 2 samples are exposed to 1.2 million lux hours with overall illumination in the visible range from 400 – 800 nm and including 200 Watt hours/m2 of near UV light at 320 – 400 nm. Light at wavelengths below 320 are filtered out.
In the third post in this series, I will talk about environmental conditions in testing. Stay tuned.
ICH, Guidance for industry Q1B photostability testing of new drug substances and products, Fed. Regist. 62 (1996) 27115–27122.
Clayton Anderson de Azevedo Filhoa,, Daniel de Filgueiras Gomes b, João Paulo de Mélo Guedes , Rayana Muniz Falcão Batista, Beate Saegesser Santos Considerations on the quiine actinometry calibration method used in photostability testing of pharmaceuticals. Journal of Pharmaceutical and Biomedical Analysis 54 (2011) 886–888.
Hanne Hjorth Tønnesen (Ed.) Photostability of Drugs and Drug Formulations Second Edition.2004 CRC press LLC. ISBN 0-415-30323-0
ISO 10977, 1993