Pharmaceutical manufacturers must establish the stability of their drug products towards light. But what makes a drug molecule or formulation unstable to light, and how can appropriate protection be given? Find out in this guest post from Dr. Mark Powell on photostability testing.
So, if we’re performing a forced degradation study to check drug product degradation modes and qualify the stability-indicating potential of analytical methods, how should we go about that? If you’d like to know the answers to this and other typical questions around photostability studies, keep reading!
Properties of light
First, let’s consider the properties of light that drug molecules or drug products might be exposed to during normal use. Visible light falls between the ultraviolet and infrared regions of the electromagnetic spectrum (Figure 1). The shorter the wavelength, the more energetic the light and the more damage it can do to our product.
Sunlight contains an ultraviolet component in addition to visible light, but the lower UV wavelengths (higher energies) are normally filtered out by the time the light reaches our product. This filtering effect is provided by the Earth’s atmosphere (the ozone layer is especially effective) but also ordinary window glass removes some of the more energetic wavelengths (Figure 2).
From this, we can gather that the most energetic wavelength of light that our drug molecule/product is likely to see is approximately 320 nm. This is why the ICH guidance on photostability studies  says: “For a light source emitting significant radiation below 320 nm, an appropriate filter may be fitted to eliminate such radiation.”
Why do drug molecules degrade in light?
Now that we know what wavelengths of light our drug molecules might be exposed to, let’s consider the ways in which this light can cause chemical degradation. There are two main mechanisms.
Firstly, the drug molecule may absorb light directly. For this to happen, the spectrum of the light source must overlap to some extent with the molecule’s absorbance spectrum. So, molecules that can absorb light at wavelengths of 320 nm or higher are a photostability risk. To illustrate this point, Figure 3 shows the UV spectra of two drug molecules: ibuprofen and sulindac. For the chemists amongst you, note the extended conjugation in sulindac’s structure. This is responsible for its absorbance properties.
The second way in which light can cause photodegradation is by a process called photosensitisation. This is where another component of the formulation absorbs light energy and then passes it on to the drug molecule, thus causing degradation. To illustrate this effect, Figure 4 shows the structure and UV absorbance spectrum of losartan. We wouldn’t expect losartan to be a photodegradation risk, and it proves to be light stable in most formulations. But in a liquid oral formulation with cherry flavouring, losartan is light-sensitive . Cherry flavouring is, of course, coloured and able to absorb light. Furthermore, degradation occurs faster in the presence of oxygen. Photodegradation reactions usually proceed via an oxidation pathway.
Figure 4. Absorbance spectrum of losartan
ICH Q1B sets out the process by which we establish whether a drug product is photosensitive (Figure 5). Photostability problems can usually be addressed successfully by the selection of appropriate packaging: amber containers for liquid formulations, and opaque bottles or blister packs for oral solids. The minimum light exposure levels in ICH Q1B need to be achieved:
- Illumination not less than 1.2 x 106 lux hours (equivalent to 2 to 3 days’ exposure close to a sunny window in the summer)
- Integrated near UV energy (320 nm to 400 nm: UV A) not less than 200 watt hours per m2 (equivalent to 1 to 2 days close to a sunny window)
One factor that we need to consider is the degradation that might occur in the photostability chamber independently of light exposure. For example, if the ambient temperature is too warm. To allow for this, we prepare dark control samples. These are identical to the exposed samples, but are protected from light, often by wrapping them in aluminium foil. They are placed in the photostability chamber at the same time as the exposed samples. If the impurity profiles of both dark control and exposed samples are the same, no photodegradation has taken place.
Lux hours and watt hours per m2?
If the terms “lux hours” and “watt hours” mean nothing to you, here’s a quick explanation.
Lux is the standard unit for illumination (the brightness of light as perceived by the human eye). Watt hours, as you might have guessed, is a measure of the amount of energy that the sample is exposed to which, as we’ve seen, is related to the wavelength distribution of the light source. So, the ICH guidance requires us to measure both the brightness and energy of the light to which the sample has been exposed.
Photostability is normally a component of stress studies that are designed to qualify an impurity method as stability indicating. However, there is little regulatory guidance on conditions for such a study. The experimental set-up is the same as for a confirmatory study: directly exposed and dark control samples. The question is how much exposure to give. ICH Q1A  suggests that for heat and humidity stress, the conditions used should be more forcing than those experienced during accelerated stability testing. It has rather less to say about photostability stress studies besides referring to ICH Q1B.
Alsante and co-workers  published a study in 2003 in which they surveyed industry stress study practice. A summary of the 18 responses received for photostability stress study practice is shown in Figure 6. The majority of companies surveyed (67 %) used the standard ICH exposure levels for photostability stress studies. Personally, I see some value in going a little bit further (e.g., 2x ICH exposure levels) to be sure that any photodegradation products that might form under more forcing conditions could be detected by the impurity method.
Need help with your photostability studies?
All companies developing or manufacturing pharmaceutical drugs, require a robust photostability testing process to ensure product quality and regulatory compliance. Inadequate testing can result in costly delays and lost revenue.
Whether performing forced degradation or confirmatory studies, Q1 Scientific can create the appropriate test conditions in accordance with ICH Q1B.
Our fully qualified, temperature and humidity controlled photostability chambers can be used to help you:
- Understand how light exposure affects your products so you can take action to ensure product quality and regulatory compliance; OR
- Demonstrate that light exposure does not result in unacceptable changes
Contact us to discuss how we can help you with your photostability testing.
About Dr. Mark Powell
Dr. Mark Powell is a Fellow of the Royal Society of Chemistry (RSC) with over thirty years’ experience as a Senior Analytical Chemist.
Mark has served as both Honorary Secretary and Honorary Treasurer of the RSC’s Analytical Division and led a working group on continuing professional development until July 2016. He has worked at a senior level in a number of companies with responsibility for analytical development and equipment qualification. In 2010 Mark was appointed Scientific Manager of a UK-based pharmaceutical CRO, with responsibility for guiding the direction of drug development programmes as well as establishing collaborations with academia and instrument manufacturers.
In 2013, he set up his own company to provide training and consultancy services to the pharmaceutical industry. His consultancy work has involved, amongst other things, managing the analytical aspects of pharmaceutical development programmes and conducting data integrity audits. He is in demand as a trainer in topics such as pharmaceutical development, chromatography, spectroscopy, dissolution testing, data integrity, control of impurities, technical writing, stability/stress studies and sample preparation.
- International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Q1B: Photostability Testing of New Drug Substances and Products, November 1996, available at: https://database.ich.org/sites/default/files/Q1B%20Guideline.pdf
- R. A. Seburg, J. M. Ballard, T-L. Hwang, and C. M. Sullivan, Photosensitized Degradation of Losartan Potassium in an Extemporaneous Suspension Formulation. Journal of pharmaceutical and biomedical analysis. 42 (2006) 411-22, available at: https://pubmed.ncbi.nlm.nih.gov/16787732/
- International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Q1A (R2): Stability Testing of New Drug Substances and Products, November 1996, available at: https://database.ich.org/sites/default/files/Q1A%28R2%29%20Guideline.pdf
- K. M. Alsante, L. Martin, and S. W. Baertschi, A Stress Testing Benchmarking Study, Pharmaceutical Technology, 27, 2 (2003), 60-72, available at: https://cdn.sanity.io/files/0vv8moc6/pharmtech/9d89bcb8d1ab1914b367527ddac43942d988d5cb.pdf/article-47384.pdf