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Stability Testing: Photostability Testing of New Drug Substances and Products
1. General Overview
Photostability Testing The International Council for Harmonisation (ICH) Harmonized Tripartite Guideline for the stability testing of new drug substances and products (referred to as the Parent Guideline) outlines the importance of light testing as a critical aspect of stress testing. This document serves as an annex to the Parent Guideline and provides specific recommendations for photostability testing, a crucial process for determining how drug substances and products react to light exposure.
Preamble: Photostability Testing
It is essential to evaluate the photostability characteristics of new drug substances and products to ensure that light exposure does not cause undesirable changes. Typically, photostability testing is performed on a single batch of material, chosen according to the guidelines set out in the Parent Guideline. In some cases, these tests must be repeated if there are modifications to the product, such as changes in formulation or packaging. Whether or not such testing should be repeated depends on the results obtained from initial photostability evaluations and the nature of the changes made to the product.
This guideline primarily addresses the generation of photostability data for inclusion in Registration Applications for new molecular entities and their associated drug products. It is important to note that the photostability of drugs after administration, under conditions of use, and for applications not covered by the Parent Guideline, are outside the scope of this document. If scientifically justified, alternative approaches can be considered.
A systematic approach to photostability testing is recommended, involving studies such as:
- i) Testing the drug substance.
- ii) Testing the drug product after it has been exposed outside of its immediate packaging.
- iii) If necessary, testing the drug product within its immediate packaging.
- iv) If necessary, testing the drug product within the marketing packaging.
The level of testing required for the drug product is determined by assessing whether any unacceptable changes occur during light exposure. These changes should be within acceptable limits, which must be justified by the applicant.
Labeling requirements for photolabile drug substances and products are regulated by national and regional requirements.
2. Light Sources
Two primary light source options can be used for photostability testing, both of which have specific guidelines to ensure accurate results. It is crucial that temperature control is maintained to minimize the impact of temperature variations during testing, or alternatively, a dark control sample should be included unless otherwise justified.
Option 1:
Any light source that emits an output similar to the D65/ID65 emission standard (such as artificial daylight fluorescent lamps that combine visible and ultraviolet (UV) outputs, xenon, or metal halide lamps) is suitable. D65 is the internationally recognized standard for outdoor daylight (ISO 10977, 1993), and ID65 is its equivalent for indoor indirect daylight. If the light source emits significant radiation below 320 nm, an appropriate filter should be used to block that radiation.
Option 2:
This involves exposure to both a cool white fluorescent lamp and a near ultraviolet (UV) lamp:
- Cool white fluorescent lamp: It should produce an output similar to that specified in ISO 10977 (1993).
- Near UV fluorescent lamp: It should have a spectral distribution from 320 nm to 400 nm, with maximum energy emission between 350 nm and 370 nm, ensuring that significant UV radiation falls within both the 320-360 nm and 360-400 nm ranges.
3. Procedure for Photostability Testing
Confirmatory studies should expose the samples to light for a total illumination of at least 1.2 million lux hours and an integrated near-ultraviolet energy of no less than 200 watt hours/square meter. This exposure level ensures that the results are directly comparable for both drug substances and drug products.
During exposure, samples should be monitored using a validated chemical actinometric system, which ensures that the required light exposure is achieved. Alternatively, calibrated radiometers and lux meters can be used to track the exposure duration and intensity. In cases where dark controls are used (e.g., samples wrapped in aluminum foil), these should be placed alongside the test samples to evaluate the impact of thermally induced changes.
4. Decision Flow Chart for Photostability Testing of Drug Products
Flow Chart Process:
- Directly Exposed Formulation:
- If changes are detected, determine if they are acceptable. If no significant changes are observed, the testing concludes.
- Immediate Packaging:
- If changes are noted, assess whether they are acceptable or not.
- Marketing Packaging:
- Similar evaluation applies, with a focus on ensuring the final product remains protected from light exposure in its marketed form.
If unacceptable changes are observed at any stage, it may be necessary to redesign the packaging or reformulate the product.
5. Photostability Testing of Drug Substances
Photostability testing for drug substances is typically conducted in two phases: forced degradation testing and confirmatory testing.
- Forced Degradation Testing
The primary purpose of forced degradation testing is to evaluate the photosensitivity of the drug substance, either for method development or to understand the potential degradation pathways. This may involve testing the drug substance in simple solutions or suspensions to develop and validate analytical methods.
Samples should be placed in chemically inert and transparent containers. The intensity and duration of light exposure will vary depending on the substance’s photosensitivity. If extensive decomposition occurs during these forced degradation studies, it is usually acceptable to terminate the testing. For photostable substances, testing can be concluded once an appropriate exposure level has been reached.
While forced degradation studies can produce decomposition products that are unlikely to form under typical conditions, this data can be valuable for developing and validating appropriate analytical methods. If no such products are observed in confirmatory studies, they need not be further examined.
- Confirmatory Testing
Confirmatory testing provides the information necessary for the appropriate handling, packaging, and labeling of the drug substance. Normally, only one batch of the drug substance is tested during development. Photostability characteristics should be confirmed in subsequent testing, based on the Parent Guideline. If confirmatory studies yield unclear results, testing on up to two additional batches is recommended.
- Sample Presentation
Careful consideration of the physical properties of the drug substance under test is essential. Efforts to minimize sublimation, evaporation, or melting should be made by cooling the samples or placing them in sealed containers. Interactions between the samples and the materials used for containers should also be avoided, unless relevant to the test.
6. Analysis of Samples
At the end of the exposure period, the samples should undergo a thorough examination to identify any physical changes such as alterations in appearance, clarity, or color of the solution. Additionally, the assay and any photochemical degradation products should be analyzed using suitably validated methods.
For solid drug substances, ensure that representative portions are used in individual tests, with appropriate homogenization if necessary. The analysis of exposed samples should occur alongside any protected samples used as dark controls.
7. Evaluation and Judgement of Results
The forced degradation studies are designed to provide information for developing and validating test methods, rather than to establish specific limits for acceptable changes. The confirmatory studies, on the other hand, aim to identify necessary precautions in manufacturing or formulation, including whether light-resistant packaging is required.
In evaluating the results, it is crucial to compare the data from confirmatory studies with results from other formal stability studies to ensure that the drug product remains within acceptable limits at the time of use.
8. Photostability Testing of Drug Products
Typically, drug product testing follows a sequential process, starting with the fully exposed product and progressing to testing within the immediate and marketing packaging. This process continues until it is demonstrated that the drug product is adequately protected from light exposure.
- Presentation of Drug Product Samples
Similar to drug substances, when testing drug products outside their immediate packaging, samples should be exposed in a way that maximizes their exposure to light. Solid dosage forms like tablets and capsules should be arranged in a single layer. If direct exposure is impractical due to concerns like oxidation, the sample should be placed in a suitable inert transparent container, such as quartz.
When testing the drug product within its immediate or marketing packaging, the samples should be positioned to ensure the most uniform exposure to light.
- Analysis of Drug Product Samples
After the exposure period, the samples should be evaluated for any changes in physical properties such as appearance, dissolution/disintegration rates, or color. The samples should also undergo assays to detect any photochemical degradation products.
Similar to drug substance testing, for solid dosage forms, the samples should be tested in representative groups (e.g., 20 tablets or capsules). If creams, ointments, or suspensions are tested, it is essential to account for the potential lack of homogeneity in the sample.
- Evaluation and Judgement of Drug Product Results
If significant changes are observed in the drug product due to light exposure, special labeling or packaging may be necessary to mitigate further exposure. As with drug substances, it is vital to consider the results from other stability studies to ensure that the product remains within specification throughout its shelf life.
Conclusion
Photostability testing is an essential component of stability testing for new drug substances and products. The process involves forced degradation studies to assess photosensitivity and confirmatory studies to evaluate the potential impact of light exposure on drug quality. Testing is carried out using specific light sources and conditions, with a focus on ensuring that the drug product remains stable throughout its shelf life.
To summarize the key points:
- Purpose and Scope: The document emphasizes the importance of evaluating the photostability of new drug substances and products to ensure they do not undergo unacceptable changes when exposed to light. Photostability testing should be conducted on drug substances, drug products outside the immediate packaging, and possibly the marketing pack, depending on the circumstances.
- Testing Procedures:
- Forced Degradation Testing: Involves exposing drug substances to stress conditions (including light) to evaluate their overall photosensitivity. This step is particularly important for method development and degradation pathway elucidation.
- Confirmatory Testing: This follows forced degradation and establishes photostability characteristics under controlled light conditions. It helps determine if the drug substance or product needs special packaging or labeling to protect it from light.
- Light Sources: The guideline outlines two options for light sources to be used in photostability testing:
- Option 1: Light sources like D65/ID65 standard fluorescent lamps or xenon lamps.
- Option 2: A combination of cool white fluorescent lamps and near-UV lamps. Both options ensure that the light exposure simulates natural light conditions.
- Testing Duration and Monitoring:
- The document specifies the light exposure levels required for effective testing, including the total light intensity (1.2 million lux hours) and integrated near-UV energy (200 watt hours/square meter).
- The testing duration and light intensity should be monitored using calibrated instruments, like radiometers and lux meters, or through actinometry, such as using a quinine chemical actinometer.
- Judgment of Results: The results of photostability testing are used to determine if the drug needs special packaging or labeling to mitigate light exposure, ensuring the drug remains within acceptable limits of stability during its shelf life.
- Actinometric Procedure: A specific method is provided for using quinine chemical actinometry to monitor exposure to UV light. This involves measuring the change in absorbance at 400 nm after light exposure to calculate the total light exposure received by the samples.
- Glossary:
- Immediate pack: The direct packaging of the drug product, in contact with the drug.
- Marketing pack: The combination of immediate pack and secondary packaging (e.g., a carton).
- Forced Degradation Testing: Stress testing to degrade the sample deliberately, primarily used during the development phase.
- Confirmatory Studies: Studies to confirm photostability characteristics under standard conditions.
- References: The document references studies and industry standards that support the methodologies used for photostability testing.
This guideline helps pharmaceutical developers ensure the quality and stability of drug products, especially when exposed to light, which is vital for maintaining their effectiveness and safety. If you need further elaboration on any section, feel free to ask!
