by The intrinsic photo stability characteristics of new drug substances and products should be evaluated to demonstrate that, as appropriate, light exposure does not result in unacceptable change. Normally, photo stability testing is carried out on a single batch of material selected as described under Selection of Batches in the Parent Guideline. Under some circumstances these studies should be repeated if certain variations and changes are made to the product (e.g., formulation, packaging). Whether these studies should be repeated depends on the photo stability characteristics determined at the time of initial filing and the type of variation and/or change made.
The guideline primarily addresses the generation of photo stability information for submission in Registration Applications for new molecular entities and associated drug products. The guideline does not cover the photo stability of drugs after administration(i.e. under conditions of use) and those applications not covered by the Parent Guideline. Alternative approaches may be used if they are scientifically sound and justification is provided.
A systematic approach to photo stability testing is recommended covering, as appropriate, studies such as:
- Tests on the drug substance;
- Tests on the exposed drug product outside of the immediate pack; and if necessary ;
- Tests on the drug product in the immediate pack;
And if necessary;
4. Tests on the drug product in the marketing pack.
The extent of drug product testing should be established by assessing whether or not acceptable change has occurred at the end of the light exposure testing as described in the Decision Flow Chart for Photo stability Testing of Drug Products. Acceptable change is change within limits justified by the applicant.
The formal labeling requirements for photo labile drug substances and drug products are established by national/regional requirements.
Light Sources
The light sources described below may be used for photo stability testing. The applicant should either maintain an appropriate control of temperature to minimize the effect of localized temperature changes or include a dark control in the same environment unless otherwise justified. For both options 1 and 2, a pharmaceutical manufacturer/applicant may rely on the spectral distribution specification of the light source manufacturer.
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 combining visible and ultraviolet (UV) outputs, xenon, or metal halide lamp.D65 is the internationally recognized standard for out door day light as defined in ISO10977(1993). ID65 is the equivalent indoor indirect daylight standard. For a light source emitting significant radiation below 320 nm, an appropriate filter(s) may be fitted to eliminate such radiation.
Option 2
For option 2 the same sample should be exposed to both the cool white fluorescent and near ultraviolet lamp.
- A cool white fluorescent lamp designed to produce an output similar to that specified in ISO 10977(1993) ; and
- A near UV fluorescent lamp having a spectral distribution from 320 nm to 400 nm with a maximum energy emission between 350nm and 370nm; a significant proportion of UV should be in both bands of 320 to 360 nm and 360 to 400 nm.
Procedure
For confirmatory studies, samples should be exposed to light providing an overall illumination of not less than 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200 watt hours/square meter to allow direct comparisons to be made between the drug substance and drug product.
Samples may be exposed side-by-side with a validated chemical act in ometric system to ensure the specified light exposure is obtained, or for the appropriate duration of time when conditions have been monitor educing calibrated radio meters/luxmeters. An example of an actinometric procedure is provided in the Annex.
If protected samples (e.g., wrapped in aluminum foil) are used as dark controls to evaluate the contribution of thermally induced change to the total observed change, these should be placed along side the authentic sample.
Drug Substances
For drug substances, photo stability testing should consist of two parts: forced degradation testing and confirmatory testing.
The purpose of forced degradation testing studies is to evaluate the overall photosensitivity of the material for method development purposes and/or degradation pathway elucidation. This testing may involve the drug substance alone and/or in simple solutions/suspensions to validate the analytical procedures. In these studies, the samples should be in chemically inert and transparent containers. In these forced degradation studies, a variety of exposure conditions may be used, depending on the photosensitivity of the drug substance involved and the intensity of the light sources used.
For development and validation purposes it is appropriate to limit exposure and end the studies if extensive decomposition occurs.For photostable materials, studies may be terminated after an appropriate exposure level has been used. The design of the se experiments is left to the applicant’s discretional though the exposure levels used should be justified.
Under forcing conditions, decomposition products may be observed that are unlikely to be formed under the conditions used for confirmatory studies. This information may be useful indeveloping and validating suitable analytical methods. If in practice it has been demonstrated they are not formed in the confirmatory studies, these degradation products need not be further examined.
Normally, only one batch of drug substance is tested during the development phase, and then the photo stability characteristics should be confirmed on a single batch selected as described in the Parent Guideline if the drug is clearly photostable or photolabile. If the results of the confirmatory study are equivocal, testing of up to two additional batches should be conducted. Samples should be selected as described in the Parent Guideline.
Presentation of Samples
Care should be taken to ensure that the physical characteristics of the samples under test are taken in to account and efforts should be made, such as cooling and/or placing the samples in sealed containers, to ensure that the effects of the changes in physical states such as sublimation, evaporation or melting are minimized. All such precautions should be chosen to provide minimal interference with the exposure of samples under test. Possible interactions between the samples and any material used for containers or for general protection of the sample, should also be considered and eliminated wherever not relevant to the test being carried out.
As a direct challenge for samples of solid drug substances, an appropriate amount of sample should be taken and placed in a suitable glass or plastic dish and protected withasuitabletransparentcoverifconsiderednecessary.Soliddrugsubstances should be spread across the container to give a thickness of typically not more than 3 millimeters. Drug substances that are liquids should be exposed in chemically inert and transparent containers.
Analysis of Samples
At the end of the exposure period, the samples should be examined for any changes in physical properties (e.g., appearance, clarity, or color of solution) and for assay and degradants by a method suitably validated for products likely to arise from photochemical degradation processes.
Where solid drug substance samples are involved, sampling should ensure that a representative portion is used in individual tests. Similar sampling considerations, suchashomogenizationoftheentiresample,applytoothermaterialsthatmaynot be homogeneous after exposure. The analysis of the exposed sample should be performed concomitantly with that of any protected samples used as dark controls if these are used in the test.
Drug Products
Normally, the studies on drug products should be carried out in a sequential manner starting with testing the fully exposed product then progressing as necessary to the productintheimmediatepackandtheninthemarketingpack.Testingshould progress until the results demonstrate that the drug product is adequately protected from exposure to light. The drug product should be exposed to the light conditions described under the procedure in section I.C.
Normally, only one batch of drug product is tested during the development phase, and then the photostability characteristics should be confirmed on a single batch selected as described in the Parent Guideline if the product is clearly photostable or photolabile. If the results of the confirmatory study are equivocal, testing of up to two additional batches should be conducted.
For some products where it has been demonstrated that the immediate pack is completely impenetrable to light, such as aluminium tubes or cans, testing should normally only be conducted on directly exposed drug product.
It may be appropriate to test certain products such as infusion liquids, dermal creams, etc., to support their photo stability in-use. The extent of this testing should depend on and relate to the directions for use, and is left to the applicant’s discretion.
The analytical procedures used should be suitably validated.
