Photostability Study in Pharmaceutical

What is photostability?

The current ICH (International Conference for Harmonization) guidelines specify that drug and drug products must be photo tested to ensure that exposure to light does not cause photochemical degradation of the product or packaging.

What is a photostability chamber?

Photostability chambers are specifically designed to perform near UV and visual light testing with fluorescent lamps per ICH Q1B Guidelines. This unit controls light and temperature conditions through an easy-to-use color touch-screen interface.

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Photostability:

• We check the stability of samples under environmental condition such as light (photo).
• An artificial light similar to natural light will be exposed to the samples and check the quality before explore and after exposure will be monitored and justified.

• The intrinsic photostability characteristics of new drug substances and products should be evaluated to demonstrate that, as appropriate, light exposure does not result in unacceptable change. Normally, photostability testing is carried out on a single batch.
• Under some circumstances these studies should be repeated if certain changes are made to the product (e.g., formulation, packaging). Whether these studies should be repeated depends on the photostability characteristics determined.
• A systematic approach to photostability testing is recommended covering, as appropriate, studies such as :

1. Tests on the active substance;
2. Tests on the exposed product outside of the immediate pack, and if necessary ;
3. Tests on the product in the immediate pack; and if necessary ;
4. Tests on the product in the marketing pack.

• The extent of 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 Photostability Testing of Medicinal Products.

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Light sources

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 outdoor daylight as defined in ISO 10977. 

Procedure

• 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.
• Samples may be exposed side-by-side with a validated chemical actinometric system to ensure the specified light exposure is obtained, or for the appropriate duration of time when conditions have been monitored using calibrated radiometers/lux meters. 
• If protected samples (e.g., wrapped in aluminium foil) are used as dark controls to evaluate the contribution of thermally induced change to the total observed change, these should be placed alongside the authentic sample.

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Defining the Test Conditions

• In order to fully define the test conditions during photostability testing it is necessary to measure not only the visible light (illuminance) to which products are exposed but also the UV content (irradiance) since many drugs absorb little or no visible light but absorb in the UV range present in natural light (290-400 nm). 
• Data on UV irradiance are not necessary for sources that are known to provide a good simulation of sunlight (e.g. xenon lamps) in order to predict product behavior in natural light. However, for other sources of light, such a prediction cannot be made without knowledge of their UV irradiance.

Active Substance

For substances, photostability testing should consist of two parts: 

1.   Forced Degradation Testing

2.   Confirmatory testing.

Forced Degradation 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 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 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. 
• 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 in developing 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.
• Confirmatory studies should then be undertaken to provide the information necessary for handling, packaging, and labelling 
• Normally, only one batch of substance is tested during the development phase, and then the photostability characteristics should be confirmed on a single batch selected. If the results of the confirmatory study are equivocal, testing of up to two additional batches should be conducted.

Presentation of samples

• Care should be taken to ensure that the physical characteristics of the samples under test are taken into 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 minimised.  
• 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 substances, an appropriate amount of sample should be taken and placed in a suitable glass or plastic dish and protected with a suitable transparent cover if considered necessary. Solid substances should be spread across the container to give a thickness of typically not more than 3 millimeters. 
• Substances that are liquids should be exposed in chemically inert and transparent containers.

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Analysis of Samples

• 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 substance samples are involved, sampling should ensure that a representative portion is used in individual tests. Similar sampling considerations, such as homogenization of the entire sample, apply to other materials that may not 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.

Judgment of Results

• The forced degradation studies should be designed to provide suitable information to develop and validate test methods for the confirmatory studies. These test methods should be capable of resolving and detecting photolytic degradants that appear during confirmatory studies.
• When evaluating the results of these studies, it is important to recognize that they form part of the stress testing and are not therefore designed to establish qualitative or quantitative limits for change.
• The confirmatory studies should identify precautionary measures needed in manufacturing or in the formulation of the product, and if light-resistant packaging is needed. When evaluating the results of confirmatory studies to determine whether change due to exposure to light is acceptable, it is important to consider the results from other formal stability studies in order to assure that the substance will be within justified limits at the time of use.

Pharmaceutical Formulation

• Studies on products were carried out by testing the fully exposed product then the product in the immediate pack and then in the marketing pack. Testing should progress until the results demonstrate that the product is adequately protected from exposure to light. 
• Only one batch of product is tested during the development phase, and then the photostability characteristics should be confirmed on a single batch selected.
• 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 the directly exposed products.
• It may be appropriate to test certain products such as infusion liquids, dermal creams, etc., to support their photostability 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 validated.

Presentation of samples

• Care should be taken to ensure that the physical characteristics of the samples under test are taken into account and efforts, such as cooling and/or placing the samples in sealed containers, should be made to ensure that the effects of the changes in physical states are minimized, such as sublimation, evaporation, or melting. 
• All such precautions should be chosen to provide minimal interference with the irradiation 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.
• Where practicable when testing samples of the product outside of the primary pack, these should be presented in a way similar to the conditions mentioned for the active substance. The samples should be positioned to provide a maximum area of exposure to the light source. For example, tablets, capsules, etc., should be spread in a single layer.
• If direct exposure is not practical (e.g., due to oxidation of a product), the sample should be placed in a suitable protective inert transparent container (e.g., quartz).
• If testing of the product in the immediate container or as marketed is needed, the samples should be placed horizontally or transversely with respect to the light source, whichever provides for the most uniform exposure of the samples. 
• Some adjustments of testing conditions may have to be made when testing large-volume containers (e.g., dispensing packs).

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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 the solution, dissolution/disintegration for dosage forms such as capsules, etc.) and for assay and degradants by validated method for products likely to arise from photochemical degradation processes.

• When powder samples are involved, sampling should ensure that a representative portion is used in individual tests. 
• For solid oral dosage form products, testing should be conducted on an appropriately sized composite of, for example, 20 tablets or capsules. Similar sampling considerations, such as homogenization or solubilization of the entire sample, apply to other materials that may not be homogeneous after exposure (e.g., creams, ointments, suspensions, etc.). 
• 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.

Evaluation of Results

• Evaluating the results of photostability studies determine whether change due to exposure to light is acceptable, it is important to consider the results obtained from other formal stability studies in order to assure that the product will be within proposed specifications during the shelf life.

The factor that influences the photostability

In Solid dosage form:

Particle size

• As the particle size is decreased the rate of degradation increases because of the increased surface area exposed to light. However, the influence of particle size of drug powder will have no effect when incorporated into tablets.

Drug content

• The rate of decomposition of drugs, in solution is decreased by higher drug concentrations. This phenomenon is due to light absorption by the drug substance itself, protecting the molecules in the inner area of the reaction volume but for the tablets photostability increases by increasing the drug content.

Tablet geometry

• The diameter and size of the tablet depend on the drug content. By increasing the diameter the photostability of the drug was improved. Though the difference is low, it is of importance. Degradation in biconvex-shaped tablets was higher when compared to biplanar tablets. However, the difference was little.

Preparation method

• Tablets can be prepared by granulation or by direct compression. Granulation will decrease the photostability of tablets.

In the case of solution dosage forms:

Concentration

• The rate of decomposition of drugs, in solution is decreased by higher drug concentrations. This phenomenon is due to light absorption by the drug substance itself, protecting the molecules in the inner area (inner filter effect). Most of the light will be absorbed close to the sample surface if a solution contains the drug substance in high concentration.
• Hence, a concentrated solution is likely to be more stable than the same product in a diluted form.

pH and Ionization

• pH will significantly affect the photodegradation process. Some drugs undergo degradation at lower pH while the others undergo at higher pH. 
• The photodegradation process is also dependent on the ionized form of the molecule because most medicinal agents are salts. 
• The influence of pH modifying compounds can influence the stability. The phosphate buffer is known to influence the photochemical properties of compounds (e.g. tyrosine) by facilitating proton transfer from the excited state of the reacting species.

Ionic strength

• An increase in the ionic strength is reported to have a photostabilizing effect on certain drugs by providing a protective film of solvated ions around the reacting molecule on the contrary a study on lomefloxacin reported that higher ionic strength in lomefloxacin hydrochloride aqueous solution, the higher the photodegradation kinetic rate constant is. 
• As the dielectric constant of the solution increased, the photodegradation kinetic rate constant also increased as more drugs are in ionic form.

Oxidation

• Oxygen plays an important role in many photochemical processes and thus a reduction in oxygen concentration would stabilize the product. The effect of antioxidants and chelating agents is unpredictable. 
• The effect is strongly dependent on the environment and light conditions and must, therefore, be carefully evaluated. It is also known that Fe (III) - EDTA chelates are reduced by superoxide quite quickly and EDTA will, therefore, not inhibit photodegradation in such systems. 
• The addition of colored substances; which have the same absorption wavelength as of drug molecules, showed to stabilize drugs in various preparations. 

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