2. PHARMACEUTICAL SUBSTANCE

For pharmaceutical substances, photostability 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 pharmaceutical 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 pharmaceutical 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 these experiments is left to the applicant’s discretion although 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 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 labeling (see section I.C., Procedure, and II.A.,

Presentation, for information on the design of these studies).

Normally, only one batch of drug substance 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 pharmaceutical 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.

A. 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 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 pharmaceutical 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 pharmaceutical substances

should be spread across the container to give a thickness of typically not more than 3

millimeters.Pharmaceutical substances that are liquids should be exposed in chemically inert

and transparent containers.

4

Photostability Testing of New Pharmaceutical Substances and Products

B. 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 Pharmaceutical 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.

C. Judgement 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

the 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 formulation of the pharmaceutical 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 pharmaceutical will be within

justified limits at time of use (see the relevant ICH Stability and Impurity

Guidelines).

3. PHARMACEUTICAL PRODUCT

Normally, the studies on pharmaceutical products should be carried out in a sequential manner

starting with testing the fully exposed product then progressing as necessary to the

product in the immediate pack and then in the marketing pack. Testing should

progress until the results demonstrate that the pharmaceutical product is adequately protected

from exposure to light. The pharmaceutical product should be exposed to the light conditions

described under the procedure in section I.C.

Normally, only one batch of pharmaceutical 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 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 suitably validated.

5

Photostability Testing of New Pharmaceutical Substances and Products

A. 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 a 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 drug product outside of the primary

pack, these should be presented in a way similar to the conditions mentioned for the

pharmaceutical substance. The samples should be positioned to provide 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 drug 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

adjustment of testing conditions may have to be made when testing large volume

containers (e.g., dispensing packs).

B. 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,

dissolution/disintegration for dosage forms such as capsules, etc.) and for assay and

degradants by a method suitably validated 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.

C. Judgement of Results

Depending on the extent of change special labeling or packaging may be needed to

mitigate exposure to light. When evaluating the results of photostability studies to

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 (see the

relevant ICH Stability and Impurity Guidelines).

6

Photostability Testing of New Pharmaceutical Substances and Products

4. ANNEX

A. Quinine Chemical Actinometry

The following provides details of an actinometric procedure for monitoring exposure to

a near UV fluorescent lamp (based on FDA/National Institute of Standards and

Technology study). For other light sources/actinometric systems, the same approach

may be used, but each actinometric system should be calibrated for the light source

used.

Prepare a sufficient quantity of a 2 per cent weight/volume aqueous solution of

quinine monohydrochloride dihydrate (if necessary, dissolve by heating).

Option 1

Put 10 milliliters (ml) of the solution into a 20 ml colorless ampoule seal it

hermetically, and use this as the sample. Separately, put 10 ml of the solution into a

20 ml colourless ampoule (see note 1), seal it hermetically, wrap in aluminum foil to

protect completely from light, and use this as the control. Expose the sample and

control to the light source for an appropriate number of hours. After exposure

determine the absorbances of the sample (AT) and the control (Ao) at 400 nm using a

1 centimeter (cm) path length. Calculate the change in absorbance, Δ A = AT - Ao.

The length of exposure should be sufficient to ensure a change in absorbance of at

least 0.9.

Option 2

Fill a 1 cm quartz cell and use this as the sample. Separately fill a 1 cm quartz cell,

wrap in aluminum foil to protect completely from light, and use this as the control.

Expose the sample and control to the light source for an appropriate number of hours.

After exposure determine the absorbances of the sample (AT) and the control (Ao) at

400 nm. Calculate the change in absorbance, Δ A = AT - Ao. The length of exposure

should be sufficient to ensure a change in absorbance of at least 0.5.

Alternative packaging configurations may be used if appropriately validated.

Alternative validated chemical actinometers may be used.

Note 1: Shape and Dimensions (See Japanese Industry Standard (JIS) R3512 (1974)

for ampoule specifications)