Guidance for Industry

Q1B Photostability Testing of New

Drug Substances and Products

November 1996

ICH
Guidance for Industry

Q1B Photostability Testing of New

Drug Substances and Products

Additional copies are available from:

 the Drug Information Branch (HFD-210),

Center for Drug Evaluation and Research (CDER),

5600 Fishers Lane, Rockville, MD 20857 (Tel) 301-827-4573

http://www.fda.gov/cder/guidance/index.htm

or

Office of Communication,

Training, and Manufacturers Assistance (HFM-40)

Center for Biologics Evaluation and Research (CBER)

1401 Rockville Pike, Rockville, MD 20852-1448,

http://www.fda.gov/cber/guidelines.htm

(Fax) 888-CBERFAX or 301-827-3844

(Voice Information) 800-835-4709 or 301-827-1800

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

November 1996

ICH
i

Table of Contents

I. GENERAL .......................................................... 1

A. Preamble ...................................................... 1

B. Light Sources .................................................. 4

C. Procedure ..................................................... 4

II. DRUG SUBSTANCE .................................................. 5

A. Presentation of Samples .......................................... 5

B. Analysis of Samples ............................................. 6

C. Judgment of Results ............................................. 6

III. DRUG PRODUCT .................................................... 7

A. Presentation of Samples .......................................... 7

B. Analysis of Samples ............................................. 8

C. Judgment of Results ............................................. 8

IV. ANNEX: Quinine Chemical Actinometry ................................. 8

V. GLOSSARY ........................................................ 11

VI. REFERENCES ..................................................... 11
This guidance was developed within the Expert Working Group (Quality) of the International Conference on 1

Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been

subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been endorsed

by the ICH Steering Committee at Step 4 of the ICH process, November 1996. At Step 4 of the process, the final draft is

recommended for adoption to the regulatory bodies of the European Union, Japan, and the United States. This guidance

was published in the Federal Register on May 16, 1997 (62 FR 27116), and is applicable to drug and biological

products. This guidance represents the Agency’s current thinking on photostability testing of new drug substances and

products. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. 

An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or

both.

1

GUIDANCE FOR INDUSTRY1

Q1B Photostability Testing of New Drug

Substances and Products

I. GENERAL

The ICH Harmonized Tripartite Guideline on Stability Testing of New Drug Substances and

Products (hereafter referred to as the parent guideline) notes that light testing should be an

integral part of stress testing. This document is an annex to the parent guideline and addresses the

recommendations for photostability testing.

A. Preamble

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 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 photostability characteristics determined at the time of initial

filing and the type of variation and/or change made.

The guideline primarily addresses the generation of photostability information for

submission in registration applications for new molecular entities and associated drug

products. The guideline does not cover the photostability 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.
2

A systematic approach to photostability testing is recommended covering, as appropriate,

studies such as:

(i) Tests on the drug substance;

(ii) Tests on the exposed drug product outside of the immediate pack; and if

necessary,

(iii) Tests on the drug product in the immediate pack; and if necessary,

(iv) 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 Photostability Testing of Drug Products. Acceptable change is

change within limits justified by the applicant.

The formal labeling requirements for photolabile drug substances and drug products are

established by national/regional requirements.
3
4

B. Light Sources

The light sources described below may be used for photostability 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 outdoor daylight as defined in ISO 10977

(1993). ID65 is the equivalent indoor indirect daylight standard. For a light

source emitting significant radiation below 320 nanometers (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.

1. A cool white fluorescent lamp designed to produce an output similar to

that specified in ISO 10977 (1993); and

2. A near UV fluorescent lamp having a spectral distribution from 320 nm to

400 nm with a maximum energy emission between 350 nm and 370 nm; a

significant proportion of UV should be in both bands of 320 to 360 nm and

360 to 400 nm.

C. 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 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. An

example of an actinometric procedure is provided in the Annex.
5

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 alongside the authentic sample.

II. DRUG SUBSTANCE

For drug 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 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 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 examined further.

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 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.

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. 
6

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 with a

suitable transparent cover if considered necessary. Solid drug substances 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.

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 drug 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 control if these are used in

the test.

C. 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 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 drug 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 drug will be within justified limits at time of use

(see the relevant ICH Stability and Impurity Guidelines).
7

III. DRUG PRODUCT

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 product in the immediate

pack and then in the marketing pack. Testing should 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 aluminum 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 or dermal creams, 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.

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 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 drug

substance. The samples should be positioned to provide maximum area of exposure to the

light source. For example, tablets, capsules, 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).
8

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) 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). 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. Judgment 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).

IV. ANNEX: Quinine Chemical Actinometry

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

near UV flourescentofamp (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 percent weight/volume aqueous solution of quinine

monohydrochloride dihydrate (if necessary, dissolve by heating). 
9

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 colorless 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) pathlength. Calculate the change in absorbance, ) A = A - T

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, ) 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.
10

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

ampoule specifications)
11

V. GLOSSARY

! Immediate (primary) pack is that constituent of the packaging that is in direct contact

with the drug substance or drug product, and includes any appropriate label.

! Marketing pack is the combination of immediate pack and other secondary packaging

such as a carton.

! Forced degradation testing studies are those undertaken to degrade the sample

deliberately. These studies, which may be undertaken in the development phase normally

on the drug substances, are used to evaluate the overall photosensitivity of the material for

method development purposes and/or degradation pathway elucidation.

! Confirmatory studies are those undertaken to establish photostability characteristics

under standardized conditions. These studies are used to identify precautionary measures

needed in manufacturing or formulation and whether light-resistant packaging and/or

special labeling is needed to mitigate exposure to light. For the confirmatory studies, the

batch(es) should be selected according to batch selection for long-term and accelerated

testing which is described in the parent guideline.

VI. REFERENCES

Drew, H.D., J.F. Brower, W.E. Juhl, and L.K. Thornton, "Quinine Photochemistry: A

Proposed Chemical Actinometer System to Monitor UV-A Exposure in Photostability Studies of

Pharmaceutical Drug Substances and Drug Products," Pharmacopeial Forum, 24(3):6334, 1998.

Drew, H.D., L.K. Thornton, W.E. Juhl, and J.F. Brower, "An FDA/PhRMA

Interlaboratory Study of the International Conference on Harmonization's Proposed Photostability

Testing Procedures and Guidelines," Pharmacopeial Forum, 24(3):6317, 1998.

Sager, N., R.G. Baum, R.J. Wolters, and T. Layloff, "Photostability Testing of

Pharmaceutical Products," Pharmacopeial Forum, 24(3):6331, 1998.

Yoshioka, S., et al., "Quinine Actinometry as a Method for Calibrating Ultraviolet

Radiation Intensity in Light-Stability Testing of Pharmaceuticals," Drug Development and

Industrial Pharmacy, 20(13):2049-2062, 1994.