75 

 Guidance for Industry

STABILITY TESTING: PHOTOSTABILITY TESTING 

OF NEW VETERINARY DRUG SUBSTANCES AND 

MEDICINAL PRODUCTS

VICH GL5 

FINAL GUIDANCE

This guidance is an annex to the VICH parent guidance entitled “Stability Testing of New 

Veterinary Drug Substances and Medicinal Products” (VICH GL3). It primarily addresses the 

generation of photostability information for submission in new animal drug applications 

(referred to as Registration Applications in the VICH parent guidance) for new molecular 

entities and associated drug products. The guidance does not cover the photostability of drugs 

after administration (i.e. under conditions of use) and those applications not covered by the 

VICH parent guidance. 

This guidance represents current thinking and does not create or confer any rights for or 

on any person and does not operate to bind FDA or the public. You may use alternative 

methods as long as they satisfy the requirements of the applicable statute and regulation. 

Comments and suggestions regarding the document should be submitted to Division of Dockets 

Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, 

Rockville, MD 20852. Submit electronic comments to http://www.regulations.gov. All 

comments should be identified with the Docket No. 1998D-0566. 

For questions regarding this document, contact Norman Gregory, Center for Veterinary 

Medicine, (HFV-143), Food and Drug Administration, 7500 Standish Place, Rockville, MD 

20855, 240-276-8253, e-mail: norman.gregory@fda.hhs.gov. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Veterinary Medicine 

September 1999 
Contains Non-Binding Recommendations 

VICH GL5 (STABILITY 3) 

May 1999 

For implementation at Step 7 

Stability Testing: Photostability Testing of New 

Veterinary Drug Substances and Medicinal 

Products 

Recommended for Implementation 

at Step 7 of the VICH Process 

on 20 May 1999 

by the VICH Steering Committee 

THIS FINAL GUIDANCE HAS BEEN DEVELOPED BY THE APPROPRIATE VICH EXPERT WORKING 

GROUP ON THE BASIS OF THE ICH GUIDANCES ON THE SAME SUBJECT AND IS SUBJECT TO 

CONSULTATION BY THE PARTIES, IN ACCORDANCE WITH THE VICH PROCESS. AT STEP 7 OF THE 

PROCESS THE FINAL DRAFT WILL BE RECOMMENDED FOR ADOPTION TO THE REGULATORY BODIES 

OF THE EUROPEAN UNION, JAPAN, AND USA. 

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Contains Non-Binding Recommendations 

STABILITY TESTING : PHOTOSTABILITY TESTING OF NEW 

VETERINARY DRUG SUBSTANCES AND MEDICINAL PRODUCTS

Recommended for Implementation at Step 7 of the VICH Process 

on 20 May 1999 by the VICH Steering Committee 

TABLE OF CONTENTS 

1. General.......................................................................................................... 4 

A. Preamble ............................................................................................... 4 

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

Option 1 .................................................................................................................................5 

Option 2 .................................................................................................................................5 

C. Procedure.............................................................................................. 5 

DECISION FLOW CHART FOR PHOTOSTABILITY TESTING OF DRUG 

PRODUCTS............................................................................................... 6 

2. Drug Substance............................................................................................ 7 

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

B. Analysis of Samples .............................................................................. 7 

C. Evaluation of Results............................................................................. 8 

3. Drug Product ................................................................................................ 8 

A. Presentation of Samples........................................................................ 8 

B. Analysis of Samples .............................................................................. 9 

C. Evaluation of Results............................................................................. 9 

4. Annex ............................................................................................................ 9 

Quinine Chemical Actinometry................................................................... 9 

Option 1 .................................................................................................................................9 

Option 2 .................................................................................................................................9 

5. Glossary...................................................................................................... 10 

6. References.................................................................................................. 10 

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Contains Non-Binding Recommendations 

STABILITY TESTING: PHOTOSTABILITY TESTING OF 

NEW VETERINARY DRUG SUBSTANCES AND MEDICINAL PRODUCTS 

1. General 

The VICH Harmonized Tripartite Guidance covering the Stability Testing of New Drug 

Substances and Products in the Veterinary Field (hereafter referred to as the Parent Guidance) 

notes that light testing should be an integral part of stress testing. This document is an annex to 

the Parent Guidance 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 Guidance. 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 guidance primarily addresses the generation of photostability information for submission in 

Registration Applications for new molecular entities and associated drug products. The 

guidance does not cover the photostability of drugs after administration (i.e. under conditions of 

use) and those applications not covered by the Parent Guidance. Alternative approaches may 

be used if they are scientifically sound and justification is provided. 

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. 

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. 

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Contains Non-Binding Recommendations 

Option 1 

Any light source that is designed to produce an output similar to the D65/lD65 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 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. 

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. 

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Contains Non-Binding Recommendations 

DECISION FLOW CHART FOR PHOTOSTABILITY TESTING OF DRUG 

PRODUCTS 

START

DIRECTLY EXPOSED

ACCEPTABLE 

CHANGE?

ACCEPTABLE 

CHANGE?

IMMEDIATE PACK

MARKETING PACK

ACCEPTABLE 

CHANGE?

REDESIGN PACKAGE 

OR REFORMULATION

FORMULATION 

CHANGE?

iMMEDIATE 

PACK 

CHANGE?

MARKETING 

PACK 

CHANGE?

TEST END

TEST END

TEST END

yes

yes

yes

yes

yes

yes

no

no

no

no

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Contains Non-Binding Recommendations 

2. 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 further 

examined. 

Confirmatory studies should then be undertaken to provide the information necessary for 

handling, packaging, and labeling (see section 1.C., Procedure, and 2.A., Presentation of 

Samples, 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 Guidance 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 Guidance. 

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 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 

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Contains Non-Binding Recommendations 

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. Evaluation 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 VICH Stability 

and Impurity Guidances). 

3. 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 1.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 Guidance 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, 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. 

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 drug 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). 

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Contains Non-Binding Recommendations 

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. Evaluation 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 should be within proposed 

specifications during the shelf life (see the relevant VICH Stability and Impurity Guidances). 

4. Annex 

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 percent weigh/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. 

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Contains Non-Binding Recommendations 

Page 10 

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

ampoule specifications) 

Stem diameter: 21.8 ± 0.40 mm 

Bore (at cutting portion) 

 Bore: 7.0 ± 0.7 mm, 

Stem diameter 

Stem length

Stem length: 80.0 ± 1.2 mm 

5. 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 testings which is described 

in the Parent Guidance. 

6. References 

Quinine Actinometry as a method for calibrating ultraviolet radiation intensity in light-stability 

testing of pharmaceuticals. 

Yoshioka S. et al., Drug Development and Industrial Pharmacy, 20 (13), 2049 - 2062 (1994)