**75**

**Guidance for Industry**

**[Stability testing: Photostability testing of New Veterinary Drug
Substances and Medicinal Products]{.smallcaps}**

####### 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
Carol Haley, Policy & Regulations Team, Center for Veterinary Medicine,
(HFV-6), Food and Drug Administration, 7500 Standish Place, Rockville,
MD 20855.**

**For questions regarding this guidance document, contact William G.
Marnane, Center for Veterinary Medicine, (HFV-140), Food and Drug
Administration, 7500 Standish Place, Rockville, MD 20855, 301-827-6966,
E-mail: wmarnane@cvm.fda.gov.**

**U.S. Department of Health and Human Services**

###### Food and Drug Administration

######## Center for Veterinary Medicine

**September 1999**

**VICH GL5 [(stability 3)]{.smallcaps}**

**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]{.smallcaps} USA.

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](#general)

A. Preamble [4](#a.-preamble)

B. Light Sources [4](#b.-light-sources)

Option 1 [5](#option-1)

Option 2 [5](#option-2)

C. Procedure [5](#c.-procedure)

DECISION FLOW CHART FOR PHOTOSTABILITY TESTING OF DRUG PRODUCTS
[6](#decision-flow-chart-for-photostability-testing-of-drug-products)

2\. Drug Substance [7](#drug-substance)

A. Presentation of Samples [7](#a.-presentation-of-samples)

B. Analysis of Samples [7](#b.-analysis-of-samples)

C. Evaluation of Results [8](#c.-evaluation-of-results)

3\. Drug Product [8](#drug-product)

A. Presentation of Samples [8](#a.-presentation-of-samples-1)

B. Analysis of Samples [9](#b.-analysis-of-samples-1)

C. Evaluation of Results [9](#c.-evaluation-of-results-1)

4\. Annex [9](#annex)

Quinine Chemical Actinometry [9](#quinine-chemical-actinometry)

Option 1 [9](#option-1-1)

Option 2 [9](#option-2-1)

5\. Glossary [10](#glossary)

6\. References [10](#references)

**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.

### 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.

## DECISION FLOW CHART FOR PHOTOSTABILITY TESTING OF DRUG PRODUCTS

![](media/image1.wmf){width="5.09375in" height="6.958333333333333in"}

# 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 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).

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, ∆ 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, ∆ 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)

# 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)