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discussions, stats, and author profiles for this publication at: http://www.researchgate.net/publication/41410325

A critical assessment of the ICH guideline on

photostability testing of new drug substances
and products (Q1B): Recommendation for
revision
ARTICLE in JOURNAL OF PHARMACEUTICAL SCIENCES JULY 2010
Impact Factor: 3.01 DOI: 10.1002/jps.22076 Source: PubMed

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COMMENTARY
A Critical Assessment of the ICH Guideline on Photostability
Testing of New Drug Substances and Products (Q1B):
Recommendation for Revision
STEVEN W. BAERTSCHI,1 KAREN M. ALSANTE,2 HANNE H. TNNESEN3
1

Eli Lilly and Company, Analytical Sciences Research and Development, Lilly Research Laboratories, Indianapolis, Indiana 46285

Pzer Global Research & Development, Analytical Research & Development, Eastern Point Rd., Box 4077,
Groton, Connecticut 06340

Department of Pharmaceutics, School of Pharmacy, University of Oslo, PO Box 1068, Blindern, 0316 Oslo, Norway

Received 20 November 2009; accepted 4 December 2009

Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.22076
ABSTRACT: The ICH guideline on photostability (ICH Topic Q1B) was published in November
1996 and has been implemented in all three regions (US, EU, and Japan). The guideline
describes a useful basic protocol for testing of new drug substances and associated drug products
for manufacturing, storage, and distribution, but it does not cover the photostability of drugs
under conditions of patient use. The pharmaceutical industry now has considerable experience
in designing and carrying out photostability studies within the context of this guideline, and
issues have been identied that would benet from the revision process. The purpose of this
commentary is to accomplish the following: (i) highlight issues proposed for consideration in
the ICH revision process, (ii) offer a rationale for why these issues may compromise the design of
a testing protocol and/or the results of the testing program, and (iii) provide recommendations
for clarication of the guideline. 2010 Wiley-Liss, Inc. and the American Pharmacists Association J
Pharm Sci 99:29342940, 2010

Keywords:
stability

physical stability; chemical stability; analytical chemistry; stability; solid state

INTRODUCTION
The ICH guideline on photostability (ICH Topic
Q1B)1 was published in November 1996 and has
been implemented in all three regions (US and
Canada, EU, and Japan). After January 1, 1998, it
is obligatory to provide photostability information
constructed according to this guideline for all new
drug license applications led in these regions.
The guideline describes a useful basic protocol for
testing of new drug substances and associated drug
products for manufacturing, storage, and distribution, but it does not cover the photostability of

drugs under conditions of patient use. It recommends

a systematic approach to photostability testing on the
drug substance and drug product according to a
decision ow chart. The outline of the guideline is as
follows:

Correspondence to: Steven W. Baertschi (Telephone: 317-2761388; Fax: 317-277-2154; E-mail: baertschi@lilly.com)
Journal of Pharmaceutical Sciences, Vol. 99, 29342940 (2010)
2010 Wiley-Liss, Inc. and the American Pharmacists Association

2934

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010

(I) General
(A) Preamble
(B) Light sources
(C) Procedure
(II) Drug substance
(A) Presentation of samples
(B) Analysis of samples
(C) Judgment of results
(III) Drug product
(A) Presentation of samples
(B) Analysis of samples
(C) Judgment of results

ICH GUIDELINE ON PHOTOSTABILITY

(IV) Annex
(A) Quinine chemical actinometry
(V) Glossary
(VI) Reference
The tests are pass/fail tests where acceptable
change is change within limits justied by the applicant. Despite the implementation of the
ICH photostability guideline, issues remain that
are not specically covered in the document
and which are left to the applicants discretion.2,3
The guideline allows for alternative approaches
assuming that these are scientically sound.
The aim of the photostability testing should be
to demonstrate that exposure to irradiation does
not result in an unacceptable change. It is left to
the applicant to establish how the product will
be used and to undertake appropriate photostability
studies. The pharmaceutical industry now has considerable experience in designing and carrying out
photostability studies within the context of this
guideline, and issues have been identied that would
benet from a revision process. The purpose of this
commentary is to accomplish the following:
(i) highlight issues proposed for consideration in
the ICH revision process;
(ii) offer a rationale for why these issues may
compromise the design of a testing protocol
and/or the results of the testing program;
(iii) provide recommendations for clarication of
the guideline.

FORCED AND CONFIRMATORY STUDIES

The guideline calls for forced degradation studies
(stress testing) and a conrmatory study. A
forced degradation study is testing under forcing
conditions to characterize intrinsic stability characteristics of the drug substance or drug product,
to determine degradation products and reaction
mechanisms, and to develop appropriate methodology
for detection and quantitation. Conrmatory studies
involve testing under conditions designed to generate
data to predict what might happen during ambient
storage, and to determine whether precautionary
measures are needed during formulation, production,
and storage. A conrmatory study can be regarded as
a limit test, and should conclude with acceptable or
unacceptable change.
Comments:
a. In II. Drug Substance, the rst paragraph reads:
For drug substances, photostability testing should
consist of two parts: forced degradation testing and
conrmatory testing.
DOI 10.1002/jps

2935

This is not stated in section III. Drug product.

Additional guidance should be given to the
applicant for photostability forced degradation of
drug product samples. It is recommended that the
guidance clearly state that photostability/photodegradation is a function of the system (i.e., the
formulation plus the drug) and not just the
drug molecule, as clearly evidenced by examples
documented in the literature.4,5
b. In V. Glossary, drug product testing is not
mentioned in the denition of forced degradation
testing studies.

SEQUENTIAL TESTING
A sequential testing approach is recommended. The
sample should rst be tested unpacked, with direct
exposure to the radiation source. If necessary, a
transparent (with known UV/Vis transmittance)
container may be used for liquid or semisolid
products. Samples that are found to be unstable
should then be further tested in primary and
secondary (market) packs as necessary. Products
that are stable in the primary pack but unstable
without it should be labeled in such a way that a
transfer into a less protective pack, for example, by a
pharmaceutical wholesaler or in a hospital pharmacy,
is prevented. It is unnecessary to conduct tests in
containers completely impenetrable to radiation
(e.g., aluminum foil) when these are used for direct
dispensing to the patient.
Comments:
c. The rst paragraph of III. Drug product states:
Testing should progress until the results demonstrate that the drug product is adequately protected from exposure to light.
To avoid confusion, it should be clearly stated
that if no light degradation is observed in the fully
exposed sample, no further testing needs to be
performed. This text change would more clearly
support the Decision Tree diagram.
d. III. Drug Product, foil/foil blisters should be
added to the list of immediate packs impenetrable
to light to be more complete.

IRRADIATION SOURCE
The ICH guideline gives two options for the selection
of the irradiation source. Option 1 addresses exposure
to outdoor daylight or window glass ltered daylight.
Option 1 advises exposing the samples to UVB, UVA,
and visible light simultaneously. In practice, Option 1
offers the choice between three different types of
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2936

BAERTSCHI, ALSANTE, AND TNNESEN

sources. Glass-ltered daylight can be obtained by

use of a full spectrum or daylight uorescent lamp,
which has both UV and Vis output, or by use of a
xenon lamp or metal halide lamp, both in combination
with appropriate lters. Option 2 radiation sources
attempt to mimic indoor lighting conditions which
(assuming that the room has a window) is composed of
glass-ltered daylight and articial radiation provided by cool white uorescent lamps. This option
allows for the use of two separate lamps; one for the
UVA emission and one for the visible light. The lamps
can be used in combination or sequentially. It has
been noted that a combination of sources specied in
Option 2 may produce little or no output between 380
and 430 nm.4 It is important to check that the sample
(API or drug substance) does not absorb primarily in
this region to avoid an articial lack of photodegradation.
Comments:
e. The term light source is used throughout the
guideline. Light refers, however, to the photopic
response, i.e., radiant energy acting on the retina.
Visual perception is normally taken to cover the
range 400800 nm with a maximum in response
sensitivity around 550 nm. Although the term light
often is recognized as having a broader meaning,
the scientically correct terms in this context are
radiation, photon, or photolysis source. These will
cover both the UV regions and the visible light.
f. Clarity on sequential/simultaneous nature of
Option 2 exposure to UVA and cool white
uorescent light is needed. The guideline gives
no guidance as to whether samples should be
exposed to the two Option 2 light sources simultaneously or sequentially, and if sequentially, does
order matter? Clarication is needed.
g. Clarity on description of Option 1 and Option 2
lamp output/emission is needed. What is similar
to? The guideline states Any light source that
is designed to produce an output similar to the D65/
ID65 emission standard . . . D65 and ID65 are two
different standards, so there is some confusion
as to which should be used for studies with
Option 1 light sources. It appears that the guideline is suggesting that either one of the standards
(D65 or ID65) is appropriate, yet the suggestion for
use of a window-glass lter to eliminate radiation
below 320 nm indicates that the ID65 emission
standard is preferred. Rewording of this section for
clarity would be useful to the industry.
The specic wording of the guideline with regard
to the description of Option 2 sources is also
confusing. Researchers in the industry often
struggle to nd a cool white uorescent light
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010

as dened in ISO10977, and some guidance

would be helpful. Similarly, the description of
the near UV uorescent lamp is also vague, which
can increase the risk of improper choice of near UV
lamps.6
It is notable that Riehl et al.7 describe in the
Pharmacopeial Forum requirements for the UVA
uorescent lamp emission that are more specic
and detailed than the guideline presents. The ICH
guideline simply states that the lamp provide a
spectral distribution from 320 to 400 nm with a
maximum energy emission between 350 and
370 nm; a signicant proportion of UV should be
in both bands of 320360 nm and 360400 nm. In
contrast, Riehl asserts in his Pharmacopeial
Forum article that at least 25% of the ultraviolet-A must be between 320 and 360 nm and at least
25% must be between 360 and 400 nm. Consideration should be given to incorporating these
requirements into the revised guidance.

OVERALL ILLUMINATION AND EXPOSURE TIME

The ICH guideline recommends a total exposure of
not less than 200 W-h m 2 in the UV range (320
400 nm) and 1.2 million lux-h in the visible range
(400800 nm) for conrmatory studies. For a lamp
with a spectral output similar to the ID65 standard
(i.e., Option 1) a total irradiance of 200 W-h m 2 in the
UV region corresponds to 0.45 million lux-h in the
visible region. A test run with the end criterion
1.2 million lux h will therefore exceed the minimum
requirement 200 W-h m 2 by a factor of 2.53 by use
of irradiation sources that are compliant with either
the D65 or ID65 standards, according to Option 1. The
problem can be avoided by selecting the following
approach:
 Option 1 and Option 2 approaches can be combined.
The minimum 200 W-h/m2 could be met using an
Option 1 source and the visible light exposure could
then be fullled by exposure to a cool white uorescent light. The Option 1 source would serve as a
surrogate for the UVA component of the exposure.
Further, the ICH guideline does not specify an
irradiance level, only the overall illumination (i.e.,
end criterion). Test conditions corresponding to
the maximum output of the lamp will often be the
rst choice as the exposure time thereby can be
reduced. It is, however, important to realize that a
high irradiance level can change the mechanisms
of the degradation process even when the spectral
distribution of the radiation source is kept
constant.8,9
DOI 10.1002/jps

ICH GUIDELINE ON PHOTOSTABILITY

2937

Comments:
h. Clarity on length of exposure when using Option
1 conditions is needed. In I. C. Procedure, the
guidelines state: For conrmatory studies, samples should be exposed to light providing an overall
illumination of not less than 1.2 million lux-h and
an integrated near ultraviolet energy of not less
than 200-h/m2 to allow direct comparisons to be
made between the drug substance and drug
product. This statement is clear for exposure
time when using Option 2 with separate UV and
visible light sources; however, the minimum
exposure of 1.2 million lux-h and 200-h/m2 needs
to be specied when using Option 1. What could be
made clear in the guideline is that both requirements need to be met (at a minimum), and that a
combined Option 1 then Option 2 approach is
acceptable (in addition to the other approaches
suggested above).

PRESENTATION OF SAMPLES
The presentation of samples within the test chamber
can have a signicant effect on the outcome of the
photostability study. Important issues are alignment
of the samples relative to the irradiation source,
thickness of sample layer, selection of protective
material, uniform exposure of the samples, change in
temperature and humidity, and appropriate dark
controls.2,10
Comments:
j. In II. Drug substance, A. Presentation of Samples,
the guideline states: Solid drug substances should
be spread across the container to give a thickness
of typically not more than 3 mm. We suggest
removing typically stating . . . to give a thickness
not more than 3 mm.
k. In III. Drug Product, A. Presentation of Samples,
the guideline states: Some adjustment of testing
conditions may have to be made when testing large
volume containers (e.g., dispensing packs).
Guidance should be provided to the applicant to
ensure that the samples tested are those samples
with the greatest light exposure in the container.
This would make the photostability testing in
the containers more consistent with the direct
exposure testing, where it is stated that The
samples should be positioned to provide maximum
area of exposure to the light source. For example,
tablets and capsules, should be spread in a single
layer. An example diagram has been provided in
Figure 1.
l. Use of dark controls should be more rmly
stated. In I. C. Procedure, the guidelines state: If
DOI 10.1002/jps

Figure 1. Illustration of sample presentation for solid

oral dosage forms in their immediate packaging.

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. A suggested change to
this statement is Protected samples (e.g., wrapped
in aluminum foil) should be 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.
m. In II. Drug Substance, B. Analysis of Samples
and III. Drug Product, B. Analysis of Samples, the
last sentence states: 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. We suggest removing
the clause if these are used in the test to more
rmly stress the use of dark controls.

JUDGMENT OF RESULTS
Photostability testing according to the ICH guideline
will give an indication as to whether photochemical
degradation of the drug substance or drug product is
likely to occur during its synthesis, manufacture,
packaging, or shelf-life. Quantitative photostability
results must be evaluated together with long-term
stability results. The results obtained are used to
make packaging and labeling decisions as well as
patient use decisions (labeling directions for use).
When the combined results from photostability and
thermal studies do not meet the specications at the
proposed expiry, the results must be considered as
unacceptable unless a reduction in expiration date is
an option.
The guideline does not include the design of in-use
tests or cover abridged applications.
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2938

BAERTSCHI, ALSANTE, AND TNNESEN

Comments:
o. Clarity on interpretation of results is needed. In
I. A. Preamble, it is stated: Acceptable change is
change within limits justied by the applicant.
It would be useful to have more clarity on
determining an acceptable result.
In II. Drug Substance, C. Judgment of Results,
second paragraph, it is stated that the conrmatory studies should identify precautionary
measures needed in manufacturing or in formulation of the drug product, and if light resistant
packaging is needed. It would be useful to consider
parsing out manufacturing, formulation, and
storage/distribution for both the drug substance
and drug product. The more critical area of concern
is manufacturing (for both the drug substance and
product); a failure of a full conrmatory test
may or may not present a signicant problem
for manufacturing light exposures since these
light exposures are typically much less than the
minimum recommended conrmatory exposure. It
would be useful to briey discuss this topic to bring
clarity for the industry.
p. In the case of section III. Drug Product, C.
Judgment of Results, the guideline states that it is
important to consider the results obtained from
other formal stability studies in order to assure
that the product will be within proposed specications during the shelf life . . .. Anderson11 illustrated the concepts intended by the ICH Expert
Working group in a presentation in 1997, and this
illustration has been published by Thatcher et al.12
(see Fig. 2). Some modication of the guideline to
provide clarity as found in this illustration would
be helpful.

Figure 2. Example showing how conrmatory photostability results can be used in conjunction with denitive
stability results for the judgement of shelf-life of a drug
substance or product.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 7, JULY 2010

q. Clarity on term equivocal is needed. In II. Drug

Substance, the last paragraph, and in III. Drug
Product the term equivocal is used. Equivocal
apparently means doubtful, questionable, or
suspicious, and in the context it can be understood to mean that the results are such that it is
not obvious whether or not the drug is clearly
photostable or photolabile. Some clarity is needed
to enable meaningful decisions regarding the
assessment of whether the results of a conrmatory photostability test are equivocal.
r. Clarity on use and interpretation of dark
controls (section C. Procedure, last paragraph)
is needed. It is inferred that the dark control is to
enable differentiation between thermal degradation and photodegradation. This should be specically mentioned under Judgment of Results.
s. In-use photostability testing guidance (e.g.,
dermal creams, IV preparations, transdermal
patches, topical agents) is not covered by the
guideline. Some guidance would be helpful to the
industry, but perhaps this should come in a
separate guidance.

CALIBRATION
The ICH guideline recommends the use of a
calibrated radiometer or a validated actinometric
system to monitor the exposure in the UV region. A
calibrated luxmeter is recommended to determine the
overall illumination in the visible range. Neither
the UV lter radiometer nor the luxmeter provide
information on the spectral power distribution (SPD,
the plot of radiation intensity vs. wavelength) of the
sources. Further, these devices cannot be used to
obtain an absolute measurement of irradiance or to
compare irradiance between sources unless they are
calibrated specically for each source.13 Spectroradiometric data should be provided by the lamp
manufacturer upon request. A detailed estimate of
the SPD is obtained by use of a spectroradiometer.
The total irradiance (i.e., actual number of photons)
can be determined by chemical actinometry using a
reaction of known photochemical efciency. The
chemical actinometer listed in the ICH guideline
(quinine hydrochloride) has its limitations and it is
not suitable for calibration of Option 1 radiation
sources.
Comments:
t. Quinine is listed in the guideline for use in a
primary actinometric procedure for monitoring
exposure to the near UV region of the light source.
The next sentence states that The actinometric
DOI 10.1002/jps

ICH GUIDELINE ON PHOTOSTABILITY

systems should be calibrated for the type of sources

used. (IV. Annex A. Chemical Actinometry, rst
paragraph). The third paragraph states For near
UV lamps, the length of the exposure should be
sufcient to ensure a change in absorbance
observed of at least 0.8. There has been signicant
confusion in the industry around the proper use of
this actinometer.
The actinometer has only been validated for one
particular lamp (Sylvania F20T12/BLB UVA
uorescent lamp) with a certain spectral power
distribution (SPD).11,14 Other lamps with similar
SPDs should give similar results, but UVA
uorescent lamps with a different SPD will give
signicantly different results. This limitation
needs to be made clear in the guideline. It would
be useful to publish the SPD of the lamp for which
quinine was calibrated in the guideline.
Another problem that has been discovered since
the publication of the guideline is that the timing of
the measurement of absorbance at 400 nm is
critical to the result. That is, Kester et al.15 has
shown that the quinine absorbance at 400 nm
continues to increase after the exposure to the
lamp has ceased (for more than 60 h!) at approximately one-fth the rate of increase in absorbance
that is observed during exposure to the source.
Signicantly different results can be observed,
depending on whether or not the quinine solution
absorbance is measured immediately after exposure to the lamp or after a delay. This source of
error should be eliminated.
It should also be made clear in the guideline that
Option 1 light sources are not amenable to use with
quinine as an actinometer. Many researchers have
spent considerable time trying to calibrate/validate
quinine for Option 1 sources only to discover that
this is not feasible. For example, Baertschi16
showed that with a xenon lamp that quinine is
sensitive to dissolved oxygen content and temperature. Christensen et al.17 also showed the
temperature dependence of the quinine actinometry system and proposed recommended maximum
holding times of 2 h prior to absorbance measurement. Thatcher et al.18 and Gauglitz19 also
discussed limitations of the actinometer. Brower
et al.14 explicitly state that quinine is not suitable
for Option 1 sources. Nonetheless, it is apparent
that many in the industry are not aware of these
limitations because of the absence of such critical
information in the guideline.
Another line in the actinometry section deserves
some attention. The last line of this section states
that Alternative validated chemical actinometers
may be used. Coupled with the last sentence in the
rst paragraph, The actinometric systems should
be calibrated for the type of sources used, it is
DOI 10.1002/jps

2939

apparent that some guidance should be provided

for the term validated so the researcher is not left
to invent the validation procedure.
Finally, only one container is recommended for
the actinometric solution (a 20-mL colorless
ampoule), and that container is not adequately
dened by the guideline. The dimensions are given,
but the type of glass, thickness of the glass, and the
transmission characteristics of the glass are
undened. Such details are critically important
to dene since variations can lead to dramatically
different results. Provision for other containers
(specically, quartz UV cells of dened dimensions
and spectral characteristics) would be helpful.
There has been some confusion as to whether
Option 1 and Option 2 as listed in the Annex
is intended to indicate that that these are the
intended actinometric solution containers for
Option 1 light sources (the glass ampoule) and
Option 2 light sources (quartz UV cells), or if
these are just two Options for containers to use
with the actinometric solution.

CONCLUSION
The ICH guideline on photostability has provided the
industry with needed guidance on photostability
testing since its approval and publication in 1996.
Since then, various issues of signicance have been
identied by both academic and industry researchers
that point to the need for the guidance to undergo the
revision process as outlined by ICH. Notwithstanding, many who use the guideline are not aware of
these issues and potential ramications. We have
attempted to capture the major issues in this
commentary, along with suggestions for revising
the guidance. It is our hope that a revised photostability guidance document will provide clarity to
the industry and eliminate potential errors and
misapplication.

ACKNOWLEDGMENTS
The authors gratefully acknowledge helpful comments provided by Robert A. Reed and Bernard A.
Olsen during the preparation and review of this
commentary.

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