[Federal Register Volume 62, Number 95 (Friday, May 16, 1997)]
[Notices]
[Pages 27116-27122]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-12850]
[[Page 27115]]
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Part II
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
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International Conference on Harmonisation; Guidelines for the
Photostability Testing of New Drug Substances and Products;
Availability; Notice
Federal Register / Vol. 62, No. 95 / Friday, May 16, 1997 / Notices
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 96D-0010]
International Conference on Harmonisation; Guideline for the
Photostability Testing of New Drug Substances and Products;
Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is publishing a
guideline entitled ``Guideline for the Photostability Testing of New
Drug Substances and Products.'' The guideline was prepared under the
auspices of the International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use (ICH).
The guideline describes the basic testing protocol for photostability
testing of new drug substances and products in original new drug
application submissions. The guideline is an annex to the ICH guideline
entitled ``Stability Testing of New Drug Substances and Products.''
DATES: Effective May 16, 1997. Submit written comments at any time.
ADDRESSES: Submit written comments on the guideline to the Dockets
Management Branch (HFA-305), Food and Drug Administration, 12420
Parklawn Dr., rm. 1-23, Rockville, MD 20857. Copies of the guideline
are available from the Drug Information Branch (HFD-210), Center for
Drug Evaluation and Research, Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-827-4573.
FOR FURTHER INFORMATION CONTACT:
Regarding the guideline: Nancy B. Sager, Center for Drug Evaluation
and Research (HFD-357), Food and Drug Administration, 5600 Fishers
Lane, Rockville, MD 20857, 301-594-5721.
Regarding the ICH: Janet J. Showalter, Office of Health Affairs
(HFY-20), Food and Drug Administration, 5600 Fishers Lane, Rockville,
MD 20857, 301-827-0864.
SUPPLEMENTARY INFORMATION: In recent years, many important initiatives
have been undertaken by regulatory authorities and industry
associations to promote international harmonization of regulatory
requirements. FDA has participated in many meetings designed to enhance
harmonization and is committed to seeking scientifically based
harmonized technical procedures for pharmaceutical development. One of
the goals of harmonization is to identify and then reduce differences
in technical requirements for drug development among regulatory
agencies.
ICH was organized to provide an opportunity for tripartite
harmonization initiatives to be developed with input from both
regulatory and industry representatives. FDA also seeks input from
consumer representatives and others. ICH is concerned with
harmonization of technical requirements for the registration of
pharmaceutical products among three regions: The European Union, Japan,
and the United States. The six ICH sponsors are the European
Commission, the European Federation of Pharmaceutical Industries
Associations, the Japanese Ministry of Health and Welfare, the Japanese
Pharmaceutical Manufacturers Association, the Centers for Drug
Evaluation and Research and Biologics Evaluation and Research, FDA, and
the Pharmaceutical Research and Manufacturers of America. The ICH
Secretariat, which coordinates the preparation of documentation, is
provided by the International Federation of Pharmaceutical
Manufacturers Associations (IFPMA).
The ICH Steering Committee includes representatives from each of
the ICH sponsors and the IFPMA, as well as observers from the World
Health Organization, the Canadian Health Protection Branch, and the
European Free Trade Area.
In the Federal Register of March 7, 1996 (61 FR 9310), FDA
published a draft tripartite guideline entitled ``Guideline for the
Photostability Testing of New Drug Substances and Products.'' The
notice gave interested persons an opportunity to submit comments by
June 5, 1996.
After consideration of the comments received and revisions to the
guideline, a final draft of the guideline was submitted to the ICH
Steering Committee and endorsed by the three participating regulatory
agencies at the ICH meeting held on November 5, 1996.
In the Federal Register of September 22, 1994 (59 FR 48754), the
agency published a guideline entitled ``Stability Testing of New Drug
Substances and Products.'' The guideline addresses the generation of
stability information for submission to FDA in new drug applications
for new molecular entities and associated drug products. In the
discussion of ``stress testing'' for both drug substances and drug
products, the guideline states that ``light testing'' should be an
integral part of stress testing and will be considered in a separate
ICH document.
This guideline is an annex to that guideline and describes the
basic testing protocol for photostability testing of new drug
substances and products in original new drug application submissions.
This guideline 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.
As with all of FDA's guidelines, the public is encouraged to submit
written comments with new data or other new information pertinent to
this guideline. The comments in the docket will be periodically
reviewed, and, where appropriate, the guideline will be amended. The
public will be notified of any such amendments through a notice in the
Federal Register.
Interested persons may, at any time, submit written comments on the
guideline to the Dockets Management Branch (address above). Two copies
of any comments are to be submitted, except that individuals may submit
one copy. Comments are to be identified with the docket number found in
brackets in the heading of this document. The guideline and received
comments may be seen in the office above between 9 a.m. and 4 p.m.,
Monday through Friday. An electronic version of this guideline is
available on the Internet using the World Wide Web (WWW) (http://
www.fda.gov/cder/guidance.htm).
The text of the guideline follows:
Guideline for the 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
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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.
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.
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BILLING CODE 4160-01-C
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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.
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 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 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. 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).
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.
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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).
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
A. Quinine Chemical Actinometry
The following provides details of an actinometric procedure for
monitoring exposure to a near UV flourescent 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 weight/volume
aqueous solution of quinine monohydrochloride dihydrate (if
necessary, dissolve by heating).
Option 1
Put 10 milliliters (mL) of the solution into a 20 mL colorless
ampoule, seal it hermetically, and use this as the sample.
Separately, put 10 mL of the solution into a 20 mL 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 = 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)
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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
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.
Dated: May 2, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-12850 Filed 5-15-97; 8:45 am]
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