[Federal Register Volume 61, Number 46 (Thursday, March 7, 1996)]
[Notices]
[Pages 9310-9313]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-5295]
[[Page 9309]]
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Part V
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
International Conference on Harmonisation; Draft Guideline for the
Photostability Testing of New Drug Substances and Products;
Availability; Notice
Federal Register / Vol. 61, No. 46 / Thursday, March 7, 1996 /
Notices
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[[Page 9310]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 96D-0010]
International Conference on Harmonisation; Draft 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 draft
guideline entitled ``Guideline for the Photostability Testing of New
Drug Substances and Products.'' The draft guideline was prepared under
the auspices of the International Conference on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for Human
Use (ICH). The draft guideline describes the basic testing protocol for
photostability testing of new drug substances and products in original
new drug application (NDA) submissions. The draft guideline is an annex
to the ICH guideline entitled ``Stability Testing of New Drug
Substances and Products.''
DATES: Written comments by June 5, 1996.
ADDRESSES: Submit written comments on the draft guideline to the
Dockets Management Branch (HFA-305), Food and Drug Administration,
12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857. Copies of the draft
guideline are available from the Division of Communications Management
(HFD-210), Center for Drug Evaluation and Research, Food and Drug
Administration, 7500 Standish Pl., Rockville, MD 20855, 301-594-1012.
An electronic version of this draft guideline is also available via
Internet by connecting to the CDER file transfer protocol (FTP) server
(CDVS2.CDER.FDA.GOV).
FOR FURTHER INFORMATION CONTACT:
Regarding the guideline: Robert J. Wolters, Center for Drug
Evaluation and Research (HFD-110), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-594-5300.
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.
At a meeting held on November 29, 1995, the ICH Steering Committee
agreed that a draft guideline entitled ``Guideline for the
Photostability Testing of New Drug Substances and Products'' should be
made available for public comment. The draft guideline is the product
of the Quality Expert Working Group of the ICH. Comments about this
draft will be considered by FDA and the Quality Expert Working Group.
Ultimately, FDA intends to adopt the ICH Steering Committee's
guideline.
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 NDA's 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 draft guideline is an annex to that guideline and describes
the basic testing protocol for photostability testing of new drug
substances and products in original NDA submissions.
In the past, guidelines have generally been issued under
Sec. 10.90(b) (21 CFR 10.90(b)), which provides for the use of
guidelines to state procedures or standards of general applicability
that are not legal requirements but are acceptable to FDA. The agency
is now in the process of revising Sec. 10.90(b). Although this
guideline does not create or confer any rights on or for any person and
does not operate to bind FDA in any way, it does represent the agency's
current thinking on photostability testing of new drug substances and
products.
Interested persons may, on or before June 5, 1996, submit written
comments on the draft 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 draft guideline and received comments may be seen in the
office above between 9 a.m. and 4 p.m., Monday through Friday.
The text of the draft guideline follows:
Guideline for the Photostability Testing of New Drug Substances and
Products
I. General
The ICH Harmonized Tripartite Guideline covering the Stability
Testing of New Drug Substances and Products (hereafter referred to
as the parent guideline) notes that light testing should be an
integral part of stress testing. This document is an annex to the
parent guideline and addresses the recommendations for
photostability testing.
A. Preamble
The intrinsic photostability characteristics of new drug
substances and products should be evaluated to demonstrate that, as
appropriate, light exposure does not result in unacceptable change.
Normally, photostability testing is carried out on a single batch of
material selected as described under ``Selection of Batches'' in the
parent guideline. Under some circumstances, these studies should be
repeated if certain variations and changes are made to the product
(e.g., formulation, packaging). Whether these studies are repeated
depends on the photostability characteristics determined at the time
of initial filing and the type of variation and/or change made, but
photostability testing is not part of stability studies for marketed
products.
The guideline seeks to describe the basic testing protocol for
photostability testing of
[[Page 9311]]
new drug substances and products at the time of the first
submission. Alternative approaches are acceptable 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.
BILLING CODE 4160-01-F
[GRAPHIC] [TIFF OMITTED] TN07MR96.039
BILLING CODE 4160-01-C
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B. Light Sources
The light sources described below may be used for photostability
testing. To minimize the effect of localized temperature changes,
the applicant should either maintain an appropriate control of
temperature 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), a
window glass filter may be fitted to eliminate such radiation.
Option 2
1. A cool white fluorescent lamp as defined 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 (e.g., quinine for near UV region) 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.
Any protected samples (e.g., wrapped in aluminum foil) used as
dark controls should be placed alongside the authentic sample.
II. Drug Substance
For drug substances, photostability testing should consist of
two parts: Forced degradation testing and confirmatory testing.
The purpose of forced degradation testing studies is to evaluate
the overall photosensitivity of the material for method development
purposes and/or degradation pathway elucidation. This testing may
involve the drug substance alone and/or in simple solutions/
suspensions to validate the analytical procedures. In these studies,
the samples should be in chemically inert and transparent
containers. In these forced degradation studies, a variety of
exposure conditions may be used, depending on the photosensitivity
of the drug substance involved and the intensity of the light
sources used. For development and validation purposes, it is
appropriate to limit exposure and end the studies if extensive
decomposition occurs. For photostable materials, studies may be
terminated after an appropriate exposure level has been used. The
design of these experiments is left to the applicant's discretion
although the exposure levels used should be justified.
Under forcing conditions, decomposition products may be observed
that are unlikely to be formed under the conditions used for
confirmatory studies. This information may be useful in developing
and validating suitable analytical methods. If in practice it has
been demonstrated they are not formed in the confirmatory studies,
these degradation products need not be examined further.
Confirmatory studies should then be undertaken to provide the
information necessary for handling, packaging, and labeling (see
section I.C., Procedure, and II.A., Presentation, for information on
the design of these studies).
Normally, only one batch of drug substance is tested during the
development phase, and then the photostability characteristics
should be confirmed on a single batch selected as described in the
parent guideline if the drug is clearly photostable or photolabile.
If the results of the confirmatory study are equivocal, testing of
up to two additional batches should be conducted. Samples should be
selected as described in the parent guideline.
A. Presentation of Samples
Care should be taken to ensure that the physical characteristics
of the samples under test are taken into account and efforts should
be made, such as cooling and/or placing the samples in sealed
containers, to ensure that the effects of the changes in physical
states such as sublimation, evaporation, or melting are minimized.
All such precautions should be chosen to provide minimal
interference with the exposure of samples under test. 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 fully exposed product then
progressing as necessary to product in the immediate pack and 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 the immediate pack is completely
impenetrable to light, such as aluminum tubes or cans, which are
intended for direct dispensing to the patient, testing should
normally only be conducted on directly exposed drug product.
It may be appropriate to test certain products such as infusion
liquids, and dermal creams, to support their photostability in-use.
The extent of this testing should depend on and relate to the
directions for use, and is left to the applicant's discretion.
The analytical procedures used should be suitably validated.
A. Presentation of Samples
Care should be taken to ensure that the physical characteristics
of the samples under test are taken into account and efforts, such
as cooling and/or placing the samples in sealed containers, should
be made to ensure
[[Page 9313]]
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 and 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 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) 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 necessary 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 the primary actinometric
procedure for monitoring exposure to the near UV region of the light
source. The actinometric systems should be calibrated for the type
of sources used.
Prepare a sufficient quantity of a 2 percent weight/volume
aqueous solution of quinine monohydrochloride dihydrate (if
necessary dissolve by heating). 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) pathway. Calculate the change in
absorbance, A = AT - AO.
For near UV lamps, the length of the exposure should be
sufficient to ensure a change in absorbance observed of at least
0.8.
Alternative packaging configurations (e.g., use of a 1 cm fused
silica cell) may be used if appropriately validated. Alternative
validated chemical actinometers may be used.
Note 1: Shape and Dimensions
BILLING CODE 4160-01-F
[GRAPHIC] [TIFF OMITTED] TN07MR96.040
BILLING CODE 4160-01-C
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 substance,
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.
VI. Reference
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: February 27, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-5295 Filed 3-6-96; 8:45 am]
BILLING CODE 4160-01-F