[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]



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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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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]
BILLING CODE 4160-01-F