INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL
`REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN
`USE
`
`ICH HARMONISED TRIPARTITE GUIDELINE
`
`STABILITY TESTING:
`PHOTOSTABILITY TESTING OF
`NEW DRUG SUBSTANCES AND PRODUCTS
`Q1B
`
`Current Step 4 version
`dated 6 November 1996
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`This Guideline has been developed by the appropriate ICH Expert Working Group and
`has been subject to consultation by the regulatory parties, in accordance with the ICH
`Process. At Step 4 of the Process the final draft is recommended for adoption to the
`regulatory bodies of the European Union, Japan and USA.
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`MYLAN Ex. 1011, Page 1
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`

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`Q1B
`Document History
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`History
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`First
`Codification
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`Q1B
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`Approval by the Steering Committee under Step 2
`and release for public consultation.
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`New
`Codification
`November
`2005
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`Q1B
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`Date
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`28
`November
`1995
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`Q1B
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`Current Step 4 version
`Approval by the Steering Committee under Step 4
`and recommendation for adoption to the three ICH
`regulatory bodies.
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`6 November
`1996
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`Q1B
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`2
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`MYLAN Ex. 1011, Page 2
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`

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`STABILITY TESTING:
`PHOTOSTABILITY TESTING OF
`NEW DRUG SUBSTANCES AND PRODUCTS
`ICH Harmonised Tripartite Guideline
`Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting
`on 6 November 1996, this guideline is recommended for adoption
`to the three regulatory parties to ICH
`
`TABLE OF CONTENTS
`
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`1. General......................................................................................................................1
`A. Preamble .............................................................................................................1
`B. Light Sources ......................................................................................................2
`C. Procedure ............................................................................................................2
`2. Drug Substance .......................................................................................................4
`A. Presentation of Samples.....................................................................................4
`B. Analysis of Samples............................................................................................5
`C. Judgement of Results.........................................................................................5
`3. Drug Product ...........................................................................................................5
`A. Presentation of Samples.....................................................................................6
`B. Analysis of Samples............................................................................................6
`C. Judgement of Results.........................................................................................6
`4. Annex.........................................................................................................................7
`A. Quinine Chemical Actinometry .........................................................................7
`5. Glossary.....................................................................................................................8
`6. References ................................................................................................................8
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`MYLAN Ex. 1011, Page 3
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`MYLAN Ex. 1011, Page 4MYLAN Ex. 1011, Page 4
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`MYLAN Ex. 1011, Page 4
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`STABILITY TESTING:
`PHOTOSTABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS
`
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`1. 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.
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`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 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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`1
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`MYLAN Ex. 1011, Page 5
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`

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`Photostability Testing of New Drug Substances and Products
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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 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.
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`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.
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`2
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`MYLAN Ex. 1011, Page 6
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`

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`Photostability Testing of New Drug Substances and Products
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`DECISION FLOW CHART FOR
`PHOTOSTABILITY TESTING
`OF DRUG PRODUCTS
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`TEST END
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`TEST END
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`TEST END
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`START
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`DIRECTLY EXPOSED
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`ACCEPTABLE
`CHANGE?
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`IMMEDIATE PACK
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`REDESIGN PACKAGE
`OR REFORMULATION
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`CHANGE?
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`3
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`MYLAN Ex. 1011, Page 7
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`

`
`Photostability Testing of New Drug Substances and Products
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`2. DRUG SUBSTANCE
`For drug substances, photostability testing should consist of two parts: forced
`degradation testing and confirmatory testing.
`The purpose of forced degradation testing studies is to evaluate the overall
`photosensitivity of the material for method development purposes and/or degradation
`pathway elucidation. This testing may involve the drug substance alone and/or in
`simple solutions/suspensions to validate the analytical procedures. In these studies,
`the samples should be in chemically inert and transparent containers. In these forced
`degradation studies, a variety of exposure conditions may be used, depending on the
`photosensitivity of the drug substance involved and the intensity of the light sources
`used. For development and validation purposes it is appropriate to limit exposure
`and end the studies if extensive decomposition occurs. For photostable materials,
`studies may be terminated after an appropriate exposure level has been used. The
`design of these experiments is left to the applicant’s discretion although the exposure
`levels used should be justified.
`Under forcing conditions, decomposition products may be observed that are unlikely
`to be formed under the conditions used for confirmatory studies. This information
`may be useful in developing and validating suitable analytical methods. If in practice
`it has been demonstrated they are not formed in the confirmatory studies, these
`degradation products need not be further examined.
`Confirmatory studies should then be undertaken to provide the information necessary
`for handling, packaging, and labeling (see section 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.
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`4
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`MYLAN Ex. 1011, Page 8
`
`

`
`Photostability Testing of New Drug Substances and Products
`
`B. Analysis of Samples
`At the end of the exposure period, the samples should be examined for any changes in
`physical properties (e.g., appearance, clarity, or color of solution) and for assay and
`degradants by a method suitably validated for products likely to arise from
`photochemical degradation processes.
`Where solid drug substance samples are involved, sampling should ensure that a
`representative portion is used in individual tests. Similar sampling considerations,
`such as homogenization of the entire sample, apply to other materials that may not be
`homogeneous after exposure. The analysis of the exposed sample should be
`performed concomitantly with that of any protected samples used as dark controls if
`these are used in the test.
`
`C. Judgement 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).
`
`3. DRUG PRODUCT
`Normally, the studies on drug products should be carried out in a sequential manner
`starting with testing the fully exposed product then progressing as necessary to the
`product in the immediate pack and then in the marketing pack. Testing should
`progress until the results demonstrate that the drug product is adequately protected
`from exposure to light. The drug product should be exposed to the light conditions
`described under the procedure in section 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 aluminium tubes or cans, testing should
`normally only be conducted on directly exposed drug product.
`It may be appropriate to test certain products such as infusion liquids, dermal creams,
`etc., to support their photostability in-use. The extent of this testing should depend
`on and relate to the directions for use, and is left to the applicant’s discretion.
`The analytical procedures used should be suitably validated.
`
`
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`5
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`MYLAN Ex. 1011, Page 9
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`

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`Photostability Testing of New Drug Substances and Products
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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 a minimal interference with the irradiation of
`samples under test. Possible interactions between the samples and any material used
`for containers or for general protection of the sample should also be considered and
`eliminated wherever not relevant to the test being carried out.
`Where practicable when testing samples of the drug product outside of the primary
`pack, these should be presented in a way similar to the conditions mentioned for the
`drug substance. The samples should be positioned to provide maximum area of
`exposure to the light source. For example, tablets, capsules, etc., should be spread in
`a single layer.
`If direct exposure is not practical (e.g., due to oxidation of a product), the sample
`should be placed in a suitable protective inert transparent container (e.g., quartz).
`If testing of the drug product in the immediate container or as marketed is needed,
`the samples should be placed horizontally or transversely with respect to the light
`source, whichever provides for the most uniform exposure of the samples. Some
`adjustment of testing conditions may have to be made when testing large volume
`containers (e.g., dispensing packs).
`
`B. Analysis of Samples
`At the end of the exposure period, the samples should be examined for any changes in
`physical
`properties
`(e.g.,
`appearance,
`clarity
`or
`color
`of
`solution,
`dissolution/disintegration for dosage forms such as capsules, etc.) and for assay and
`degradants by a method suitably validated for products likely to arise from
`photochemical degradation processes.
`When powder samples are involved, sampling should ensure that a representative
`portion is used in individual tests. For solid oral dosage form products, testing
`should be conducted on an appropriately sized composite of, for example, 20 tablets or
`capsules. Similar sampling considerations, such as homogenization or solubilization of
`the entire sample, apply to other materials that may not be homogeneous after
`exposure (e.g., creams, ointments, suspensions, etc.). The analysis of the exposed
`sample should be performed concomitantly with that of any protected samples used as
`dark controls if these are used in the test.
`
`C. Judgement 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).
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`6
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`MYLAN Ex. 1011, Page 10
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`

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`Photostability Testing of New Drug Substances and Products
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`4. ANNEX
`A. Quinine Chemical Actinometry
`The following provides details of an actinometric procedure for monitoring exposure to
`a near UV fluorescent lamp (based on FDA/National Institute of Standards and
`Technology study). For other light sources/actinometric systems, the same approach
`may be used, but each actinometric system should be calibrated for the light source
`used.
`Prepare a sufficient quantity of a 2 per cent 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 colourless ampoule (see note 1), seal it hermetically, wrap in aluminum foil to
`protect completely from light, and use this as the control. Expose the sample and
`control to the light source for an appropriate number of hours. After exposure
`determine the absorbances of the sample (AT) and the control (Ao) at 400 nm using a
`1 centimeter (cm) path length. Calculate the change in absorbance, Δ 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, Δ 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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`7
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`MYLAN Ex. 1011, Page 11
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`

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`Photostability Testing of New Drug Substances and Products
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`5. GLOSSARY
`Immediate (primary) pack is that constituent of the packaging that is in direct contact
`with the drug substance or drug product, and includes any appropriate label.
`Marketing pack is the combination of immediate pack and other secondary packaging
`such as a carton.
`Forced degradation testing studies are those undertaken to degrade the sample
`deliberately. These studies, which may be undertaken in the development phase
`normally on the drug substances, are used to evaluate the overall photosensitivity of
`the material for method development purposes and/or degradation pathway
`elucidation.
`Confirmatory studies are those undertaken to establish photostability characteristics
`under standardized conditions. These studies are used to identify precautionary
`measures needed in manufacturing or formulation and whether light resistant
`packaging and/or special labeling is needed to mitigate exposure to light. For the
`confirmatory studies, the batch(es) should be selected according to batch selection for
`long-term and accelerated testings which is described in the Parent Guideline.
`
`6. REFERENCES
`Quinine Actinometry as a method for calibrating ultraviolet radiation intensity in
`light-stability testing of pharmaceuticals.
`Yoshioka S. et al., Drug Development and Industrial Pharmacy, 20 (13), 2049 - 2062
`(1994).
`
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`8
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`MYLAN Ex. 1011, Page 12