Stability testing :

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
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. Document History
November
Approval by the Steering Committee under Step 2 Current Step 4 version
Approval by the Steering Committee under Step 4 6 November and recommendation for adoption to the three ICH 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 TABLE OF CONTENTS
STABILITY TESTING:
PHOTOSTABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS
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.
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. Photostability Testing of New Drug Substances and Products 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.
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.
Photostability Testing of New Drug Substances and Products DECISION FLOW CHART FOR
PHOTOSTABILITY TESTING
OF DRUG PRODUCTS
FORMULATION
DIRECTLY
ACCEPTABLE

IMMEDIATE
IMMEDIATE
ACCEPTABLE

MARKETING
MARKETING
ACCEPTABLE

REDESIGN
REFORMULATION
Photostability Testing of New Drug Substances and Products 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.
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.
Photostability Testing of New Drug Substances and Products 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).
Photostability Testing of New Drug Substances and Products 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)
Photostability Testing of New Drug Substances and Products 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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