PHOTOSTABILITY

TESTING

PRESENTED BY : HARSHAVARDHAN VIJAY

KONDHARE
1ST YEAR M.PHARM (DRUG REGULATORY AFFAIRS)
GUIDE : DR. R.N. PUROHIT
H.O.D DRUG REGULATORY AFFAIRS
POONA COLLEGE OF PHARMACY
29-12-2015
 IMPORTANT TERMS
2

 Stability : time period in which the drug product retains the same properties
and characteristics that it possessed at the time of its manufacturing.

 Stress testing : is a form of deliberately intense or thorough testing used to

determine the stability of a given drug substance or product.

 Photosensitivity : amount to which a drug substance or product reacts

upon receiving photons, especially visible light.

 Photostability : stability of a drug substance or product on exposure to light.

 IMPORTANT TERMS
3

 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.
 IMPORTANT TERMS
4

 Confirmatory studies are those undertaken to establish photostability

characteristics under standardized conditions.

 Parent Guideline : Q1A(R2) Stability Testing of New Drug Substances and

Products.
 INDEX
5

 Why to perform photostability studies ?

 When do we do photostability testing?
 Factors that influence photostability of drug products
 Some typical examples of photostability studies of drugs
 Pharmaceutical product sensitivity classification
 Photostability testing of new drug substances and products as per ICH
Q1B guideline
 Light sources
 General procedure
 Drug substance: Presentation of samples, Analysis of sample, Judgement of
results
 Drug product: Presentation of samples, Analysis of sample, Judgement of
results
 Challenges of photostability testing
 Solutions to photostability testing challenges
 Why to perform photostability
6
studies ?
Quality perspective: To avoid

• Instability - may lead to under medication due to lowering of active

drug concentration in dosage form.
• Drug decomposition - leads to formation of toxic products.
• Instability leads to changes in physical appearance.

Regulatory perspective:

• Regulatory requirement and scientific necessity during drug

development.
• Mandatory to perform before filing in registration dossier.
 When do we do photostability
7
testing?

FDA guidance
states

Starting early in
The results should
In phase III of preclinical phase or
be summarized and
regulatory phase I of clinical
submitted in an
submission process. trials is highly
annual report.
encouraged
 Factors that influence photostability
8
of drug products
Particle size

Drug content

Tablet geometry

Preparation method

Concentration

pH and Ionization

Ionic strength

Oxidation
 Some typical examples of
9
photostability studies of drugs
Carbamazepine : polymorphs in
solid dosage form (tablets),
surface discoloured to yellow and
then orange with results
indicating polymorph II to be the
least stable.

Cyanocobalamin : photolysis in
the presence of visible light at
various pH, confirmed that
protonated form was more
susceptible to photolysis.

Furosemide : forms
sulphamoylanthranilic acid after
exposure to sunlight.
 Pharmaceutical Product sensitivity
10
Classification
 PHOTOSTABLITY
TESTING OF NEW
DRUG SUBSTANCES
AND PRODUCTS AS
PER
ICH Q1B
GUIDELINE

11
 The guideline
Alternative
The guideline is does not cover
approaches may
for photostability the photostability
be used if they
information for of drugs after
are scientifically
Registration for administration
sound and
new molecular (i.e. under
justification is
entities. conditions of
provided.
use).

12
 The intrinsic
photostability
characteristics of
Studies should be
new drug
repeated if certain
substances and
Normally, carried variations and
products should be
out on a single changes are made
evaluated to
batch of material. to the product (e.g.,
demonstrate light
formulation,
exposure does not
packaging).
result in
unacceptable
change.

13
 LIGHT SOURCES
14

 The applicant should 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.

 There are two options-

• Option 1
• Option 2
 LIGHT SOURCES
15

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 metal halide
combining visible xenon
and ultraviolet (UV) lamp.
outputs
*D65 is the internationally recognized standard for outdoor daylight as
defined in ISO 10977 (1993). ID65 is the equivalent indoor indirect daylight
standard.
 LIGHT SOURCES
16

Option 2
Similar sample should be exposed
to both the cool white fluorescent
and near ultraviolet lamp.

A cool white fluorescent lamp

A near UV fluorescent lamp
designed to produce an output
having a spectral distribution from
similar to that specified in ISO
320 nm to 400 nm*.
10977(1993) ; and

*a maximum energy emission between 350 nm and 370 nm

 LIGHT SOURCES: ISO 10977
17

 Describes test equipment, test procedure and analytical

methods for
• predicting the long-term dark storage stability of colour
photographic images (based on the Arrhenius method) and
• measuring the colour stability of such products when
subjected to certain illuminants at specified temperatures
and humidities.

 Does not specify limits of acceptability for the

stability.
 GENERAL PROCEDURE
18

 For confirmatory studies:

Samples should be exposed to light providing
• 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 .

Samples may be exposed side-by-side with a validated chemical

actinometric system.
 Tests on the
drug
substance

Tests on the
Tests on the A systematic exposed drug
drug product approach to product
in the
photostability outside of the
marketing
immediate
pack testing pack

Tests on the
drug product in
the immediate
pack

19
 DRUG SUBSTANCE
20

Forced degradation
testing
Consist of two
parts:
Confirmatory
testing.

Forced degradation testing studies: is to evaluate the

overall photosensitivity of the material for method
development purposes and/or degradation pathway
elucidation.

• samples should be in chemically inert and transparent containers.

• variety of exposure conditions may be used

Contd.>
 DRUG SUBSTANCE
21

Under forcing conditions, decomposition products may be

observed that are unlikely to be formed under the conditions used
for confirmatory studies.
Confirmatory studies: provide the information necessary for
handling, packaging, and labeling.

• If the drug is clearly photostable or photolabile the

photostability characteristics should be confirmed on a single
batch.

• If the results of the confirmatory study are equivocal, testing of

up to two additional batches should be conducted.
 DRUG SUBSTANCE:
22
PRESENTATION OF SAMPLES
 Ensure that the effects of the changes in physical states such
as sublimation, evaporation or melting are minimized.
 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.

• Solid drug substances spread across the container to give a

thickness of not more than 3 millimeters.
• Liquids should be exposed in chemically inert and transparent
containers.
 DRUG SUBSTANCE: ANALYSIS OF
23
SAMPLE
the samples should be examined for;
 any changes in physical properties (e.g., appearance,
clarity, or color of solution)

 for assay and;

 degradants by a method suitably validated for products

likely to arise from photochemical degradation
processes.

Analysis of the exposed sample should be performed

concomitantly with protected samples used as dark
 DRUG SUBSTANCE: JUDGEMENT
24
OF RESULTS
 Forced degradation 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.

 Confirmatory studies: should identify precautionary

measures needed
• In manufacturing or in formulation of the drug product, and
• If light resistant packaging is needed.
 DRUG PRODUCT
25

Studies should be carried out in a sequential manner viz.

fully exposed in immediate in marketing
product pack 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 General Procedure.

• If the drug is clearly photostable or photolabile the photostability is

confirmed on a single batch.

• If the results of the confirmatory study are equivocal, testing of up to two

additional batches should be conducted.
26
 DRUG PRODUCT: PRESENTATION
27
OF SAMPLES
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).
 DRUG PRODUCT: ANALYSIS OF
28
SAMPLES
the samples should be examined for;
 any changes in physical properties (e.g., appearance, clarity, or color of
solution)
 for assay and;
 degradants by a method suitably validated for products likely to arise from
photochemical degradation processes.

 For solid oral dosage form products, testing should be

conducted on an appropriately sized composite , for example,
20 tablets or capsules.
 Homogenization or solubilization of the entire sample - creams,
ointments, suspensions, etc.

Analysis of the exposed sample should be performed concomitantly with

protected samples used as dark controls.
 DRUG PRODUCT: JUDGEMENT
29
OF RESULTS

Depending on the extent of change special

labeling or packaging may be needed.

When evaluating the results of photostability

studies it is important to consider the results
obtained from other formal stability studies.
 DRUG PRODUCT: JUDGEMENT OF
RESULTS
30

 Example showing how confirmatory photostability results

can be used in conjunction with definitive stability results
for the judgement of shelf-life of a drug substance or
product.
 CHALLENGES OF
PHOTOSTABILITY TESTING

31
 1. Troublesome Lamp Selection
32

Option I light sources (fluorescent D65, metal halide or xenon)

cause:

 Over exposure: it produces both UVA and visual irradiance in

fixed ration, but the exposure requirement for photopic and UVA
are different, one of the dose gets overexposed.

 Production of excessive heat

 dark controls are needed to segregate photochemical degradation from
thermal degradation.
 Large internal cooling fans are necessary to dissipate this heat and can
pose presentation problems by blowing samples around.
 Sample colour changes due to high temperatures cannot easily be
 1. Troublesome Lamp Selection
33

 Xenon and metal halide lamps have a short life span and need
replaced every 750 to 1500 hours.
 Require light filters to eliminate radiation below 320nm.
 They also have a relatively small illumination area.
 2. Irradiance Measurement Difficulty
34

Chemical actinometers can be used to measure sample dose

 ICH describes the use of quinine hydrochloride dehydrate as an

example of a chemical actinometer.

 Quinine has a ‘dark reaction’ where the reaction continues after it is
used. Not only is quinine wavelength dependent, it is affected by
temperature and pH variations. Due to these characteristics, quinine
has been shown to be inaccurate with lamps that produce significant
amounts of heat, such as xenon lamps.

 Irradiance measurements with instrumental radiometers have

high margins of uncertainty; 10% is not uncommon.

 Radiometers need to be calibrated or certified before use.

 3. Test Completion Control Issues
35

 Chemical actinometers do not provide a mechanism to

automatically turn the lamps off or alert the operator when the
desired exposure level is reached.

 Chemical actinometers cannot record irradiance levels

throughout the test.

 As lamps age, their intensity decreases → causes irradiance

levels of full-power light sources to fluctuate over time→ light
intensity would terminate prematurely compared to the desired
dose→ This is particularly troublesome for confirmatory studies.
 4. Distorting the Spectral Power Distribution
36

 Interior chamber materials that reflect light onto samples should

reflect/ absorb radiation uniformly across the UVA and photopic
spectrums.
 If not, samples will be subjected to light having a spectral power
distribution different than that specified by ICH.
 5. Humidity Control Factor
37

 State of hydration affects the photostability of some samples.

 This means identical drug substances subjected to

identical irradiance and temperature conditions can have
very different results if exposed to different humidity
levels.
 SOLUTIONS TO PHOTOSTABILITY
TESTING CHALLENGES

38
 1. Prudent Lamp Selection
Option II of ICH guidelines (cool white and near- UV fluorescent lighting)
• Independent control of illuminance and UVA irradiance eliminates overexposure.
• Fluorescent lamps generate minimal heat.
• Eliminate the need for expensive light filters and dark controls.
• Small internal fans can be employed to subtly maintain proper air temperature
without disturbing sample presentation.
• Typically last over ten thousand hours, have low replacement costs, and provide a
large illumination area.

2. Accurate Light Measurements

• Achieved with a built-in radiometer.
• Detectors utilizing a Teflon hemisphere may result in an exceptionally good cosine
response.
• Detectors should be both cosine corrected and calibrated.
• It is best if radiometer displayed units for illuminance and UVA irradiance are
consistent with ICH documentation.

3. Precise Test Completion Controls

• An integrating radiometer combined with chamber controls should be used to
ensure precise dose levels at test completion.
• Advanced systems are capable of running based on exposure level or timed tests,
39 the radiometer should show irradiance, test time remaining and accumulated dose
levels.
 4. Preserving the Spectral Power Distribution
• Using specular aluminium on interior reflective surfaces, it reflects light
across both UVA and photopic spectrums
• Available with a 95% total reflection.
• Outshines mirrored stainless steel and white painted surfaces for not only
illuminance reflection but also UVA irradiance.

5. Tight Humidity Control

• Use ultrasonic nebulizers, they vaporize water droplets as small as a 3 micron
mean diameter, this enhances uniform humidity distribution throughout the
chamber without injecting additional unwanted heat.
• Dehumidification is often accomplished through mechanical refrigeration.

6. Value Added Features

Chamber features are available that enhance the end-user experience:
• keep track of accumulated lamp hours
• alert the operator when to replace the lamps
Validation is simple with pre-written IQ/OQ/PQ validation protocols.

Chart recorders assist in demonstrating regulatory compliance by permanently

recording illuminance, UVA irradiance, temperature and humidity testing
conditions.

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Sliding shelves, access ports and security lockouts are other features that can
 CONCLUSION
41

 Product should be shown to be light stable by photostability

studies.

 Showing the dosage form or dosage form in packaging is

photostable.

 By light transmission studies showing adequate protection of

the packaging.

 For blisters, which are not light protective, store blister in carton.

 If product is not light stable; label should state that protect form
light and container should be light protective; light transmission
 CONCLUSION
42

 Photo stability studies are performed to generate primary

degradants of drug substance by exposure to UV or fluorescent
conditions.

 Important to help develop determine the degradation pathways

and degradation products of the active ingredients.

 The various factors affecting the photostability of dosage form

should be clearly indicated so as to prevent their interference with
the testing and the stability of dosage form.
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 REFERENCES
44

1. ICH Harmonised tripartite guideline, Stability testing: Photostability Testing of New

Drug Substances and Products Q1B Current Step 4 version dated 6 November
1996
2. Jitendra Kumar, Review: Development of forced degradation studies of drugs,
International Journal of Advances in Pharmaceutics 2 (3) 2013; 35,37-38.
3. Abhijjeet Welankiwar, Photostability Testing of Pharmaceutical Products,
International Research Journal of Pharmacy 2013; 11-15.
4. Steven W Baertschi, Commentary: A critical assessment of the ICH guideline on
photostability testing of new drug substances and products (Q1B), Journal of
Pharmaceutical Sciences, vol. 99, No. 7, July 2010; 2934-2939.
5. Robert A. Reed, Implications of Photostability on the Manufacturing, Packaging,
Storage, and Testing of Formulated Pharmaceutical Products; Pharmaceutical
technology March 2005; 70-71.
6. Bob Dotterer, Using photostability chambers to meet the requirements of drug
testing in accordance with ICH, Q1B; CARON; 1-5.
7. PowerPoint Presentation: Gabriel K. Kaddu, Stability Principles and Case Studies:
Active Pharmaceutical Ingredient (API) and Finished Pharmaceutical Product
(FPP); WHO Prequalification of Medicines Programme; Assessment training,
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