PHOTOSTABILITY TESTING

PRESENTED BY : HARSHAVARDHAN VIJAY KONDHARE1ST YEAR M.PHARM (DRUG REGULATORY AFFAIRS)

GUIDE : DR. R.N. PUROHIT H.O.D DRUG REGULATORY AFFAIRS

POONA COLLEGE OF PHARMACY

29-12-2015

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IMPORTANT TERMS 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.

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IMPORTANT TERMS 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.

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IMPORTANT TERMS Confirmatory studies are those undertaken to establish

photostability characteristics under standardized conditions.

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

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INDEX 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 Conclusion References

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Why to perform photostability studies ?

• 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.

Quality perspective: To avoid

• Regulatory requirement and scientific necessity during drug development.

• Mandatory to perform before filing in registration dossier.

Regulatory perspective:

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When do we do photostability testing?

FDA guidance states

In phase III of regulatory submission

process.

The results should be

summarized and submitted in an annual report.

Starting early in preclinical phase

or phase I of clinical trials is

highly encouraged

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Factors that influence photostability of drug products

Particle size

Drug content

Tablet geometry

Preparation method

Concentration

pH and Ionization

Ionic strength

Oxidation

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Some typical examples of 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.

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Pharmaceutical Product sensitivity Classification

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PHOTOSTABLITY TESTING OF NEW

DRUG SUBSTANCES AND PRODUCTS AS

PER ICH Q1B

GUIDELINE

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The guideline is for

photostability information

for Registration

for new molecular entities.

The guideline does not cover

the photostability of drugs after administration

(i.e. under conditions of

use).

Alternative approaches

may be used if they are

scientifically sound and

justification is provided.

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The intrinsic photostability

characteristics of new drug

substances and products should be evaluated to

demonstrate light exposure does not

result in unacceptable

change.

Normally, carried out on a single

batch of material.

Studies should be repeated if certain

variations and changes are made

to the product (e.g., formulation,

packaging).

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LIGHT SOURCES 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

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LIGHT SOURCES

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 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.

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LIGHT SOURCES

Option 2Similar sample should be exposed to both the cool

white fluorescent and near ultraviolet lamp.

A cool white fluorescent lamp designed to produce an

output similar to that specified in ISO

10977(1993) ; and

A near UV fluorescent lamp having a spectral

distribution from 320 nm to 400 nm*.

*a maximum energy emission between 350 nm and 370 nm

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LIGHT SOURCES: ISO 10977

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.

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GENERAL PROCEDURE 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.

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A systematic approach to

photostability testing

Tests on the drug

substance

Tests on the

exposed drug

product outside of

the immediate

pack

Tests on the drug product

in the immediate

pack

Tests on the drug

product in the

marketing pack

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DRUG SUBSTANCE

Consist of two parts:

Forced degradation

testingConfirmatory

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 usedContd.>

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DRUG SUBSTANCEUnder 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.

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DRUG SUBSTANCE: 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.

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DRUG SUBSTANCE: ANALYSIS OF 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 controls.

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DRUG SUBSTANCE: JUDGEMENT 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.

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DRUG PRODUCT

fully exposed product

in immediate

pack

in marketing

pack.

Studies should be carried out in a sequential manner viz.

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.

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DRUG PRODUCT: PRESENTATION 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).

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DRUG PRODUCT: ANALYSIS OF 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.

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DRUG PRODUCT: JUDGEMENT 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.

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DRUG PRODUCT: JUDGEMENT OF RESULTS

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.

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CHALLENGES OF PHOTOSTABILITY TESTING

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1. Troublesome Lamp Selection

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

compensated for.

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1. Troublesome Lamp Selection

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.

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2. Irradiance Measurement Difficulty

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.

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3. Test Completion Control Issues

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.

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4. Distorting the Spectral Power Distribution

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.

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5. Humidity Control Factor

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.

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SOLUTIONS TO PHOTOSTABILITY TESTING

CHALLENGES

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1. Prudent Lamp SelectionOption 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, the radiometer should show irradiance, test time remaining and accumulated dose levels.

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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 FeaturesChamber features are available that enhance the end-user experience:• keep track of accumulated lamp hours• alert the operator when to replace the lampsValidation 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.

Sliding shelves, access ports and security lockouts are other features that can enhance ease of operation.

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CONCLUSION 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 tests should be carried out on the container closure system.

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CONCLUSION 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

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, Copenhagen; May 2014.

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