Regulatory guidelines for photostability

testings of drug substances and products

Department of Pharmaceutics, IIT (BHU)

Presented by-Zartab Khanam10121EN019B.Pharm. Part-4

1.General.....................................................................................................A brief introduction to ICH

A. Photostability testingB. Light SourcesC. Procedure

2.Drug substance........................................................................................A. Presentation of SamplesB. Analysis of SamplesC. Judgement of Results

3.Drug product...........................................................................................A. Presentation of SamplesB. Analysis of SamplesC. Judgement of Results

4.Annexure..................................................................................................A. Quinine Chemical Actinometry

Content

What ICH is?

The International Conference on Harmonisation of Technical

Requirements for Registration of Pharmaceuticals for Human

Use (ICH)

• It is a project that brings together the regulatory authorities

of Europe, Japan and the United States and experts from

the pharmaceutical industry in the three regions to discuss scientific

and technical aspects of pharmaceutical product registration.

What is the goal of ICH?

to identify and then reduce the differences in technical requirements for drug

development among regulatory agencies.

What is its Purpose?

• reduce the need to duplicate the testing carried out

during R&D of new medicines

• economical use of resources

• availibility of new drugs

History of ICH:

1980: EU began harmonising regulatory requirements

1989: Europe, japan, US began creating plans for harmonisation;

1990: ICH was created at a meeting in Brussels.

Structure of ICH :

The ICH has four major parts

• ICH Steering Committee (gov . Body of ICH)• ICH Coordinators (representatives of ICH parties)• ICH Secretariat and (documentation of meetings)• ICH Working Groups. (develp. Of harmonised guidelines)

The Steering Committee:

• the policies and procedures,

• selection of topics for harmonisation

• monitoring progress of harmonisation initiatives.

The ICH consists of:

1.European Commission,

2.European Federation of Pharmaceutical Industries and

Associations (EFPIA)

3.Ministry of Health, Labour and Welfare (Japan)

4.Japan Pharmaceutical Manufacturers Association (JPMA)

5.Food and Drug Administration (FDA)

6.Pharmaceutical Research and Manufacturers of America (PhRMA)

Process OF ICH function:

The ICH process consists of five steps:

Step 1: Expert Working Group consensus building

Step 2: Confirmation of EWG consensus by the SC

Step 3: Regulatory consultation and discussion

Step 4: Adoption of an ICH harmonised tripartite guideline

Step 5: Implementation

A. Photostability testing on new drugsubstances and products:

The ICH Harmonized Tripartite Guideline covering the Stability Testing of New Drug

Substances and Products notes that light testing should be an integral part of stress testing.

• Evaluation of the intrinsic photostability characteristics to demonstrate light exposure does

not result in unacceptable change.

• photostability testing iscarried out on a single batch of material selected .

• Whether 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.

-does not cover the photostability of drugs after administration (i.e. under conditions of use)

and those applications not covered by the Parent Guideline

A systematic approach to

photostabilitytesting

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

B. Light Sources in photostability stability testing:

Maintenance of an appropriate control of temperature to minimize the effect of localized

temperature changes

inclusion of a dark control in the same environment

Option 1:

Artificial daylight lamp combining both visible & UV output similar to D65 & ID65

For a light source emitting significant radiation below 320 nm, an appropriate filter(s)

may be fitted to eliminate such radiation.

Option 2: Cool white fluorescent & near UV lamp

UV: a spectral distribution from 320 nm to 400 nm

D65 is the internationally recognized standard for outdoor daylight as defined in ISO

10977 (1993).

ID65 is the equivalent indoor indirect daylight standard

C. Procedure of photostability testing:

For confirmatory studies samples are exposed to light to allow direct

comparision between drug substance and drug product

illumination : not less than 1.2 million lux hour

UV energy : not less than 200 watt hours/square meter

• Samples exposed side-by-side with a validated chemical actinometric

system to ensure the specified light exposure

• Exposure for appropriate duration of time

• monitoring is done using calibrated radiometers/lux meters.

• dark controls, if specified(wrapped in Al foil,) placed alongside the

authentic sample to evaluate contribution of thermally induced change

Fig: Photo testing chamber

2. PHOTOSTABILITY TESTING ON DRUG SUBSTANCES:

For drug substances, photostability testing should consist of two parts: forced degradation testing and confirmatory testing

Photostability testing

Forced degradation Confirmatory testing

• Evaluates the photosensitivity

• drug used alone or in solution/suspension

• Placed in chemically inert & transparent containers.

• Variety of exposure condition(depends on photosensitivity & intensity of light)

• Provides Information necessary for handling, packaging and labeling

• Gives idea of precautionary measures needed in manufacturing or in formulation development

The purpose of forced degradation testing

studies

to evaluate the overall photosensitivity of the material for-

• method development purposes

• degradation pathway elucidation.

1-the testing involves the drug substance alone and/or in simple

solutions/suspensions to validate the analytical procedures.

2-containers: chemically inert and transparent

3-a variety of exposure conditions are employed.

4-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.

-Under forcing conditions, decomposition products may be observed that are

unlikely to be formed under the conditions used for confirmatory studies.

• development and validation of suitable analytical methods.

• But If not formed in the confirmatory studies, these degradation products

need not be further examined.

Purpose of confirmatory studies:

To provide the information necessary for handling, packaging, and

labelling.

- only one batch of drug substance is tested during the development phase

,if the drug is clearly photostable or photolabile,then photostability

characteristics is confirmed.

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

two additional batches should be conducted.

A. Presentation of Samples to light:

Consideration of:• the physical characteristics of the samples under test.

• the effects of the changes in physical states such as

sublimation, evaporation or melting

• interactions between the samples and container material.

Appropriate amount of samples should be taken in suitable glass

or plastic dish, protected with suitable transparent cover if necessary

Solid drug substances : spread; thickness 3mm

Liquid substances :container-chemically inert and transparent

containers.

By cooling and/or

placing the samples in

sealed containers

To minimize the effects

of the changes in

physical states

sublimation

evaporation

melting

physical

characteristic

s of the

samples are

taken into

account

B. Analysis of Samples :At the end of the exposure period, the samples should be examined for :

1.Any changes in physical properties (e.g., appearance, clarity, or colour of

solution)

2. the assay

3. Any degradants ,likely to arise from photochemical degradation processes( by a

method suitably validated for products )

Sampling consideration• A representative portion of solid substances should be taken in individual tests.

• Homogenisation of entire sample

Analysis of exposed samples should be performed parallely with protected sample

used as dark control (if used in test).

Fig: Photo degradation results of a cough syrup sample.

C. Judgement of Results :

-The forced degradation studies provides 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.

-identification of precautionary measures during manufacturing

-ascertain if light resistant pack needed

While 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.

3. PHOTOSTABILITY TESTING ON DRUG

PRODUCT:

Studies on drug products

• The analytical procedures used should be suitably validated.

• done sequentially

• should progress until the results demonstrate that the drug product

is adequately protected from exposure to light.

• Procedure of photostability testing of drug

products:

• The drug product is exposed to the light conditions

• Normally, only one batch of drug product is tested during the development phase

if the product is clearly photostable or photolabile then 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.

• For aluminium tubes or cans, testing conducted on directly exposed drug product.

• extent of this testing for infusion liquids, dermal creams, etc depend on the

directions for use

A.Presentation of Samples

Consideration of:

• the physical characteristics of the samples under test.

• the effects of the changes in physical states such as

sublimation, evaporation or melting

• interactions between the samples and container material.

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.

• samples positioned to provide maximum exposure to the light

e.g. tablets, capsules, etc., should be spread in a single layer.

• If direct exposure 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,

• samples should be placed horizontally or transversely with respect to the

light

B. Analysis of Samples:

At the end of the exposure period, the samples should be examined for:

1 . Any changes in physical properties (e.g., appearance, clarity, or colour of solution)

2. the assay

3. Any degradants ,likely to arise from photochemical degradation processes( by a

method suitably validated for products

Sampling consideration

• A representative portion of solid substances should be taken in individual tests.

For solid oral dosage form products: appropriately sized composite of,e.g, 20

tablets or capsules.

• Homogenisation of entire sample

(e.g., creams, ointments, suspensions, etc.).

The analysis of the exposed sample should be performed paralelly with that of

any protected samples used as dark controls if these are used in the test.

C. Judgement of Results-special labeling or packaging requirement

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 to assure that the product

will be within proposed specifications during the shelf life .

Quinine Chemical Actinometryactinometric procedure for monitoring exposure to a near UV fluorescent lamp

• calibration of actinometric system FOR THE LIGHT SOURCE

• Prepare a sufficient quantity of a 2 per cent weight/volume aqueous solution

of quinine monohydrochloride dihydrate

Sample exposed to light source/actinometric systemEg: Quinine chemical actinometry

- 2%w/v aq.solution of quinine monohydrochloride dihydrate

Option 1: In 20ml colourless ampoule at 400 nm

Option 2:In 1cm quartz cell-(sample) and control wrapped with Aluminium

foil

Change in absorbance calculated byA = AT-A0

Note 1: Shape and Dimensions ( Japanese Industry Standard (JIS) R3512 (1974) for ampoule specifications)

Fig: Different ampoules

Fig: Photo chamber

DISCUSSION:Objection by researchers on generalisation of Quinine Chemical Actinometry due to:• poorly described actinometric method in guidlines

• reproducibility depends upon environmental factors(e.g.

measurement of time enterval,PH ,temp,oxygenation,lamp emission

spectrum etc.)

references:

1.ICH,guidance for industry Q1B Photostability testing of new drug substances and

products, Fed.Regst. (1996)27115-27122.

2.Journal of Pharmaceutical and Biomedical analysis 54(2011)886-888.

THANK YOU