Stability testing of formulations

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Stability testing of formulations & ICH guidelines for stability studies of drugs A.Solairajan, 1 st year, M.Pharm (analysis)

Outline of this Section:

Outline of this Section Introduction Stability tests Types of Stability tests What is Shelf life? Shelf life predictions ICH guidelines for stability studies

Introduction:-:

Introduction:- The stability testing of cosmetic product is to ensure that the product meets the intended physical, chemical and microbiological quality standards throughout its shelf life when stored under appropriate conditions.

What is stability?:

What is stability? The stability of a pharmaceutical product is defined as “ extent to which a product retains , with in specified limits, and through out its period of storage and use i.e. its shelf life, the same properties and characteristics that it possessed at the time of its manufacture”.

Importance of stability testing:-:

Importance of stability testing:- Purpose of stability testing is to provide evidence how quality varies with time under influence as Temperature Humidity Light.

Stability testing is used to:

Stability testing is used to Provide evidence as to how the quality of the drug product varies with time. Establish shelf life for the drug product. Determine the recommended storage conditions. Determine container closure system suitability.

Why stability studies are necessary?:

Why stability studies are necessary? Chemical degradation of the product leads to lowering of the concentration of the drug in the dosage form. Toxic products may be formed, due to chemical degradation of the active ingredient

General Stability of a Cosmetic Product :

General Stability of a Cosmetic Product Under the accelerated conditions, following tests should be done in order to assure: Physical stability under appropriate conditions of storage, transport and use. Chemical stability Microbiological stability The compatibility between the contents and the container.

Stability Tests:

Stability Tests 1.Physical and chemical integrity tests : Evaluate- Color, Odor / Fragrance, pH value, Viscosity, Texture, Flow, and Emulsion stability (signs of separation) 2. Microbiological stability tests : Evaluate- The degree of contamination with bacteria, mold, and yeast. 3. Packaging stability tests : Evaluate- The impact of packaging on the contained product

1.Physical / Chemical Stability Tests:

1.Physical / Chemical Stability Tests This tests to predict, how well cosmetics will resist common stresses such as temperature and light. This test procedure is based on the vulnerabilities of the particular cosmetic product and its anticipated shipping, storage display and usage conditions. Common test procedures :- Temperature variations Cycle test Centrifuge test Light test Mechanical shock test

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1.1 Temperature variation:- High temperature testing is now commonly used as a predictor of long-term stability. Most companies conduct their high temperature testing at 37 ⁰ C (98F) and 45 ⁰ C (113F). If a product is stored at 45 ⁰ C for three months (and exhibits acceptable stability) then it should be stable at room temperature for two years. A good control temperature is 4 ⁰ C (39F) where most products will exhibit excellent stability.

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1.2Cycle test:- The product should pass three cycles of temperature testing from -10 ⁰ C (14F) to 25 ⁰ C (77F). Place the product at -10 ⁰ C for 24 hours and place it at room temperature (25 ⁰ C) for 24 hours. This completes one cycle. If the product passes three cycles then you can have a good degree of confidence in the stability of the product.

1.3Centrifuge test:-:

1.3Centrifuge test:- Creaming is one of the first signs of impending emulsion instability. A good test method to predict creaming is centrifugation. Heat the emulsion to 50 ⁰ C (122F) and centrifuge it for thirty minutes at 3000 rpm. Then inspect the resultant product for signs of creaming. This test is an absolute necessity for those products that contain powders of any kind such as liquid/cream make-up.

1.4 Light testing:-:

1.4 Light testing:- Both products and packaging can be sensitive to the UV radiation. All products should be placed, in glass and the actual package. Place another glass jar completely covered with aluminum foil in the window to serve as a control. This discoloration may be due to the fragrance or some other sensitive ingredient.

1.5 Mechanical shock testing: :

1.5 Mechanical shock testing: Cosmetic products and their packaging is checked by mechanical shock testing . Vibration testing (e.g. on a pallet shaker) can help to determine whether de-mixing (separation) of powders or granular products is likely to occur.

2.Microbiological Stability Tests   :

2.Microbiological Stability Tests Microbial contaminants usually come from two different origins: During production and filling, During the use of the cosmetic by the consumer. It is necessary to carry out routine microbiological analysis of each batch of the finished product. Main potential pathogens in cosmetic products are, Pseudomonas aeruginosa, Staphylococcus aureus Candida albicans.

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These specific potential pathogens must not be detectable in 0.1 g or 0.1 ml of a cosmetic product. Common Test Procedures :- Screening tests: Quantitative tests:

2.1 Screening test:-(Dip slides or Plate count methods) :

2.1 Screening test:-(Dip slides or Plate count methods) Dip Slide method is used to detect aerobic bacteria in aqueous samples. Dip slide is coated on both sides with a solid culture medium like agar gels. A small quantity of the dye 2,3,5- triphenyltetrazolium chloride (TTC ) is added to detect Aerobic bacteria in the sample. Dip the slide into the aqueous samples for 10 seconds. Drain off excess liquid from the slide. Incubate at 35–37°C for 18-48 hours. The slide appearance is compared to calibration charts.

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Aerobic bacteria species grow on this medium and can be detected by their ability to reduce TTC to a red colored formozan dye. Developing bacterial colonies alter the TTC and they appear as red spots . Application:- To determine the total aerobic microbial contamination in aqueous samples.

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Instructions for Use Dipslides are convenient, inexpensive and simple to use. To use them simply follow steps 1, 2 and 3 below : Step 1 - Remove dipslide from tube. Immerse slide in liquid sample for 10 seconds. Step 2 - Allow excess liquid to drain for a few seconds, replace slide in tube and incubate for 24 - 48 hours. Step 3 - After incubation, compare the dipslide surface against the appropriate chart to obtain the bacteria, yeast or mould count.

2.2 Quantitative tests: :

2.2 Quantitative tests: Quantitative tests determine the actual count level of bacteria, mold and yeast in a cosmetic product. Typically , methods for isolation of microorganisms from cosmetic products include direct colony counts and enrichment culturing.

3.Packaging Stability Tests:

3.Packaging Stability Tests Packaging can directly affect finished product stability because of interactions between the product, the package, and the external environment. For example:- Product constituents may be absorbed into the container or may chemically react with the container. Common test procedures :- Powdered Glass tests Weight loss tests Leaking tests

3. Powdered Glass tests: :

3. Powdered Glass tests: Glass is the most inert material and does not react with a cosmetic product in any way. For this reason all testing should be done in glass and the actual packaging. Interactions between the product and the container e.g. Adsorption of product constituents into the container, corrosion, chemical reactions, migration

Principle of this test:-:

Principle of this test:- To estimate the amount of alkali leached from the glass powder. The amount of acid is necessary to neutralize the released alkali is specified in the pharmacopoeia. The basic analysis is acid base titration using methyl red indicator. • The glass specimen is crushed before the test Step-1

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Step-2 Step-3

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Step-3 Tests Containers Limits, ml of 0.02 N H 2 SO 4 Powdered Glass test Type-1 1.0 Type-2(100 ml or less) 0.7 Type-2(Over 100 ml) 0.2 Type-3 8.5 Type-4 15.0

3.2 Weight loss tests: :

3.2 Weight loss tests: To determine evaporation (water loss through the container wall or closure gaps) weight loss evaluation is one of the most important tests that must be conducted. This testing is done at room temperature and at 45 ⁰ C for a period of three months. The weight loss should not exceed 1% per month for the package to be considered acceptable.

3.3 Leaking tests::

3.3 Leaking tests: It may be advisable to test the packaged product in various orientations (upright, inverted, on its side, etc.) to determine whether the packaging may leak (especially during transport).

FACTORS AFFECTING DRUG STABILIY:

FACTORS AFFECTING DRUG STABILIY Physical form Particle size Surface area Drug excipient ratio Processing method Temperature Relative Humidity Packaging Light Oxygen Drug and Excipient Formulation Environment

What is Shelf life ?:

What is Shelf life ? Shelf life is the recommendation of time that products can be stored, during which the defined quality of a specified proportion of the goods remains acceptable under expected (or specified) conditions of distribution, storage and usage.

some cosmetics shelf life chart:

some cosmetics shelf life chart Name of the product Shelf life period After Shelf life over the product becomes Eye pencil 3 – 6 months Rancid Toner 6 – 12 months Cloudiness or foul odor Styling products 1 year or more Liquify or smell strange Eye cream 6 – 12 months Rancid Lip balm 1 – 2 years Rancid Shampoo 6 – 12 months Changes in smell or appearance Conditioner 6 – 12 months Changes in consistency and odor Lip pencils 6 – 12 months Rancid Lip sticks 2 – 3 years Rancid

Shelf life prediction:-:

Shelf life prediction:- Shelf life is the period during which a dosage form keeps its qualities. The prediction of shelf life is based on applying Arrhenius equation, which gives the effect of temperature on rate constant K, of a chemical reaction.

Steps involved in prediction of shelf life:-:

Steps involved in prediction of shelf life:- 1.The preparation divided into different portions and stored at different elevated temperatures. 2.Samples are withdraw at various intervals of time and remaining concentration of active ingredient is measured. 3.The order of reaction is determined by suitable method. 4.Then the amount of drug degraded can be determined.

Accelerated stability testing:-:

Accelerated stability testing:- Main aim of accelerated stability study to predict the stability profile of a drug product that prediction of self life of the product before launching into market. Prediction of shelf life which is the time, a product will remain satisfactory when stored under expected or directed storage condition.

Significant change occurs due to accelerated testing :

Significant change occurs due to accelerated testing Significant change at the accelerated conditions is defined as: A 5% potency loss from the initial assay value of a batch. Any specified degradants exceeding its specified limit. The product exceeding its pH limits. Dissolution exceeding the specified limits for 12 capsules or tablets. Physical Changes under Accelerated conditions of Temperature & Humidity

Contd….:

Contd …. Under Light, both Primary and Secondary packaging affected, and fading of container color, and the print is fading. Effervescent Tablet : Gain of moisture, loss of integrity Capsule : Color fading in Blister and Sticking in a Glass bottle. Powder : Spread within strip pockets Suppositories : Softening Change in Viscosity of a Gel, Jelly, Cream & Ointment Lozenges : melting Emulsions : Phase separation

Stability profile: Accelerated stability study:

Stability profile: Accelerated stability study Storage Condition Testing Condition Controlled room temperature 20-25⁰C 40⁰C and 75 % RH for 6 months Refrigerated condition 2-8⁰C 25⁰C and 60 % RH for 6 months Freezer condition -2⁰ to -10⁰C 5⁰C for 6 months

Prediction of shelf life from accelerated stability data :

Prediction of shelf life from accelerated stability data Based on the principle of chemical kinetics demonstrated by Garret and Carper method Free and Blythe method

Garret and Carper method:

Garret and Carper method The mathematical prediction of shelf life is based on the application of the Arrhenius equation, which indicates the effect of temperature on the rate constant, k of a chemical reaction of thermodynamic temperature, 1/T, is a straight line. 1. Keep several samples of the drug product at atleast three temperatures, such as 40 ⁰ C, 50 ⁰ C and 60 ⁰ C. 2. Determine the drug content at all three storage points by taking a number of samples and take the mean drug content.

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3. At each temperature we plot a graph between time and log percent drug remaining. 4. If the decomposition is first order this gives a straight line. If it is zero order, percent drug remaining versus time will give a straight line. Arrhenius plot for predicting drug stability at room temp.

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Next, we take the log K or log of reaction constant on Y axis and 1/T x 10-3 on X axis and draw a best fit line. This line is the Arrhenius Plot, extrapolate this line to get k at 25 ⁰ C and from this we calculate the shelf-life.

SHELF LIFE DETERMINATION Based on t90 values (Free and Blythe /method):

SHELF LIFE DETERMINATION Based on t 90 values (Free and Blythe /method) In this method the fraction life period is plotted against a reciprocal temp and the time in days required for drug to decompose to some fraction of its original potency at room temp. This approach clearly illustrate in below fig. The log% of drug remaining is plotted against time and days and the time for the loss line at several temp. to reach 90% of the theoretical potency is noted by the doted line. Shelf life and expiration date are estimated in this way.

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The log time to 90% is then plotted against 1/T and the time for 10% loss of potency at room temp. can be obtain from the resulting straight line by extrapolation to 25 ⁰ C

Accelerated stability testing in Emulsions:

Accelerated stability testing in Emulsions An emulsion is stored at elevated temperature. This decreases viscosity of the continuous phase. If the emulsion withstands this stress it is assumed to be stable at normal conditions of storage. Centrifugation Method: Creaming and flocculation are slow processes Centrifugation accelerates rate of creaming and flocculation in emulsions. The emulsion is subjected to different centrifugal speeds and separation of phases is observed at different time periods. Bad emulsions separates oil instantly. Good emulsion does not exhibit detectable separation of oil phase until certain time period.

Accelerated tests for suspensions:

Accelerated tests for suspensions Cake formation is accelerated by centrifugation. High speed centrifugation is hence not preferred, low speed centrifugation is used to study the physical stability. A Freeze- Thaw cycling technique is one of the stress testing. This cycling treatment promotes particle growth and has primarily importance for changes in absolute particle size, particle size distribution and crystal habit.

Accelerated Tests for moisture absorption:

Accelerated Tests for moisture absorption In this method , products are placed in an environment of high relative humidity and controlled temperature. Their physical and chemical stabilities are assessed. The results will indicate whether the product is susceptible to moisture and also whether the container needs to provide a high degree of protection.

Photolytic Study:-:

Photolytic Study:- Many drugs fade or darken on exposure to light and this leads to an unwanted problem which can be controlled by using 1. Amber Glass Container 2. Opaque Container 3. Incorporating a Dye By exposing drug substance to 400 & 900(FC) of illumination for 4 & 2 weeks to light and another sample examined protected from light.

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Results found on appearance and chemical loss may be recorded. Comparing color or using diffused reflectance spectroscopy for examination. EX:- Cycloprofen becomes very yellow after five days under 900 foot candles of light.

Oxidation study:

Oxidation study Stability to oxygen must be evaluated to establish that the final product should be packaged under inert atmosphere or it requires an antioxidant Here, high oxygen tension plays important role to investigate stability. Usually, 40% of oxygen atmosphere allows for rapid evaluation. Results were correlated with inert & without inert condition. Dessicators equipped with 3 way stopcocks are useful for study.

Parameters for stability testing :

Parameters for stability testing The following list of parameters for each dosage form is presented as a guide for the types of tests to be included in a stability study. Testing scope for solid dosage form:- Physical-chemical properties – Appearance – Elasticity – Mean mass – Moisture – Hardness – Disintegration – Dissolution Chemical properties – Assay – Degradation Microbial properties Container closure system properties – Functionality tests (e.g. extraction from blister)

Testing scope for LIQUID FORMS for inj. and PARENTRAL:

Testing scope for LIQUID FORMS for inj. and PARENTRAL Physical-chemical properties – pH – Loss on weight – Color & clarity of solution - Sterility Tests Chemical properties – Assay – Degradation products – Degradation preservatives – Content antioxidants Microbial properties - Pyrogen Testing Container closure system properties – Functionality tests - Leakage test

Testing scope for Oral liquid form:

Testing scope for Oral liquid form Physical-chemical properties – pH – Color & clarity of solution – Viscosity – Particle size distribution (for oral suspensions only) Chemical properties – Assay – Degradation products – Degradation preservatives – Content antioxidants Microbial properties Container closure system properties – Functionality tests

Testing scope for SEMI LIQUID FORMS:

Testing scope for SEMI LIQUID FORMS Physical-chemical properties – Appearance, odor, homogeneity, consistency – Loss on weight, Viscosity – Content uniformity (within the container) Chemical properties – Assay – Degradation products & preservatives – Content preservatives – Degradation– Content antioxidants Microbial properties Container closure system properties – Functionality tests

ICH Guidelines for stability testing of drugs:

ICH Guidelines for stability testing of drugs

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The guideline seeks to exemplify the core stability data package for new drug substances and products. The guideline addresses the information to be submitted in registration applications for new molecular entities and associated drug products

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For stability studies, Q1A – Stability testing for new drug substances and products (R2- 2003) Defines the stability data package for registration of a new molecular entity as drug substance/ drug product. Q1B- stability testing of new drug substances and products(1996) Recommendations on photostability testing

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Q1C- stability testing for new dosage forms (1996) Recommentations on new dosage forms authorised medical products. ICH Q5C – stability testing of biotechnological/ biological products

ICH GUIDELINES ON STABILITY(II):

ICH GUIDELINES ON STABILITY(II) Q1D – bracketing and matrixing designs for stability testing for new drugs substance and products(2002) Specific principles for the bracketing and matrixing in the study designs. Q1E- Evaluation of stability data (2003) Recommentations how to estabilish shelf life or retest period based on stability studies performed.

Other ICH guidelines:-:

Other ICH guidelines:- Stability – Q1A-Q1F Analytical validation Q2 Impurities Q3A – Q3D Pharmacopoeias Q4 – Q4B Quality of biotechnological products Q5A- Q5E Specifications Q6A- Q6B Good manufacturing practice Q7 Pharmaceutical development Q8 Quality risk management Q9 Pharmaceutical quality system Q10 Development and manufacture of drug substance Q11

Guidelines for Stability testing:-:

Guidelines for Stability testing:-

Some Common Definitions in ICH:

Some Common Definitions in ICH Dosage form:- A pharmaceutical product type (e.g., tablet, capsule, solution,cream ) that contains a drug substance generally, but not necessarily, in association with excipients. Drug product:- The dosage form in the final immediate packaging intended for marketing. Drug substance:- The unformulated drug substance that may subsequently be formulated with excipients to produce the dosage form.

Contd...:

Contd... Excipient :- Anything other than the drug substance in the dosage form. Shelf life (also referred to as expiration dating period):- The time period during which a drug product is expected to remain within the approved shelf life specification, provided that it is stored under the conditions defined on the container label. Re-test date:- The date after which samples of the drug substance should be examined to ensure that the material is still in compliance with the specification and thus suitable for use in the manufacture of a given drug product.

Contd…:

Contd … Re-test period:- The period of time during which the drug substance is expected to remain within its specification and, therefore, can be used in the manufacture of a given drug product, provided that the drug substance has been stored under the defined conditions. Accelerated testing:- Studies designed to increase the rate of chemical degradation or physical change of a drug substance or drug product by using exaggerated storage conditions as part of the formal stability studies. Intermediate testing:- Studies conducted at 30°C/65% RH and designed to moderately increase the rate of chemical degradation or physical changes for a drug substance or drug product intended to be stored long term at 25°C.

Contd..:

Contd.. Long term testing: Stability studies under the recommended storage condition for the re-test period or shelf life proposed (or approved) for labeling. Stress testing (drug substance): Studies undertaken to elucidate the intrinsic stability of the drug substance. It is normally carried out under more severe conditions than those used for accelerated testing.

Contd…:

Contd … Stress testing (drug product): Studies undertaken to assess the effect of severe conditions on the drug product. Such studies include photostability testing and specific testing on certain products, (e.g., metered dose inhalers, creams, emulsions, refrigerated aqueous liquid products). Container closure system: The sum of packaging components that together contain and protect the dosage form.

Contd…:

Contd … Formal stability studies:- Long term and accelerated (and intermediate) studies undertaken on primary and/or commitment batches according to a prescribed stability protocol to establish or confirm the re-test period of a drug substance or the shelf life of a drug product. Commitment batches:- Production batches of a drug substance or drug product for which the stability studies are initiated or completed post approval through a commitment made in the registration application.

Contd…:

Contd … Primary batch:- A batch of a drug substance or drug product used in a formal stability study, from which stability data are submitted in a registration application for the purpose of establishing a re-test period or shelf life. Pilot scale batch:- A batch of a drug substance or drug product manufactured by a procedure fully representative of production scale batch.

Contd…:

Contd … Production batch:- A batch of a drug substance or drug product manufactured at production scale by using production equipment in a production facility as specified in the application Specification – Release:- The combination of physical, chemical, biological, and microbiological tests and acceptance criteria that determine the suitability of a drug product at the time of its release. Specification - Shelf life:- The combination of physical, chemical, biological, and microbiological tests and acceptance criteria that determine the suitability of a drug substance throughout its re-test period, or that a drug product should meet throughout its shelf life.

General Principles:

General Principles The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light. The choice of test conditions defined in this guideline is based on an analysis of the effects of climatic conditions in the three regions of the EC, Japan and the United States. The mean kinetic temperature in any part of the world can be derived from climatic data, and the world can be divided into four climatic zones, I-IV. This guideline addresses climatic zones I and II.

The Four climatic Zones:-:

The Four climatic Zones:-

STABILITY TESTING OF DRUG SUBSTANCE:

STABILITY TESTING OF DRUG SUBSTANCE General Stress Testing Selection of Batches Container Closure System Specification Testing Frequency Storage Conditions Stability Commitment Evaluation Statements/Labelling

PowerPoint Presentation:

General:- Information on the stability of the drug substance is an integral part of the systematic approach to stability evaluation .

Stress Testing::

Stress Testing: The nature of the stress testing will depend on the individual active substance and the type of pharmaceutical product involved . Stress testing of the active substance can help in 1.Identification of Degradants 2.Identification of Degradation pathways

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Determination of which type(s) of stress affect the molecule: Photostability High Temperature Low Temperature Oxidation pH extremes Water

Typical Stress conditions::

Typical Stress conditions: STRESS FACTOR CONDITIONS Heat 10 ̊C increment Humidity 75% RH or greater Acid 0.1N HCL Base 0.1N NaoH Oxidative 3% H2O2 Photolytic Xenon,metal,halide lamp or near UV, White fluorescent lamp

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Stress testing is likely to be carried out on a single batch of the drug substance. It should include the effect of temperatures (in 10°C increments (e.g., 50°C, 60°C, etc.) above that for accelerated testing), humidity (e.g., 75% RH or greater) where appropriate, oxidation, and photolysis on the drug substance. The testing should also evaluate the susceptibility of the drug substance to hydrolysis across a wide range of pH values when in solution or suspension. Photo stability testing should be an integral part of stress testing.

Selection of Batches::

Selection of Batches: Data from stability studies should be provided • At least three primary batches • Manufactured to a minimum of pilot scale • Same synthetic route • Method of manufacture and procedure should simulate final process

Container Closure System :

Container Closure System The stability studies should be conducted on the drug substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution.

Specification::

Specification: Stability studies should include testing of those attributes of the drug substance that are susceptible to change during storage and are likely to influence quality, safety, and/or efficacy. The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes. e.g. appearance, assay, degradation.

Testing Frequency::

Testing Frequency: For long term studies: Year 1: every 3 months Year 2: every 6 months Subsequent years: annually At accelerated storage conditions: (6 month study) Minimum three points including t 0 and t final , e.g. 0 3 6 (initial) (final) At intermediate storage conditions : (12 month study) Four points including t 0 and t final , e.g. 0 6 9 12 (initial) (final)

Storage Conditions:-:

Storage Conditions:- In general, a drug substance should be evaluated under storage conditions (with appropriate tolerances) that test its thermal stability and, if applicable, its sensitivity to moisture. The storage conditions and the lengths of studies chosen should be sufficient to cover storage, shipment, and subsequent use.

General case:-:

General case:- The long-term testing should cover a minimum of 12 months’ duration on at least three primary batches at the time of submission and should be continued for a period of time sufficient to cover the proposed re-test period. Study Storage condition Study (Time period) Long term 25°C ± 2°C/60% ± 5% or 30°C ± 2°C/65% ± 5% 12 months Intermediate 30°C ± 2°C/65% ± 5% 6 months Accelerated 40°C ± 2°C/75% ± 5% 6 months

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If long-term studies are conducted at 25°C ± 2°C/60% RH ± 5% RH and “significant change” occurs at any time during 6 months’ testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted and evaluated against significant change criteria. Significant change” for a drug substance is defined as failure to meet its specification.

Drug substances intended for storage in a refrigerator :- :

Drug substances intended for storage in a refrigerator :- If significant change between 3 and 6 months at accelerated testing proposed re-test data based on real time data. Study Storage condition Minimum time period covered by data at submission Long term 5°C ± 3°C 12 months Accelerated 25°C ± 2°C/60% RH ± 5% RH 6 months

Drug substances intended for storage in a freezer :

Drug substances intended for storage in a freezer For drug substances intended for storage in a freezer, the re-test period should be based on the real time data obtained at the long term storage condition Study Storage condition Minimum time period covered by data at submission Long term - 20°C ± 5°C 12 months

Stability commitment:-:

Stability commitment:- When available long term stability data on primary batches do not cover the proposed re-test period granted at the time of approval, a commitment should be made to continue the stability studies post approval in order to firmly establish the re-test period. Commitment not necessary Submission includes data on three production batches covering proposed re-test period

EVALUATION:

EVALUATION The purpose of the stability study is to establish, based on testing a minimum of three batches of the drug substance and evaluating the stability information (including, as appropriate, results of the physical, chemical, biological, and microbiological tests), a re-test period applicable to all future batches of the drug substance manufactured under similar circumstances.

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Limited extrapolation of the real time data from the long term storage condition beyond the observed range to extend the re-test period can be undertaken at approval time, if justified. This justification should be based on what is known about the Mechanism of degradation, The results of testing under accelerated conditions, The goodness of fit of any mathematical model, Batch size, Existence of supporting stability data, etc.

Statements/Labelling::

Statements/Labelling: A storage statement should be established for the labelling based on the stability evaluation of the active substance. Where applicable, specific instructions should be provided, particularly for active substances that cannot tolerate freezing. Terms such as “ambient conditions” or “room temperature” must be avoided. Retest period should be mentioned on the display,if applicable.

PowerPoint Presentation:

Guidelines for Drug product as same as drug substance, the only difference is photostability testing in Drug products.

ICH Q1B Guidelines for Photostability testing:

ICH Q1B Guidelines for Photostability testing The intrinsic photostability characteristics of drug substances and products should be evaluated to demonstrate that, light exposure does not result in unacceptable change. Photostability testing is carried out on a single batch of material selected as described under selection of batches in the guidelines.

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A systematic approach is recommended: • 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.

Light Sources:-:

Light Sources:- The light sources described below may be used for photostability testing.It includes both option 1 and option 2. Option 1:- Light source that is designed to produce an output similar to the D 65/ID 65 emission standard such as an Artificial daylight fluorescent, Lamp combining visible and ultraviolet (UV) outputs, Xenon or metal halide lamp .

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D 65 is the internationally recognized standard for outdoor daylight as defined in ISO 10977(1993). ID 65 is the equivalent indoor indirect daylight standard. The light source emitting significant radiation below 320 nm, an appropriate filter(s) may be fitted to eliminate such radiation The light source emitting significant radiation below 320 nm, an appropriate filter(s) may be fitted to eliminate such radiation.

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Option:-2 For option 2 the same 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 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.

DRUG SUBSTANCE :

DRUG SUBSTANCE For drug substances, photostability testing should consist of two parts: Forced degradation testing Confirmatory testing.

Photostability testing for drug substance:

Photostability testing for drug substance

Presentation of Samples:-:

Presentation of Samples:- An appropriate amount of sample is placed in a Suitable glass or plastic dish and protected with transparent cover. 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 .

Analysis of Samples:-:

Analysis of Samples:- At the end of the exposure period Samples are examined for any changes in: • Appearance • Clarity • Colour of solution, and suitable method validated for products from photodegradation processes. For results comparison, it should be performed always a protected dark control sample .

Judgment of Results:-:

Judgment of Results:- Forced degradation studies should be designed 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’s not designed to establish qualitative or quantitative limits for change.

Judgement of results:-:

Judgement of results:- 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, and the drug will be within justified limits at time of use (see the relevant ICH Stability and Impurity Guidelines).

Drug Product:-:

Drug Product:- Normally,the Studies should be carried out in sequential manner starting with: • Drug product fully exposed, if unacceptable change: • Drug product in immediate pack, if unacceptable change. • Drug product in marketing pack.

Presentation of samples:-:

Presentation of samples:- The samples are taken in sealed containers to minimize sublimation,evaporation or melting. 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).

Analysis of samples:-:

Analysis of samples:- At the end of the exposure period, the samples should be examined for any changes in physical properties such as Appearance, Clarity or color of solution, Dissolution/Disintegration for dosage forms such as capsules), and suitable method validated for products from photodegradation processes. For results comparison, it should be performed always a protected dark control sample .

Judgement of results:-:

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, to assure that the product will be within proposed specifications during the shelf life (see the relevant ICH Stability and Impurity Guidelines).

Quinine Chemical Actinometry :

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). Prepare a sufficient quantity of a 2 per cent w/v, aqueous solution of quinine monohydrochloride dihydrate (if necessary, dissolve by heating).

Method:-1:

Method:-1 The length of exposure should be sufficient to ensure a change in absorbance of at least 0.9. 10ml of sol. in a 20 ml colorless ampoule (SAMPLE) 10ml of sol. in a 20 ml colorless ampoule wraped in aluminum foil (CONTROL) Expose to the light source D etermine the absorbances of the sample (AT) and the control (Ao) at 400 nm using a 1 centimeter (cm) path length Change in absorbance calculated by Δ A = AT - Ao.

Method:-2:

Method:-2 The length of exposure should be sufficient to ensure a change in absorbance of at least 0.5. Fill 1 cm quartz cell (sample) Fill 1 cm quartz cell wrap in aluminium foil (control) Expose to light source Determine the absorbances of the sample (AT) and the control ( Ao ) at 400 nm using a 1 centimeter (cm) path length Change in absorbance calculated by Δ A = AT - Ao .

References:-:

References:- www.ich.org/.../ICH.../Guidelines/.../Stability_Guideline_WHO.pdf www.ich.org/fileadmin/.../ICH.../Guidelines/.../Q1B_Guideline.pdf.

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