ASSIGNMENT -34 DIFFERENT ZONES, FEDERAL CONSIDERATIONS ON STABILITY TESTING OF DRUGS

INTRODUCTION

It is considered good practice to test the stability of drug substances according to the International Conference on Harmonization (ICH) and Committee forProprietary Medicinal Products [CPMP] guidelines, 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, and to establish a re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions.

In a standard stability program, a stress study is first carried out to determine the drug substance's degradation path and to establish suitable analytical methods. Drug substance stability studies are then conducted to define stability under long-term and accelerated storage conditions.

In the next phase of the development plan, the drug substance is formulated into a drug product and compatibility of the drug substance with excipients and container parts is then tested. When suitable conditions are determined, long-term and accelerated studies commence with the drug product. The data obtained from these studies are used to define the optimal storage conditions and corresponding retest period or shelf life for the drug substance.

Objective of stability studies:The purpose of stability testing is to provide evidence on how the quality of a drug substance [API] under the influence of a variety of environmental factors such as temperature, humidity, and light, and varies with time to establish a re-test period for the API (drug substance) to develop the understanding of the degradation pathway of the API which may influence the quality of drug product.

COMMON TERMINOLOGY USED DURING THE STABILITY STUDIES

What is a Commitment Batch?Production batches of a drug substance for which the stability studies are initiated or completed post approval through a commitment made in the registration application.

What is Drug Substance?The unformulated drug substance that may subsequently be formulated with excipients to produce the dosage form.

What is the meaning of Pilot scale batch?A batch of a drug substance manufactured by a procedure fully representative of and simulating that to be applied to a full production scale batch.

What is the meaning of Primary Batch?A batch of a drug substance 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, respectively. However, a primary batch may be a production batch.

What is the Production Batch?A batch of a drug substance manufactured at production scale by using production equipment in a production facility as specified in the application.

What is significant change?Failure to meets its specification or 5% assay variation from its initial value.

What is 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.

What is Re-test periodThe 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. After this period, a batch of drug substance destined for use in the manufacture of a drug product should be re-tested for compliance with the specification and then used immediately.A batch of drug substance can be re-tested multiple times and a different portion of the batch used after each re-test, as long as it continues to comply with the specification.

WHAT IS CLIMATIC ZONES AND HOW THE STABILITY CONDITIONS [TEMPERATURE AND RELATIVE HUMIDITY] ARE ESTABLISHED BASED ON THE CLIMATIC ZONESThe four zones in the world that are distinguished by their characteristic prevalent annual climatic conditions. This is based on the concept described by W. Grimm (Drugs Made in Germany, 28:196-202, 1985 and 29:39-47, 1986).

Climatic zones Partition of the world into three temperature classes based on kinetic averaging of monthly temperatures, &subdivision of the hottest class into predominantly wet or predominantly dryZones (Futscher & Schumacher 1972): ITemperate (21C/45%RH)IISubtropical (25C/60%RH with possibly high RH) III Hot & dry (30C/35%RH) IV Hot & wet (30C/70%RH)The temperatures above are kinetic averages International Climatic Zones & Conditions results are tabulated below:

STABILITY TESTING CONDITIONS (Zone I and II): Long-term conditions: 25C 2C/60% RH 5% Accelerated conditions: 40C 2C/75% RH 5% Intermediate conditions: 30C 2C/65% RH 5% STABILITY TESTING CONDITIONS (Zone III and IV):Long-term conditions: 30C 2C/65% RH 5% RH Accelerated conditions: 40C 2C/75% RH 5%No intermediate storage conditions for stability studies are recommended for climatic Zone III and IV. Therefore, the intermediate storage conditions are not relevant.

STRESS TESTING

Stress testing can help identity the likely degradation products which can help to establish.

The degradation pathways.[ i.e degradation impurities and based on these studies the Pharma professional can understand how the Drug substance will behave during stability studies and how the product is stored in different environmental conditions].

The intrinsic stability of the molecule.

Validate the stability indicating power of the analytical procedures used.

Stress testing is to be carried out on a single batch. It should include the effect of temperature i.e. Testing at 50/60C (i.e. 10C increment) above that accelerated testing, Humidity (75% or greater) where appropriate oxidation & photolysis on the drug substance has to be performed.

To achieve the objective of stress study, Stress study of the API is to be performed in several conditionsa. Stress study in oxidation condition by using Hydrogen peroxideb. Stress study in acidic condition by using Hydrochloric acid.c. Stress study in alkali condition by using Sodium Hydroxide.d. Stress study by heat treatment by using the 80C temperature for 48 hours.e. Stress study in Sunlight by taking in account the ICH Q1B guideline

If the significant levels of impurities are not present in the sample of API then a particular level of impurities are to spike in the stample and stress study is to performed for the aforementioned conditions to understand the degradation pathways for the API.Photo stability testing should be an integral part of stress testing.

Examining degradation products under stress conditions is useful in establishing degradation pathways and developing and validating suitable analytical procedures. However, it is not necessary to identify all the impurities in stress studies for all but it is necessary to demonstrate that they are not formed under accelerated or long term storage conditions.

The peak purity is one of the important criteria which is to be considered during stress study to ensure that there is no interference of the other impurities peak with the main peak of API.

Moreover during stress study the time period for each test should not be short because no large degradation will be observed in the short period. In addition to this strengthening of the test conditions to make sure the height or peak area of principal peak is decreased up to 20% during stress study.

SELECTION OF BATCHES

Data from formal stability studies should be provided on at least three primary batches of the drug substance. The batches should be manufactured to a minimum of pilot scale by the same synthetic route as, and using a method of manufacture and procedure that simulates the final process to be used for, production batches. The overall quality of the batches of drug substance placed on formal stability studies should be representative of the quality of the material to be made on a production scale.

Following points are to considered during submission of the information in the registration dossier to the International Regulatory Agenciesa. Data from 3 primary batches required (Batch number, date of manufacturing and size of each batch should be stated).b. Primary batches could be from pilot / plant scale. c. Plant / Pilot batches should be similar (process, equipment, route should be similar).

CONTAINER CLOSURE SYSTEM

Container closure is the sum of packaging components that together contain and protect the drug substance. This includes primary packaging components and secondary packaging components.

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.

Packaging for API

Primary packaging materialGenerally Low density polyethylene bag EU (LDPE bag) with twist tied with a plastic fastener is used as a primary packaging material. The grade of the primary packaging material should complies with EU Directive No. 2002/72/EEC and clause # 3.2.2 and clause # 3.1.3 of European Pharmacopoeia level of plastic additives phenolic antioxidants, non phenolic antioxidants and amides and sterates should be well below the prescribed level in Pharmacopoeias. Primary packaging material should also comply with FDA regulations like CFR title 21.177.1520,on the final remaining amount of the product in the olefin polymer. container.

Secondary Packaging materialPhysical test: Description, colour, clarity, particle size etc. Generally Triple laminated aluminum bag or LDPE black bagChemical test: Residue on ignition, Heavy metal, Loss on with heat sealed or twist tied are used as a second packaging drying/Water, pH, Specific optical rotation, related material. substances, Assay and Residual solvents.

Tertiary packaging material:Microbial test: Total viable count, sterility, BET. HDPE Drum is used as a tertiary packaging material.

TESTING FREQUNCY

STABILITY SPECIFICATION For long term stability studies, stability samples are to be Specification Release specification analyzed every three months for the first year, every six The combination of physical, chemical, biological, andmonth for second year. Annually thereafter through the microbiological tests and acceptance criteria that determine proposed re-test period. the suitability of a drug product at the time of its release. For accelerated storage condition, stability samples are to be Specification stability specification analyzed a minimum of three time points [eg. 0, 3 and 6 The combination of physical, chemical, biological, andmonths]. A six months study is acceptable for accelerated microbiological tests and acceptance criteria that determine storage conditions by various international authorities for the the suitability of a drug substance throughout its re-test registration dossier. period, or that a drug product should meet throughout its For Intermediate stability studies, stability samples are to be shelf life. analyzed a minimum of four time points [eg.: 0, 3, 6,9,12

If significant change occurs between 3 and 6 months testing at the accelerated storage condition, the proposed re-test period should be based on the real time data available at the long term storage condition.If significant change occurs within the first 3 months testing at the accelerated storage condition, a discussion should be provided to address the effect of short term excursions outside the label storage condition, e.g., during shipping or handling.

There is no accelerated study for above case. Drug substances intended for storage below -20CDrug substances intended for storage below -20C should be treated on a case-by-case basis.Any significant change occurs during 6 months accelerated study. Additional testing at intermediate storage should be conducted.Significant change for a drug substance is defined as failure to meet its specification.

STABILITY COMMITMENT When Initial long term data on primary batches may 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 studies in order to firmly establish the re-test period. If long-term batches cover the proposed retest period then commitment is considered unnecessary. If the submission includes data from stability studies on at least three production batches, a commitment should be made to continue these studies through the proposed re-test period. If submission of the less than 3 production batches, a commitment is made to continue the long term studies during the proposed shelf life and place additional production batches on long term studies through the proposed shelf life. If submission does not include stability data on production batches, a commitment shouldbe made to place first 3 production batches on long term studies through the proposed re-test period.

EVALUATIONOFSTABILITYDATATO ESTABLISH RETEST PERIOD/SHELF LIFEThe main purpose for evaluation to establish the re-test period, applicable to all future batches of the drug substance manufactured under similar circumstances. The degree of variability of individual batches affects the confidence that a future production batch will remain within specification throughout the assigned re-test period.

Extrapolation of dataIf real time data are supported by results from studies conductedunderaccelerated orintermediatestorage conditions, the re-test period may be extended beyond the end of real time studies.The extrapolated retest period may be up to twice, but should not be more than 12 months beyond the period covered by real time data, depending on the change over time, variability of data observed, proposed storage conditions and extent of statistical analyses performed.

LABELING CONSIDERATION FOR DRUG SUBSTANCE:

Following points are to be considered for the storage statement on labels:

A storage statement should be based on the stability evaluation.Avoid use of ambient condition or Room temperatureNeed direct link between the label storage statement & the demonstrated stability.A retest period for drug substance should be derived from stability information and displayed on the container label.

An explanation for the labeling statement should be given in the package leaflet and on the outer packaging, where space permits.**Details of evaluation and included in the committee for proprietary medicinal products (CPMP) / ICH guideline on photo stability testing.*** The actual name of the container should be used, eg. Bottle, blister.

PHOTOSTABILITYThe 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, photo stability testing is carried out on a single batch of material. 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.

Light Source:The light sources described below may be used for photostability testing. The applicant should either maintain an appropriate control of temperature to inimize the effect of localized temperature changes or include a dark control in the same environment unless otherwise justified.

Option 1Any 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.For a light source emitting significant radiation below 320 nm, an appropriate filter(s) may be fitted to eliminate such radiation.

Option 2Sample should be exposed to both the cool white fluorescent and near ultraviolet lamp.01.A cool white fluorescent lamp designed to produce an output similar to that specified in ISO 10977(1993) ;02. 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.

ProcedureFor 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. 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.

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.

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.

CONCLUSIONFrom the above work it can be concluded a successful stability study will establish the retest period and shelf life for drug substance and appropriate storage conditions. Every manufacturer of the API should perform the stability studies as per the ICH/EMEA guidelines for USA, Europe and Japan region and understand the regulatory requirements versus scientific requirements. It is the responsibility of the API manufacturer to choose the correct storage condition and re-test date so that impact on drug product quality can be minimized wrt degradation impurities.

Extended Release Oral Dosage Forms: Development, Evaluation, And Application Of In Vitro/In Vivo Correlations

I.INTRODUCTION

This guidance provides recommendations to pharmaceutical sponsors who intend to develop documentation in support of an in vitro/in vivo correlation (IVIVC) for an oral extended release (ER) drug product for submission in a new drug application (NDA), abbreviated new drug application (ANDA), or antibiotic drug application (AADA). The guidance presents a comprehensive perspective on (1) methods of developing an IVIVC and evaluating its predictability; (2) using an IVIVC to set dissolution specifications; and (3) applying an IVIVC as a surrogate for in vivo bioequivalence when it is necessary to document bioequivalence during the initial approval process or because of certain pre- or postapproval changes (e.g., formulation, equipment, process, and manufacturing site changes).

II.BACKGROUND

The concept of IVIVC, particularly for ER drug products, has been extensively discussed by pharmaceutical scientists. The ability to predict, accurately and precisely, expected bioavailability characteristics for an ER product from dissolution profile characteristics is a long sought after goal. Several workshops and publications have provided information in support of this goal. These are discussed briefly as follows:

!A report from a 1987 ASCPT/DIA/APS/FDA-sponsored workshop entitled Report of the Workshop on CR Dosage Forms: Issues and Controversies (1987) indicated that the state of science and technology at that time did not permit consistently meaningful IVIVC for ER dosage forms and encouraged IVIVC as a future objective. Dissolution testing was considered useful only for process control, stability, minor formulation changes, and manufacturing site changes.

!A USP PF Stimuli Article in July 1988 established the classification of IVIVC into Levels A, B and C, which are currently in use.

!A report from a 1990 ASCPT/DIA/APS/FDA-sponsored workshop entitled In vitro/In vivo Testing and Correlation for Oral Controlled/Modified Release Dosage Forms (1990) concluded that, while the science and technology may not always permit meaningful IVIVC, the development of an IVIVC was an important objective on a product-by-product basis. Procedures for development, evaluation, and application of an IVIVC were described. Validation of dissolution specifications by a bioequivalence study involving two batches of product with dissolution profiles at the upper and lower dissolution specifications was suggested.!USP Chapter 1088 similarly describes techniques appropriate for Level A, B, and C correlations and methods for establishing dissolution specifications.!Further information related to IVIVCs was developed in a USP/AAPS/FDA-sponsored workshop, which resulted in a report entitled Workshop II Report: Scale-up of Oral Extended Release Dosage Forms (1993). This report identified the objectives of an IVIVC to be the use of dissolution as a surrogate for bioequivalency testing, as well as an aid in setting dissolution specifications. The report concluded that dissolution may be used as a sensitive, reliable, and reproducible surrogate for bioequivalence testing. The report gave support to the concepts of USP Chapter 1088 and further found that an IVIVC may be useful for changes other than minor changes in formulation, equipment, process, manufacturing site, and batch size.

These reports document increasing confidence in IVIVC to estimate the in vivo bioavailability characteristics for an ER drug product. In this regard, increased IVIVC activity in NDA submissions has been apparent. Still, the complete process of developing an IVIVC with high quality and predictability and identifying specific applications for such correlations has not been well defined.

As part of the process of developing this guidance, the Agency conducted several surveys of NDA submissions for ER drug products to find out the number of times that IVIVCs were developed. The first survey included NDA submissions from 1982-1992 and found 9 IVIVCs in 60 submissions. A more recent survey included NDA submissions from October 1994 to October 1995 and found 9 IVIVCs in 12 submissions.

This guidance is based on these prior deliberations and publications as well as on current understanding at the FDA and elsewhere on approaches to developing reliable and useful IVIVCs. This guidance describes the levels of correlations that can be established with varying degrees of usefulness, important considerations for in vivo and in vitro experimentation, evaluation of the correlation by focusing on the critical feature of predictability, and practical applications that can be achieved using the IVIVC. With the availability of this guidance, sponsors are encouraged to develop IVIVCs for ER products in the expectation that the information will be useful in establishing dissolution specifications and will permit certain formulation and manufacturing changes without an in vivo bioequivalence study.

III.CATEGORIES OF IN VITRO/IN VIVO CORRELATIONS

A.Level A

A Level A correlation2 is usually estimated by a two-stage procedure: deconvolution followed by comparison of the fraction of drug absorbed to the fraction of drug dissolved. A correlation of this type is generally linear and represents a point-to-point relationship between in vitro dissolution and the in vivo input rate (e.g., the in vivo dissolution of the drug from the dosage form). In a linear correlation, the in vitro dissolution and in vivo input curves may be directly superimposable or may be made to be superimposable by the use of a scaling factor. Nonlinear correlations, while uncommon, may also be appropriate.

Alternative approaches to developing a Level A IVIVC are possible. One alternative is based on a convolution procedure that models the relationship between in vitro dissolution and plasma concentration in a single step. Plasma concentrations predicted from the model and those observed are compared directly. For these methods, a reference treatment is desirable, but the lack of one does not preclude the ability to develop an IVIVC.

Whatever the method used to establish a Level A IVIVC, the model should predict the entire in vivo time course from the in vitro data. In this context, the model refers to the relationship between in vitro dissolution of an ER dosage form and an in vivo response such as plasma drug concentration or amount of drug absorbed.

B.Level B

A Level B IVIVC uses the principles of statistical moment analysis. The mean in vitro dissolution time is compared either to the mean residence time or to the mean in vivo dissolution time. A Level B correlation, like a Level A, uses all of the in vitro and in vivo data, but is not considered to be a point-to-point correlation. A Level B correlation does not uniquely reflect the actual in vivo plasma level curve, because a number of different in vivo curves will produce similar mean residence time values.

C.Level C

A Level C IVIVC establishes a single point relationship between a dissolution parameter, for example, t50%, percent dissolved in 4 hours and a pharmacokinetic parameter (e.g., AUC, Cmax, Tmax). A Level C correlation does not reflect the complete shape of the plasma concentration time curve, which is the critical factor that defines the performance of ER products.

D.Multiple Level C

A multiple Level C correlation relates one or several pharmacokinetic parameters of interest to the amount of drug dissolved at several time points of the dissolution profile.

The efficacy and safety of pharmaceuticals cannot be ensured unless the quality of thepharmaceuticals is maintained during their specified shelf lives. New drug applications needto submit scientific data that guarantee the stability of the product over a specified timeperiod when maintained under specific storage conditions. The International Conferenceon Harmonisation of Technical Requirements for Registration of Pharmaceuticals forHuman Use (ICH) was organized in order to harmonize stability testing requirements fornew drug applications within the European Union (EU), the United States, and Japan. ICHGuidelines for Stability Testing of New Drug Substances and Products and for PhotostabilityTesting of New Drug Substances and Products were officially adopted in October 1993 andNovember 1996, respectively. In this chapter, the ICH harmonized guidelines are introduced,and the major concerns raised by the EU, the United States, and Japan are brieflydiscussed.

6.1. ICH Harmonised Tripartite Guideline for STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS

LIST VARIABLES FOR STABILITY PROTOCOL, DEFINE RETEST PERIOD AND RETEST DATE, WHAT IS MEAN KINETIC TEMPERATURE, VARIOUS LIMITATIONS FOR ACCELERATED STABILITY ANALYSIS FOR CHEMICAL STABILITY

PreambleThe following guideline sets out the stability testing requirement for a RegistrationApplication within the three areas of the EC, Japan and the USA. It does not seek necessarilyto cover the testing that may be required for registration in or export to other areas of theworld.

The guideline seeks to exemplify the core stability data package required for new drugsubstances and products. It is not always necessary to follow this when there are scientificallyjustifiable reasons for using alternative approaches.

The guideline provides a general indication on the requirements for stability testing, butleaves sufficient flexibility to encompass the variety of different practical situations required for specific scientific situations and characteristics of the materials being evaluated.

The principle that information on stability generated in any one of the three areas of theEC, Japan and the USA would be mutually acceptable in both of the other two areas has beenestablished, provided it meets the appropriate requirements of this guideline and the labellingis in accord with national/regional requirements.

Details of the specific requirements for sampling, test requirements for particular dosageforms/packaging etc., are not covered in this guideline.

ObjectiveThe purpose of stability testing is to provide evidence on how the quality of a drugsubstance or drug product varies with time under the influence of a variety of environmentalfactors such as temperature, humidity and light, and enables recommended storage conditions, re-test periods and shelf lives to be established.

ScopeThe guideline primarily addresses the information required in Registration Applications for new molecular entities and associated drug products.This guideline does not currently seek to cover the information required for abbreviated or abridged applications, variations, clinical trial applications, etc.The choice of test conditions defined in this guideline is based on an analysis of the effects of climatic conditions in the three areas of the EC, Japan and the USA. The mean kinetic temperature in any region of the world can be derived from climatic data.

Drug Substance

General approach to stability evaluation.Stress TestingStress testing helps to determine the intrinsic stability of the molecule by establishing degradation pathways in order to identify the likely degradation products and to validate the stability indicating power of the analytical procedures used.Formal Studiesspecification during the re-test period if stored under recommended storage conditions.

Selection of BatchesStability information from accelerated and long term testing is to be provided on at leastthree batches. The long term testing should cover a minimum of 12 months duration on at least three batches at the time of submission.The batches manufactured to a minimum of Pilot plant scale should be by the same synthetic route and use a method of manufacture and procedure that simulates the final process to be used on a manufacturing scale.

The overall quality of the batches of drug substance placed on stability should be representative of both the quality of the material used in pre-clinical and clinical studies and the quality of material to be made on a manufacturing scale.Supporting information may be provided using stability data on batches of drug substance made on a laboratory scale.The first three production batches of drug substance manufactured post approval, if not submitted in the original Registration Application, should be placed on long term stability studies using the same stability protocol as in the approved drug application.

Test Procedures and Test CriteriaThe testing should cover those features susceptible to change during storage and likely to influence quality, safety and/or efficacy. Stability information should cover as necessary the physical, chemical and microbiological test characteristics. Validated stability-indicating testing methods must be applied. The need for the extent of replication will depend on the results of validation studies.

SpecificationLimits of acceptability should be derived from the profile of the material as used in thepre-clinical and clinical batches. It will need to include individual and total upper limits forimpurities and degradation products, the justification for which should be influenced by thelevels observed in material used in preclinical studies and clinical trials.

Storage ConditionsThe length of the studies and the storage conditions should be sufficient to cover storage,shipment and subsequent use. Application of the same storage conditions as applied to thedrug product will facilitate comparative review and assessment. Other storage conditions areallowable if justified. In particular, temperature sensitive drug substances should be storedunder an alternative, lower temperature condition which will then become the designatedlong term testing storage temperature. The six months accelerated testing should then becarried out at a temperature at least 15C above this designated long term storage temperature(together with the appropriate relative humidity conditions for that temperature). Thedesignated long term testing conditions will be reflected in the labelling and re-test date.Minimum Time Period atConditions SubmissionLong term testing 12 monthsAccelerated testing 40C 2C/75% RH 5% 6 months25C 2C/60% RH 5%

Where significant change occurs during six months storage under conditions of acceleratedtesting at 40C 2C/75 percent RH 5 percent, additional testing at an intermediatecondition (such as 30C 2C/60 percent RH 5 percent) should be conducted for drugsubstances to be used in the manufacture of dosage forms tested long term at 25C/60 percent

RH and this information included in the Registration Application. The initial RegistrationApplication should include a minimum of 6 months data from a 12 months study..Significant change. at 40C/75 percent RH or 30C/60 percent RH is defined as failureto meet the specification.The long term testing will be continued for a sufficient period of time beyond 12 monthsto cover all appropriate re-test periods, and the further accumulated data can be submittedto the Authorities during the assessment period of the Registration Application.The data (from accelerated testing or from testing at an intermediate condition) may beused to evaluate the impact of short term excursions outside the label storage conditions suchas might occur during shipping.

Testing FrequencyFrequency of testing should be sufficient to establish the stability characteristics of thedrug substance. Testing under the defined long term conditions will normally be every threemonths, over the first year, every six months over the second year and then annually.

Packaging/Containers same as or simulate the actual packaging used for storage and distribution.

EvaluationThe containers to be used in the long term, real time stability evaluation should be theThe design of the stability study is to establish, based on testing a minimum of threebatches of the drug substance and evaluating the stability information (covering as necessarythe physical, chemical and microbiological test characteristics), a re-test period applicableto all future batches of the bulk drug substance manufactured under similar circumstances.The degree of variability of individual batches affects the confidence that a future production batch will remain within specification until the re-test date.

An acceptable approach for quantitative characteristics that are expected to decreasewith time is to determine the time at which the 95% one-sided confidence limit for the meandegradation curve intersects the acceptable lower specification limit. If analysis shows thatthe batch to batch variability is small, it is advantageous to combine the data into one overallestimate and this can be done by first applying appropriate statistical tests (for example, pvalues for level of significance of rejection of more than 0.25) to the slopes of the regressionlines and zero time intercepts for the individual batches. If it is inappropriate to combine datafrom several batches, the overall re-test period may depend on the minimum time a batchmay be expected to remain within acceptable and justified limits.

The nature of any degradation relationship will determine the need for transformationof the data for linear regression analysis. Usually the relationship can be represented by alinear, quadratic or cubic function on an arithmetic or logarithmic scale. Statistical methodsshould be employed to test the goodness of fit of the data on all batches and combined batches (where appropriate) to the assumed degradation line or curve.

The data may show so little degradation and so little variability that it is apparent fromlooking at the data that the requested re-test period will be granted. Under the circumstances, it is normally unnecessary to go through the formal statistical analysis but merely to providea full justification for the omission.

Limited extrapolation of the real time data beyond the observed range to extendexpiration dating at approval time, particularly where the accelerated data supports this, maybe undertaken. However, this assumes that the same degradation relationship will continueto apply beyond the observed data and hence the use of extrapolation must be justified ineach application in terms of what is known about the mechanism of degradation, thegoodness of fit of any mathematical model, batch size, existence of supportive data etc.Any evaluation should cover not only the assay, but the levels of degradation productsand other appropriate attributes.

Statements/LabellingA storage temperature range may be used in accordance with relevant national/regionalrequirements. The range should be based on the stability evaluation of the drug substance.Where applicable, specific requirements should be stated, particularly for drug substancesthat cannot tolerate freezing. The use of terms such as .ambient conditions. or .roomtemperature. is unacceptable.A re-test period should be derived from the stability information.

Drug ProductGeneralThe design of the stability programme for the finished product should be based on theknowledge of the behavior and properties of the drug substance and the experience gainedfrom clinical formulation studies and from the stability studies on the drug substance. Thelikely changes on storage and the rationale for the selection of product variables to includein the testing programme should be stated.

Selection of BatchesStability information from accelerated and long term testing is to be provided on threebatches of the same formulation and dosage form in the containers and closure proposed formarketing. Two of the three batches should be at least pilot scale. The third batch may besmaller (e.g., 25,000 to 50,000 tablets or capsules for solid oral dosage forms). The long termtesting should cover at least 12 months duration at the time of submission. The manufacturingprocess to be used should meaningfully simulate that which would be applied to large scalebatches for marketing. The process should provide product of the same quality intended formarketing, and meeting the same quality specification as to be applied for release of material.

Where possible, batches of the finished product should be manufactured using identifiablydifferent batches of drug substance.

Data on laboratory scale batches is not acceptable as primary stability information. Dataon associated formulations or packaging may be submitted as supportive information. Thefirst three production batches manufactured post approval, if not submitted in the originalRegistration Application, should be placed on accelerated and long term stability studiesusing the same stability protocols as in the approved drug application.

Test Procedures and Test CriteriaThe testing should cover those features susceptible to change during storage and likelyto influence quality, safety and/or efficacy. Analytical test procedures should be fullyvalidated and the assays should be stability-indicating. The need for the extent of replicationwill depend on the results of validation studies.The range of testing should cover not only chemical and biological stability but alsoloss of preservative, physical properties and characteristics, organoleptic properties and,where required, microbiological attributes. Preservative efficacy testing and assays on storedsamples should be carried out to determine the content and efficacy of antimicrobialpreservatives.

SpecificationsLimits of acceptance should relate to the release limits (where applicable), to be derivedfrom consideration of all the available stability information. The shelf life specification couldallow acceptable and justifiable derivations from the release specification based on thestability evaluation and the changes observed on storage. It will need to include specificupper limits for degradation products, the justification for which should be influenced by thelevels observed in material used in pre-clinical studies and clinical trials. The justificationfor the limits proposed for certain other tests such as particle size and/or dissolution rate willrequire reference to the results observed for batch(es) used in bioavailability and/or clinicalstudies. Any differences between the release and shelf life specifications for antimicrobialpreservatives should be supported by preservative efficacy testing.

Storage Test ConditionsThe length of the studies and the storage conditions should be sufficient to cover storage,shipment and subsequent use (e.g., reconstitution or dilution as recommended in thelabelling).See table below for accelerated and long term storage conditions and minimum times. Anassurance that long term testing will continue to cover the expected shelf life should be provided.

Other storage conditions are allowable if justified. Heat sensitive drug products shouldbe stored under an alternative lower temperature condition which will eventually becomethe designated long term storage temperature. Special consideration may need to be givento products which change physically or even chemically at lower storage conditions, e.g.,suspensions or emulsions which may sediment or cream, oils and semi-solid preparationswhich may show an increased viscosity. Where a lower temperature condition is used, thesix months accelerated testing should be carried out at a temperature at least 15C above itsdesignated long term storage temperature (together with appropriate relative humidityconditions for that temperature). For example, for a product to be stored long term underrefrigerated conditions, accelerated testing should be conducted at 25C 2C/60 percentRH 5 percent RH. The designated long term testing conditions will be reflected in thelabelling and expiration date.

Storage under conditions of high relative humidities applies particularly to solid dosageforms. For products such as solutions, suspensions etc., contained in packs designed toprovide a permanent barrier to water loss, specific storage under conditions of high relativehumidity is not necessary but the same range of temperatures should be applied. Low relativehumidity (e.g., 10.20 percent RH) can adversely affect products packed in semi-permeablecontainers (eg. solutions in plastic bags, nose drops in small plastic containers etc.) andconsideration should be given to appropriate testing under such conditions.Minimum Time Period atConditions SubmissionLong term testing 12 monthsAccelerated testing 40C 2C/75% RH 5% 6 months25C 2C/60% RH 5%

Where .significant change. occurs due to accelerated testing, additional testing at anintermediate condition e.g., 30C 2C/60 percent 5 percent RH should be conducted.

Significant change at the accelerated condition is defined as:1. A 5 percent potency loss from the initial assay value of a batch;2. Any specified degradant exceeding its specification limit;3. The product exceeding its pH limits;4. Dissolution exceeding the specification limits for 12 capsules or tablets.5. Failure to meet specifications for appearance and physical properties e.g., color, phaseseparation, resuspendibility, delivery per actuation, caking, hardness, etc.

Should significant change occur at 40C/75 percent RH then the initial RegistrationApplication should include a minimum of 6 months data from an ongoing one year study at30C/60 percent RH; the same significant change criteria shall then apply.

The long term testing will be continued for a sufficient time beyond 12 months to covershelf life at appropriate test periods. The further accumulated data should be submitted tothe authorities during the assessment period of the Registration Application.

The first three production batches manufactured post approval, if not submitted in theoriginal Registration Application, should be placed on accelerated and long term stabilitystudies using the same stability protocol as in the approved drug application.The fist three production batches manufactured post approval, if not submitted in theoriginal Registration Application, should be placed on accelerated and long term stabilitystudies using the same stability protocol as in the approved drug application.

Testing FrequencyFrequency of testing should be sufficient to establish the stability characteristics of thedrug product. Testing will normally be every three months over the first year, every sixmonths over the second year and then annually.The use of matrixing or bracketing can be applied, if justified. (See Glossary.)

Packaging MaterialsThe testing should be carried out in the final packaging proposed for marketing.Additional testing of unprotected drug product can form a useful part of the stress testingand pack evaluation, as can studies carried out in other related packaging materials insupporting the definitive pack(s).

EvaluationA systematic approach should be adopted in the presentation and evaluation of the stability information which should cover as necessary physical, chemical, biological, microbiological quality characteristics, including particular properties of the dosage form (for example, dissolution rate for oral solid dose forms).The design of the stability study is to establish, based on testing a minimum of three batches of the drug product, a shelf-life and label storage instructions applicable to all futurebatches of the dosage form manufactured and packed under similar circumstances. Thedegree of variability of individual batches affects the confidence that a future productionbatch will remain within specification until the expiration date.

An acceptable approach for quantitative characteristics that are expected to decreasewith time is to determine the time at which the 95% one-sided confidence limit for the meandegradation curve intersects the acceptable lower specification limit. If analysis shows thatthe batch to batch variability is small, it is advantageous to combine the data into one overallestimate and this can be done by first applying appropriate statistical tests (for example, pvalues for level of significance of rejection of more than 0.25) to the slopes of the regressionlines and zero time intercepts for the individual batches. If it is inappropriate to combine datafrom several batches, the overall shelf-life may depend on the minimum time a batch maybe expected to remain within acceptable and justified limits.

The nature of the degradation relationship will determine the need for transformationof the data for linear regression analysis. Usually the relationship can be represented by alinear, quadratic or cubic function on an arithmetic or logarithmic scale. Statistical methodsshould be employed to test the goodness of fit on all batches and combined batches (whereappropriate) to the assumed degradation line or curve.

Where the data shows so little degradation and so little variability that it is apparentfrom looking at the data that the requested shelf-life will be granted, it is normallyunnecessary to go through the formal statistical analysis but only to provide a justificationfor the omission.

Limited extrapolation of the real time data beyond the observed range to extendexpiration dating at approval time, particularly where the accelerated data supports this, maybe undertaken. However, this assumes that the same degradation relationship will continueto apply beyond the observed data and hence the use of extrapolation must be justified ineach application in terms of what is known about the mechanisms of degradation, thegoodness of fit of any mathematical model, batch size, existence of supportive data, etc.

Any evaluation should consider not only the assay but the levels of degradation productsand appropriate attributes. Where appropriate, attention should be paid to reviewing theadequacy of the mass balance, different stability and degradation performance.The stability of the drug products after reconstituting or diluting according to labellingshould be addressed to provide appropriate and supportive information.

Statements/LabellingA storage temperature range may be used in accordance with relevant national/regionalrequirements. The range should be based on the stability evaluation of the drug product.

Where applicable, specific requirements should be stated particularly for drug products thatcannot tolerate freezing.

The use of terms such as .ambient conditions. or .room temperature. is unacceptable.There should be a direct linkage between the label statement and the demonstratedstability characteristics of the drug product.

Annex I. Glossary and InformationThe following terms have been in general use and the following definitions are providedto facilitate interpretation of the guideline.

Accelerated TestingStudies designed to increase the rate of chemical degradation or physical change of anactive drug substance or drug product by using exaggerated storage conditions as part of theformal, definitive, storage programme.These data, in addition to long term stability studies, may also be used to assets longerterm chemical effects at non-accelerated conditions and to evaluate the impact of short termexcursions outside the label storage conditions such as might occur during shipping. Resultsfrom accelerated testing studies are not always predictive of physical changes.

Active Substance; Active Ingredient; Drug Substance; Medicinal SubstanceThe unformulated drug substance which may be subsequently formulated with excipientsto produce the drug product.The design of a stability schedule so that at any time point only the samples on theextremes, for example of container size and/or dosage strengths, are tested. The designassumes that the stability of the intermediate condition samples are represented by those atthe extremes.

Where a range of dosage strengths is to be tested, bracketing designs may be particularlyapplicable if the strengths are very closely related in composition (e.g., for a tablet rangemade with different compression weights of a similar basic granulation, or a capsule rangemade by filling different plug fill weights of the same basic composition into different sizecapsule shells).

Where a range of sizes of immediate containers are to be evaluated, bracketing designsmay be applicable if the material of composition of the container and the type of closure arethe same throughout the range.Climatic ZonesThe concept of dividing the world into four zones based on defining the prevalent annualclimatic conditions.Dosage Form; Preparationcontains a drug ingredient generally, but not necessarily, in association with excipients.A pharmaceutical product type, for example tablet, capsule, solution, cream etc. Thatcontains a drug ingredient generally, but not necessarily, in association with excipients.

Drug; Finished ProductThe dosage form in the final immediate packaging intended for marketing.ExcipientAnything other than the drug substance in the dosage form.Expiry/Expiration DateThe date placed on the Container/labels of a drug product designating the time duringwhich a batch of the product is expected to remain within the approved shelf-life specificationif stored under defined conditions, and after which it must not be used.Formal (Systematic) Studiesthe principles of these guidelines.Long Term (Real Time) TestingStability evaluation of the physical, chemical, biological and microbiological characteristicsof a drug product and a drug substance, covering the expected duration of the shelflife and re-test period, which are claimed in the submission and will appear on the labelling.Mass Balance; Material BalanceThe process of adding together the assay value and levels of degradation products to seehow closely these add up to 100 per cent of the initial value, with due consideration of themargin of analytical precision.This concept is a useful scientific guide for evaluating data, but it is not achievable inall circumstances. The focus may instead be on assuring the specificity of the assay, thecompleteness of the investigation of routes of degradation, and the use, if necessary, ofidentified degradants as indicators of the extent of degradation via particular mechanisms.MatrixingThe statistical design of a stability schedule so that only a fraction of the total numberof samples are tested at any specified sampling point. At a subsequent sampling point,different sets of samples of the total number would be tested. The design assumes that thestability of the samples tested represents the stability of all samples. The differences in thesamples for the same drug product should be identified as, for example, covering differentbatches, different strengths, different sizes of the same container and closure and possiblyin some cases different container/closure systems.Matrixing can cover reduced testing when more than one variable is being evaluated.Thus the design of the matrix will be dictated by the factors needing to be covered andevaluated. This potential complexity precludes inclusion of specific details and examples,and it may be desirable to discuss design in advance with the Regulatory Authority, wherethis is possible. In every case it is essential that all batches are tested initially and at the endof the long term testing.

Mean Kinetic TemperatureWhen establishing the mean value of the temperature, the formula of J. D. Haynes (J.Pharm. Sci. 60, 927-929, 1971) can be used to calculate the mean kinetic temperature. It ishigher than the arithmetic mean temperature and takes into account the Arrhenius equationfrom which Haynes derived his formula.New Molecular Entity; New Active Substancenational or regional authority concerned.Pilot Plant Scalerepresentative of and simulating that to be applied on a full manufacturing scale.that of full production or 100,000 tablets or capsules, whichever is the larger.Primary Stability Datathat support the proposed re-test date.storage conditions that support the proposed shelf life.Re-Test DateA substance that has not previously been registered as a new drug substance with theThe manufacture of either a drug substance or drug product by a procedure fullyFor oral solid dosage forms this is generally taken to be at a minimum scale of one-tenthData on the drug substance stored in the proposed packaging under storage conditionsData on the drug product stored in the proposed container-closure for marketing underThe date when samples of the drug substance should be re-examined to ensure thatmaterial is still suitable for use.Re-Test PeriodThe period of time during which the drug substance can be considered to remain withinthe specifications and is therefore acceptable for use in the manufacture of a given drugproduct, provided that it has been stored under the defined conditions; after this period, thebatch should be re-tested for compliance with specifications and then used immediately.Shelf-Life; Expiration Dating PeriodThe time interval that a drug product is expected to remain within the approved shelf-lifespecification provided that it is stored under the conditions defined on the label in theproposed containers and closure.Specification.ReleaseThe combination of physical, chemical, biological and microbiological test requirementsthat determine that a drug product is suitable for release at the time of its manufacture.

Specification.Check/Shelf-LifeThe combination of physical, chemical, biological and microbiological test requirementsthat a drug substance must meet up to its re-test date or a drug product must meetthroughout its shelf life.Storage Conditions TolerancesThe acceptable variation in temperature and relative humidity of storage facilities.The equipment must be capable of controlling temperature to a range of 2C andrelative humidity to 5%. The actual temperatures and humidities should be monitoredduring stability storage. Short term spikes due to opening of doors of the storage facility areaccepted as unavoidable. The effect of excursions due to equipment failure should beaddressed by the applicant and reported if judged to impact stability results. Excursions thatexceed these ranges (i.e., 2C and/or 5 percent RH) for more than 24 hours should bedescribed in the study report and their impact assessed.Stress Testing (Drug Substance)These studies are undertaken to elucidate intrinsic stability characteristics. Such testingis part of the development strategy and is normally carried out under more severe conditionsthan those used for accelerated tests.Stress testing is conducted to provide data on forced decomposition products and decomposition mechanisms for the drug substance. The severe conditions that may be encountered during distribution can be covered by stress testing of definitive batches of drug substance.These studies should establish the inherent stability characteristics of the molecule, suchas the degradation pathways, and lead to identification of degradation products and hencesupport the suitability of the proposed analytical procedures. The detailed nature of thestudies will depend on the individual drug substance and type of drug product.This testing is likely to be carried out on a single batch of material and to include theeffect of temperatures in 10C increments above the accelerated temperature test condition(e.g., 50C, 60C, etc.); humidity where appropriate (e.g., 75 per cent or greater); oxidationand photolysis on the drug substance plus its susceptibility to hydrolysis across a wide rangeof pH values when in solution or suspension.Results from these studies will form an integral part of the information provided toregulatory authorities.Light testing should be an integral part of stress testing. [The standard conditions forlight testing are still under discussion and will be considered in a further ICH document.]It is recognized that some degradation pathways can be complex and that under forcingconditions decomposition products may be observed which are unlikely to be formed underaccelerated or long term testing. This information may be useful in developing and validatingsuitable analytical methods, but it may not always be necessary to examine specifically forall degradation products, if it has been demonstrated that in practice these are not formed.Stress Testing (Drug Product)Light testing should be an integral part of stress testing. Special test conditions forspecific products (e.g., metered dose inhalations and creams and emulsions) may requireadditional stress studies.

Supporting Stability DataData other than primary stability data, such as stability data on early synthetic routebatches of drug substance, small scale batches of materials, investigational formulations notproposed for marketing, related formulations, product presented in containers and/or closuresother than those proposed for marketing, information regarding test results on containers,and other scientific rationale that support the analytical procedures, the proposed re-testperiod or shelf life and storage conditions.

6.21. GeneralICH Harmonised Tripartite Guideline for Photostability Testing of New Drug Substances and ProductsThe ICH Harmonized Tripartite Guideline covering the Stability Testing of New DrugSubstances and Products (hereafter referred to as the Parent Guideline) notes that light testingshould be an integral part of stress testing. This document is an annex to the Parent Guidelineand addresses the recommendations for photostability testing.A. PreambleThe intrinsic photostability characteristics of new drug substances and products shouldbe 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 forsubmission in Registration Applications for new molecular entities and associated drugproducts. 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 isprovided.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 notacceptable change has occurred at the end of the light exposure testing as described in theDecision Flow Chart for Photostability Testing of Drug Products (Fig. 216). Acceptablechange is change within limits justified by the applicant.

The formal labeling requirements for photolabile drug substances and drug products areestablished by national/regional requirements.B. Light SourcesThe light sources described below may be used for photostability testing. The applicantshould either maintain an appropriate control of temperature to minimize the effect oflocalized temperature changes or include a dark control in the same environment unlessotherwise justified. For both options 1 and 2, a pharmaceutical manufacturer/applicant mayrely on the spectral distribution specification of the light source manufacturer.Option 1Any light source that is designed to produce an output similar to the D65/1DG5 emissionstandard such as an artificial daylight fluorescent lamp combining visible and ultraviolet(W) outputs, xenon, or metal halide lamp. D65 is the internationally recognized standardfor outdoor daylight as defined in IS0 10977 (1993). ID65 is the equivalent indoor indirectdaylight standard. For a light source emitting significant radiation below 320 nm, anappropriate filter(s) may be fitted to eliminate such radiation.Option 2near ultraviolet lamp.For option 2 the same sample should be exposed to both the cool white fluorescent and1. A cool white fluorescent lamp designed to produce an output similar to that specifiedin IS0 10977 (1993); and2. A near UV fluorescent lamp having a spectral distribution from 320 nm to 400 nmwith a maximum energy emission between 350 nm and 370 nm; a significantproportion of W should be in both bands of 320 to 360 nm and 360 to 400 nm.C. ProcedureFor confirmatory studies, samples should be exposed to light providing an overallillumination of not less than 1.2 million lux hours and an integrated near ultraviolet energyof not less than 200 watt hours/square meter to allow direct comparisons to be made betweenthe drug substance and drug product.Samples may be exposed side-by-side with a validated chemical actinometric system toensure the specified light exposure is obtained, or for the appropriate duration of time whenconditions have been monitored using calibrated radiometers/lux meters. An example of anactinometric procedure is provided in the Annex.If protected samples (e.g., wrapped in aluminum foil) are used as dark controls toevaluate the contribution of thermally induced change to the total observed change, theseshould be placed alongside the authentic sample.2. Drug SubstanceFor drug substances, photostability testing should consist of two parts: forced degradationtesting and confirmatory testing.

The purpose of forced degradation testing studies is to evaluate the overall photosensitivityof 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 drugsubstance involved and the intensity of the light sources used. For development andvalidation purposes it is appropriate to limit exposure and end the studies if extensivedecomposition occurs. For photostable materials, studies may be terminated after an appropriateexposure level has been used. The design of these experiments is left to the applicant.sdiscretion although the exposure levels used should be justified.Under forcing conditions, decomposition products may be observed that are unlikely tobe formed under the conditions used for confirmatory studies. This information may beuseful in developing and validating suitable analytical methods. If in practice it has beendemonstrated they are not formed in the confirmatory studies, these degradation productsneed not be further examined. Confirmatory studies should then be undertaken to provide the information necessaryfor 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, andthen the photostability characteristics should be confirmed on a single batch selected asdescribed in the Parent Guideline if the drug is clearly photostable or photolabile. If theresults of the confirmatory study are equivocal, testing of up to two additional batches shouldbe conducted. Samples should be selected as described in the Parent Guideline.

A. Presentation of SamplesCare should be taken to ensure that the physical characteristics of the samples under testare taken into account and efforts should be made, such as cooling and/or placing the samplesin sealed containers, to ensure that the effects of the changes in physical states such assublimation, evaporation or melting are minimized. All such precautions should be chosento provide minimal interference with the exposure of samples under test. Possible interactionsbetween the samples and any material used for containers or for general protection ofthe sample should also be considered and eliminated wherever not relevant to the test beingcarried out.As a direct challenge for samples of solid drug substances, an appropriate amount ofsample should be taken and placed in a suitable glass or plastic dish and protected with asuitable transparent cover if considered necessary. Solid drug substances should be spreadacross the container to give a thickness of typically not more than 3 millimeters. Drugsubstances that are liquids should be exposed in chemically inert and transparent containers.

B. Analysis of SamplesAt the end of the exposure period, the samples should be examined for any changes inphysical properties (e.g., appearance, clarity, or color of solution) and for assay anddegradants by a method suitably validated for products likely to arise from photochemicaldegradation processes.Where solid drug substance samples are involved, sampling should ensure that arepresentative portion is used in individual tests. Similar sampling considerations, such ashomogenization of the entire sample, apply to other materials that may not be homogeneousafter exposure. The analysis of the exposed sample should be performed concomitantly withthat of any protected samples used as dark controls if these are used in the test.

C. Judgment of ResultsThe forced degradation studies should be designed to provide suitable information todevelop and validate test methods for the confirmatory studies. These test methods shouldbe capable of resolving and detecting photolytic degradants that appear during the confirmatorystudies. When evaluating the results of these studies, it is important to recognize thatthey form part of the stress testing and are not therefore designed to establish qualitative orquantitative limits for change.The confirmatory studies should identify precautionary measures needed in manufacturingor 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 exposureto light is acceptable, it is important to consider the results from other formal stability studiesin order to assure that the drug will be within justified limits at time of use (see the relevantICH-Stability and Impurity Guidelines).

3. Drug ProductNormally, the studies on drug products should be carried out in a sequential mannerstarting with testing the fully exposed product then progressing as necessary to the productin the immediate pack and then in the marketing pack. Testing should progress until theresults demonstrate that the drug product is adequately protected from exposure to light. Thedrug product should be exposed to the light conditions described under the procedure insection I.C.Normally, only one batch of drug product is tested during the development phase, andthen the photostability characteristics should be confirmed on a single batch selected asdescribed in the Parent Guideline if the product is clearly photostable or photolabile. If theresults of the confirmatory study are equivocal, testing of up to two additional batches shouldbe conducted.For some products where it has been demonstrated that the immediate pack is completelyimpenetrable to light, such as aluminium tubes or cans, testing should normally only beconducted 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 andrelate to the directions for use, and is left to the applicant.s discretion.The analytical procedures used should be suitably validated.

A. Presentation of SamplesCare should be taken to ensure that the physical characteristics of the samples under testare taken into account and efforts, such as cooling and/or placing the samples in sealedcontainers, should be made to ensure that the effects of the changes in physical states areminimized, such as sublimation, evaporation, or melting. All such precautions should bechosen to provide a minimal interference with the irradiation of samples under test. Possibleinteractions between the samples and any material used for containers or for generalprotection of the sample should also be considered and eliminated wherever not relevant tothe 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 aproduct), the sample shouldbe 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, thesamples 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., dispensingpacks).

B. Analysis of SamplesAt the end of the exposure period, the samples should be examined for any changes inphysical properties (e.g., appearance, clarity or color of solution, dissolution/disintegrationfor dosage forms such as capsules, etc.) and for assay and degradants by a method suitablyvalidated for products likely to arise from photochemical degradation processes.When powder samples are involved, sampling should ensure that a representativeportion is used in individual tests. For solid oral dosage form products, testing should beconducted on an appropriately sized composite of, for example, 20 tablets or capsules.Similar sampling considerations, such as homogenization or solubilization of the entiresample, 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 performedconcomitantly with that of any protected samples used as dark controls if these are used inthe test.C. Judgement of ResultsDepending on the extent of change, special labeling or packaging may be needed tomitigate exposure to light. When evaluating the results of photostability studies to determinewhether change due to exposure to light is acceptable, it is important to consider the resultsobtained from other formal stability studies in order to assure that the product will be withinproposed specifications during the shelf life (see the relevant ICH Stability and ImpurityGuidelines).

4. AnnexA. Quinine Chemical ActinometryThe following provides details of an actinometric procedure for monitoring exposure toa near UV fluorescent lamp (based on FDA/National Institute of Standards and Technologystudy). For other light sources/actinometric systems, the same approach may be used, buteach actinometric system should be calibrated for the light source used.Prepare a sufficient quantity of a 2 per cent weight/volume aqueous solution of quininemonohydrochloride dehydrate (if necessary, dissolve by heating).Option 1Put 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 colourlessampoule, seal it hermetically, wrap in aluminum foil to protect completely from light, anduse this as the control. Expose the sample and control to the light source for an appropriatenumber of hours. After exposure determine the absorbances of the sample (AT) and thecontrol (Ao,) at 400 nm using a 1 centimeter (cm) pathlength. Calculate the change inabsorbance, = AT . Ao. The length of exposure should be sufficient to ensure a changein absorbance of at least 0.9.

Option 2Fill a 1 cm quartz cell and use this as the sample. Separately fill a 1 cm quartz cell, wrapin aluminum foil to protect completely from light, and use this as the control. Expose thesample and control to the light source for an appropriate number of hours. After exposuredetermine the absorbances of the sample (AT) and the control (Ao) at 400 nm. Calculate thechange in absorbance, = AT . Ao. The length of exposure should be sufficient to ensurea change in absorbance of at least 0.5.Alternative packaging configurations may be used if appropriately validated. Alternativevalidated chemical actinometers may be used.

5. GlossaryImmediate (primary) pack is that constituent of the packaging that is in direct contactwith the drug substance or drug product, and includes any appropriate label.Marketing pack is the combination of immediate pack and other secondary packagingsuch 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 thedrug substances, are used to evaluate the overall photosensitivity of the material for methoddevelopment purposes and/or degradation pathway elucidation.Confirmatory studies are those undertaken to establish photostability characteristicsunder standardized conditions. These studies are used to identify precautionary measuresneeded in manufacturing or formulation and whether light resistant packaging and/or speciallabeling 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 whichis described in the Parent Guideline.

6. ReferencesQuinine Actinometry as a method for calibrating ultraviolet radiation intensity inlight-stability testing of pharmaceuticals. Yoshioka S. et al., Drug Development and IndustrialPharmacy, 20 (13), 2049-2062(1994).

6.3 Major Concerns Raised by the EU, the United States, and Japan at the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use

6.3.1. Storage Conditions for Stability TestingThe standard storage-condition for long-term storage testing was harmonized at 25C,60% RH. This standard temperature was decided upon on the basis of mean kinetictemperature. Mean kinetic temperature calculated according to Eq. (4.12) was lower than25C for all areas of the EU and Japan and most areas of the United States. Therefore,long-term storage testing carried out at 25C would allow one to evaluate the stability of the pharmaceuticals distributed in these geographical areas, taking into account the effect oftemperature fluctuations throughout the year. It was pointed out that the mean kinetictemperature may be higher than 25C for some parts of the United States. This problem wasaddressed by taking into account the relevant national/regional requirements for labeling.The storage condition for long-term storage testing for temperature-sensitive pharmaceuticalsdesignated for refrigerated storage and for freezer storage is now under discussion andwill be harmonized at 5 and .15C, respectively, in 1999.The standard temperature for accelerated testing for ordinary products is 40C, atemperature at least 15C higher than that for normal long-term testing. For productsdesignated for refrigerated and freezer storage, 25 and 5C respectively, are recommendedas accelerated temperatures. However, there are ongoing discussions on this issue, whichwill be harmonized in 1999.The standard humidity condition for long-term storage testing at 25C is 60% RH,although there has been continued discussion that higher humidity should be considered forhumidity-sensitive pharmaceutical products, especially for those products to be distributedin areas where high humidity in summer is prevalent (eg., some areas in Japan). However,it was concluded that accelerated testing at 40C/75% RH could cover the effect of higherhumidity. On the other hand, the effect of low humidity should be evaluated for liquid orsuspension products packed in semipermeable containers. Low-humidity conditions of 40%RH and 20% RH have been proposed for long-term storage testing and for acceleratedtesting, respectively. These conditions are now under discussion and will be harmonized in1999.

6.3.2. Photostability TestingFor photostability testing, the choice of light source for testing purposes was one of thematters debated at the ICH conference. Photodegradation of pharmaceuticals dependslargely on the spectral distribution of the light source; thus, testing using different lightsources might bring about differences in the evaluation of photostability. Therefore, thechoice of light source for testing is a very important issue that determines under whatconditions the photostability of pharmaceuticals should be evaluated. The photostability ofpharmaceuticals has been evaluated in European countries using light sources that simulatesunlight, such as a xenon lamp,891 whereas the effect of room lighting has been evaluated inJapan using white fluorescent lamps.A consensus on the light sources for testing could not be achieved at the ICH conference,and two options for light sources (option 1: lamps having output similar to standard daylight;option 2: white fluorescent lamps and near-W fluorescent lamps) were adopted in the ICHguidelines. To reduce the differences in evaluation between the two options, the minimumrequirement for exposure level for both visible and near UV light was designated at 1.2million lux hours and 200 watt hours per square meter, respectively.Exposure levels of a product should be confirmed by monitoring that uses calibratedradiometers or lux meters. Validated chemical actinometry can also be used for this purpose.For near-UV light, quinine actinometry is noted in the appendix of the guideline. Quinineactinometry was adopted because its usefulness was confirmed by a collaborative study ofthe ICH working group892 and by a study carried out by the U.S. Food and Drug Administration.893 However, concern has been expressed about the usefulness of quinine acti nometry, because the degradation mechanism has not been elucidated and the effect oftemperature on the calibration is not clear.894

6.3.3. Bracketing and MatrixingPharmaceutical products containing new drug substances are usually marketed in morethan one form. Also, products may be marketed simultaneously in different packaging (e.g.,different sizes or different materials). Other minor variations in formulation are alsocommon, such as changes in the ratio of drug substance to excipient without significantchange in qualitative or quantitative composition. Large-scale stability testing is needed ifstability evaluations are conducted separately for each of these forms/products. To reducethe total number of samples to be tested, the ICH guidelines introduced the concept ofbracketing and matrixing.Bracketing is a design of a stability testing schedule in which the experimental stabilitydata are obtained only from the extremes of packaging size or strengths. The stability of theintermediate-condition samples is evaluated based on the data from the extremes. Matrixingis a statistical design for stability testing that requires experimental stability data to beobtained from all forms of the drug product but permits only a fraction of the total numberof samples to be tested at any specified sampling point according to a specific samplingdesign.895 Based on the data, a single shelf life applicable to all of these forms of drug productis derived. A prerequisite for the employment of the matrixing design is that no significantdifferences in stability exist among different forms. If stability shows significant variationdue to different packaging or formulation, an unsuitable shelf life may be estimated bymatrixing.

A similar situation involves the evaluation of stability data from different batches. TheICH guideline says that if batch-to-batch variation is small, stability data from several batchescan be combined into one overall estimate to determine the shelf life of a pharmaceuticalproduct in which quantitative characteristics decrease with time. This can be performed ifbatch variation is not found to be significant according to appropriate statistical tests.

The details on the statistical method for assessing stability variations among batches,packagings, or formulations have not yet been harmonized. One method of assessment is ananalysis of variance (ANOVA). However, the power of ANOVA depends largely on the assayerror; it decreases markedly with increasing assay error. Thus, stability variation ismore easily overlooked when the stability data have a larger assay error. As another methodfor assessing stability variations, the assessment of shelf-life equivalence based on the rangeof shelf-life estimates (difference between the largest and smallest estimates) has beenproposed. A simulation study showed that the effect of assay error on the power of thisanalysis was less than on ANOVA. International harmonization on the application ofbracketing and matrixing remains a matter of discussion.

OBJECTIVE OF STABILITY TESTING: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 & light, & enables recommended storage conditions, re-test periods & shelf lives to be established

(ICH) 2003

Why Stability studies are necessary ?Stability studies play a central role in drug developmentPermit understanding of the moleculeEssential for developing analytical methodsEssential for selecting packaging for drug substance and drug productEssential for choosing storage conditions for drug substance and drug product

SELECTED DEFINITIONS

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. 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 30C/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 25C. 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. 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. 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.

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.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,