Regulatory requirement related to Stability Testing

STABILITY: “The capacity of a drug product to remain within specifications established to

ensure its identity, strength, quality and purity”.

PURPOSE OF STABILITY STUDY: To provide evidence of how the quality of drug substances or products varies with time

under the influence of environmental factors. (temperature, humidity and light) To establish a re-test period for the drug substances or the shelf-life for the drug

products and recommended storage conditions. To ensure that drug products retain their full efficacy until the end of their expiration

date. Most important guidelines are

Food and Drug Administration (FDA) International Conference on Harmonization (ICH) European Union Guidelines (EU) Japanese Guidelines (MHW) World Health Organization (WHO) Guidelines Currently ICH guidelines are most commonly accepted which provides information on stability testing within the areas of European Union (EU), Japan, and United States.

Overview of ICH guideline for stability testing…

Stability

Q1A (R2) Stability Testing in New Drugs and Products

(Revised guideline)

Q1B Photo-Stability Testing

Q1C Stability testing: New Dosage Forms

Q1D Bracketing and Matrixing Designs for Stability Testing of Drug Substances and Drug Products

Q1E Evaluation of Stability Data

Q1F Stability Data Package for Registration in Climatic

Zones III and IV

Analytical validation Q2A Definitions and Terminology

Q2B Methodology

Impurities

Q3A Impurity Testing in New Drug Substances

Q3B Impurities in Dosage Forms: Addendum to the

Guideline on Impurities in New Drug Substances

Q3C Impurities: Residual Solvents

Pharmacopeias Q4 Pharmacopeial harmonization

Biotechnology Quality

Q5A Viral Safety Evaluation

Q5B Genetic Stability

Q5C Stability of Biotechnology Products

Q5D Cell Substrates

Specification Q6A Specifications, Test Procedures, and Acceptance Criteria for New Drug Substances and Products

Q6B Biotechnological substance

GMP Q7A GMP for active pharmaceutical ingredients

Development Q8 Pharmaceutical development

Management Q9 Quality Risk Management

STABILITY GUIDELINE

S1(A) Guidelines on The Need For Carcinogenicity

studies of pharmaceuticals

S1(B) Testing for carcinogenicity of pharmaceuticals

S1(C) Dose selection for carcinogecity studies of

pharmaceuticals

S2A Guidance on specific aspect of regulatory

genotoxicity test for pharmaceuticals

S2B Standard for genotoxicity testing for

pharmaceuticals

S(3A) Note for guidance on Toxicokinetics

S(3B) Pharmacokinetic:- Guidance for repeated dose

tissue distribution studies

S4 Duration of Chronic Toxicity testing in Animals

S5 Detection of Toxicity To Reproduction for

Medicinal product and toxicity to male fertility

S6 Preclinical Safety Evaluation Of Biotechnology

derived Pharmaceuticals

S7 Safety Pharmacology studies for Human

Pharmaceuticals

S8 Immunotoxicity studies for Human

Pharmaceuticals

EFFICACY GUIDELINES

E1 The Extent of Population Exposure to Assess

clinical Safety

E2(A) Clinical safety Data management

E2(B) Implementation working group

E2C Clinical safety Data management :- periodic safety

update reports & marketed drugs

E2(D) Post aproval safety data manegemant :-

Definations and Standards for expedited reporting

E2(E) Pharmacovigillance Planning

E2(F) Development safety update report

E3 Structure and content of clinical study reports

E4 Dose response Information to support drug

regisitration

E5 Ethnic factors in the acceptability of foreign

clinical data

E6 Guideline for Good Clinical Practice

E7 Studies in support of Specific Population

E8 General Consideration For Clinical Trials

E9 Stastical Principles For Clinical Trials

E10 Clinical Investigation of medicinal products In The

Pediatric population

E11 Principles Of Clinical Evaluation of New Anti-

hypertensive drugs

E12 The Clinical Evaluation of proarrythmic potential

for Non-Antiarrythmic drugs

E13 Definations of genomic biomarkers,

pharmacoecononomics, pharmacogenetics, Genomic DATA & sample coding categories

MULTIDISCIPLINE-GUIDELINES

M1

Maintenance of The ICH Guideline on non-clinical safety studies for the conduct of human clinical

trials for pharmaceuticals

M2 Electronic Transmission of Individual Case Safety

Reports Message Specification

M3 Organisation of the Common Technical Document for the Registration of Pharmaceuticals for Human

Use

INTERNATIONAL CLIMATIC ZONES AND CLIMATIC CONDITIONS

Climatic Condition

Zone I Temperate

Zone II Mediterranean (sub-tropical)

Zone III Hot/dry or

Hot/moderate RH

Zone IV Very

hot/humid

Mean Annual Temperature

< 20°C 20.5-24°C >24°C >24°C

Kinetic Mean Temperature

(Virtual temperature)

21°C 26°C 31°C 31°C

Mean Annual Relative Humidity

45% 60% 40% 70%

REQUIREMENT OF TEMPERATURE DEPENDED ON TYPE OF TESTING

TYPE OF STUDY TEMPERATURE

RELATIVE HUMIDITY

TIME DURATION

Long term 25°C ± 2°C /60% RH ± 5% RH 12 months

Intermediate 30°C± 2°C /65% RH ± 5% RH 6 months

Accelerated 40°C± 2°C/ 75% RH ± 5% RH 6 months

DIFFERENT TEMPERATURE REQUIREMENT DEPEND UPON TYPE OF DOSAGE FORMS

FOR DISTINCT PRODUCTS

TYPE OF STUDY

AST IST LST

Solid oral DF, solids for reconstitution, dry

&lyophilized powders in glass vials

40°C ± 2°C 75 % ± 5%RH

40°C±2°C 75 % ± 5% RH

40°C±2°C 75 % ± 5% RH

Liquids in glass bottles ,vials, sealed glass

ampoules which provide an impermeable barrier to

water loss

40°C ± 2°C Ambient Humidity

30°C±2°C Ambient humidity

25°C±2°C Ambient Humidity

Drug products in semipermeable containers

40°C ± 2°C NMT 25 %

RH

30°C±2°C 65 % ± 5%

RH

25°C±2°C 40 % ± 5% RH Or 30°C±2°C

35 % ± 5% RH

SUPAC GUIDELINES

1) Stability Testing for New Drug Applications(NDA) A. Drug Substance

B. Drug Product

2) Stability Testing for Abbreviated New Drug Applications(ANDA)

A. Drug Substance Stability Data Submission Supporting information may be provided directly to the drug product ANDA or by

reference to an appropriately referenced drug master file (DMF). For ANDA bulk drug substances- on a minimum of one pilot-scale batch. ANDA bulk drug substances produced by fermentation- on three production batches,

at least two of which should be generated from different starter cultures. B. Drug Substance Testing

A program for stability assessment may include storage at accelerated, long-term, and, if applicable, intermediate stability study storage conditions (refer to IV.G. of the ICH Q1A Guidance and Section II.A. of this guidance).

C. Drug Product As per ICH Q1 A [Section II.B.]

D. ANDA Data Package Recommendations Accelerated stability data at 0, 1, 2, and 3 months. A tentative expiration dating

period of upto 24 months will be granted based on satisfactory accelerated stability data unless not supported by the available long-term stability data.

Long-term stability data Additional stability studies accelerated stability study.

E. Stability Study Acceptance

3) Stability Testing For Investigational New Drug Applications The amount of information needed to achieve that assurance will vary with

o The phase of the investigation, o The proposed duration of the investigation, o The dosage form.

A. General Supportive stability data for changes to an approved drug application (i.e. post

approval changes) required . If change does not alter the stability of the drug product, the previously approved

expiration dating period can be used. But now SUPAC-IR, MR , SS guidance are followed for stability studies . Provides 5 stability data package types .

B. Change in Manufacturing Process of the Drug Substance Carried out at approved manufacturing site . Should be supported by the submission of sufficient data to show that such change

does not compromise the quality , purity , or stability of the drug substance and the resulting drug product

Special concerns are there for biological products. C. Change in Manufacturing Site Site changes consists of change in location site of :

Manufacture Packaging operations Analytical testing laboratory both of company owned and contract

manufacturing. Sufficient data to show that such a change does not alter the characteristics or

compromise the quality, purity, or stability of the drug substance or drug product may be necessary.

The data should include a side-by-side comparison of all attributes to demonstrate comparability and equivalency of the drug substance or drug product manufactured at the two facilities.

New manufacturing locations should have a satisfactory cGMP inspection. D. Change in Formulation of the Drug Product Historically, all changes in drug product formulation were grouped together and

required extensive stability documentation, usually submitted as a prior-approval supplement.

An exception was the detection of a color from a product that could be reported in an annual report without supporting stability data

E. Addition of a New Strength for the Drug Product The addition of a new strength for an approved drug product will generally

require the submission of a prior-approval supplement. Demonstration of equivalent stability between the approved drug product and the

new strength will allow extension of the approved drug product expiration dating to the new strength.

New strengths intermediate to those of an approved drug product may be supported by bracketing/Matrixing studies (See Section VII.G. and VII.H.).

F. Change in Manufacturing Process and/or Equipment for the Drug Product Can be supported by the submission of sufficient data to show that such a change

does not alter the characteristics or compromise the stability of the drug product. The standard stability commitment to conduct and/or complete the stability studies

on the first three production batches produced by the revised manufacturing process in accordance with the approved stability protocol is necessary.

If the data are found acceptable, the approved expiration dating period may be retained.

G. Change in Batch Size of the Drug Product A key question : whether the change involves a change in equipment or its mode of

operation, or other manufacturing parameters described for the approved batch size.

Table 19 presents the recommended stability data packages for a variety of batch size situations not involving equipment or mode of operation changes.

If an equipment change is part of the batch size change, please refer to Change in Manufacturing Process of the Drug Product (Section IX.F.).

H. Reprocessing of a Drug Product Stability data submitted should take into account the nature of the reprocessing

procedure and any specific impact that might have upon the existing stability profile of the drug.

The expiration dating period for a reprocessed batch should not exceed that of the parent batch, and the expiration date should be calculated from the original date of manufacture of the oldest batch.

Reprocessing range from repackaging to regrinding and recompressing tablets. Any batch of the drug product that is reprocessed should be placed on accelerated

and long-term stability studies using the approved protocol to generate a Type 2 stability data package.

I. Change in Container and Closure of the Drug Product The first factor used in determining the stability data package recommendation is

whether or not the protective properties of the container/closure system are affected by the proposed change.

Protective properties of the container/closure system include, Moisture permeability, Oxygen permeability, Light transmission.

Changes that may affect these properties should be supported by a greater amount of data to support the change.

The second factor is the nature of the dosage form itself. A solid dosage form will generally be less affected by a container change than a liquid dosage form

PHOTOSTABILITY TESTING OF NEW DRUG SUBSTANCES AND

PRODUCTS

1. GENERAL

The ICH Harmonized Tripartite Guideline covering the Stability Testing of New Drug Substances and Products notes that light testing should be an integral part of stress testing.

A. Preamble

The 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, photostability testing is carried out on a single batch of material. Under some circumstances these studies should be repeated if certain variations and

changes are made to the product (e.g., formulation, packaging). The guideline primarily addresses the generation of photostability information for

submission in Registration Applications for new molecular entities and associated drug products. The guideline does not cover the photostability of drugs after administration (i.e. under conditions of use).

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 formal labeling requirements for photo labile drug substances and drug products are established by national/regional requirements.

B. Light Sources

The light sources described below may be used for photo stability testing. The applicant should maintain an appropriate control of temperature to minimize the

effect of localized temperature changes.

Option 1

Any light source that is designed to produce an output similar to the D65/ID65 emission standard such as an artificial daylight fluorescent lamp combining visible and ultraviolet (UV) outputs, xenon, or metal halide lamp.

D65 is the internationally recognized standard for outdoor daylight as defined in ISO 10977 (1993). ID65 is the equivalent indoor indirect daylight standard.

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

Option 2

For option 2 the same sample should be exposed to both the cool white fluorescent and near ultraviolet lamp.

1. A cool white fluorescent lamp designed to produce an output similar to that specified in ISO 10977(1993) ; and

2. 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.

C. Procedure

For 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.

DECISION FLOW CHART FOR PHOTOSTABILITY TESTING OF DRUG PRODUCTS

2. DRUG SUBSTANCE

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

The purpose of forced degradation testing studies is to evaluate the overall photosensitivity of 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 drug substance involved and the intensity of the light sources used.

For development and validation purposes it is appropriate to limit exposure and end the studies if extensive decomposition occurs.

For photo stable materials, studies may be terminated after an appropriate exposure level has been used.

Under forcing conditions, decomposition products may be observed that are unlikely to be formed under the conditions used for confirmatory studies.

Confirmatory studies should then be undertaken to provide the information necessary for handling, packaging, and labeling.

Normally, only one batch of drug substance is tested during the development phase, and then the photo stability characteristics should be confirmed on a single batch if the drug is clearly photo stable or photo labile.

If the results of the confirmatory study are equivocal, testing of up to two additional batches should be conducted.

Samples should be selected as described in the Parent Guideline.

A. 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.

B. 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.

C. Judgement of Results

The forced degradation studies should be designed to provide suitable information to develop and validate test methods for the confirmatory studies.

These test methods should be capable of resolving and detecting photolytic degradants that appear during the confirmatory studies.

When evaluating the results of these studies, it is important to recognize that they form part of the stress testing and are not therefore designed to establish qualitative or quantitative limits for change.

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, it is important to consider the results from other formal stability studies in order to assure that the drug will be within justified limits at time of use (see the relevant ICH Stability and Impurity Guidelines).

3. DRUG PRODUCT

(It is same as that described in drug substances)

4. ANNEX

A. 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).

For other light sources/actinometric systems, the same approach may be used, but each actinometric system should be calibrated for the light source used.

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

Option 1: Use 20 ml colourless ampoules (seal hermetically).

Shape and Dimensions for ampoule specifications.

Option 2: Use 1 cm quartz cell.

For both the options, prepare sample and control wrap in aluminum foil to protect completely from light, and measure their absorbance At and Ao respectively at 400nm using 1cm path length. Measure the change in absorbance.

The length of exposure should be sufficient to ensure a change in absorbance of at least 0.9.

BRACKETING AND MATRIXING DESIGNS FOR STABILITY

TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS

1. GUIDELINES

1.1 General

A full study design is one in which samples for every combination of all design factors are tested at all time points.

A reduced design is one in which samples for every factor combination are not all tested at all time points.

A reduced design can be a suitable alternative to a full design when multiple design factors are involved. Any reduced design should have the ability to adequately predict the retest period or shelf life.

During the course of a reduced design study, a change to full testing or to a less reduced design can be considered if a justification is provided and the principles of full designs and reduced designs are followed.

1.2 Applicability of Reduced Designs

Reduced designs can be applied to the formal stability study of most types of drug products, although additional justification should be provided for certain complex drug delivery systems where there are a large number of potential drug-device interactions.

Whether bracketing or matrixing can be applied depends on the circumstances. Data variability and product stability, as shown by supporting data, should be considered

when a matrixing design is applied. Bracketing and matrixing are reduced designs based on different principles. Therefore,

careful consideration and scientific justification should precede the use of bracketing and matrixing together in one design.

1.3 Bracketing

Bracketing is the design of a stability schedule such that only samples on the extremes of certain design factors (e.g., strength, container size and/or fill) are tested at all time points as in a full design. The design assumes that the stability of any intermediate levels is represented by the stability of the extremes tested.

The use of a bracketing design would not be considered appropriate if it cannot be demonstrated that the strengths or container sizes and/or fills selected for testing are indeed the extremes.

1.3.1 Design Factors

Design factors are variables (e.g., strength, container size and/or fill) to be evaluated in a study design for their effect on product stability.

1.3.1.1 Strength

Bracketing can be applied to studies with multiple strengths of identical or closely related formulations.

Examples (1) capsules of different strengths made with different fill plug sizes from the same powder blend, (2) tablets of different strengths manufactured by compressing varying amounts of the same granulation, and

(3) oral solutions of different strengths with formulations that differ only in minor excipients (e.g., colourants, flavourings).

In cases where different excipients are used among strengths, bracketing generally should not be applied.

1.3.1.2 Container Closure Sizes and/or Fills

Bracketing can be applied to studies of the same container closure system where either container size or fill varies while the other remains constant.

The characteristics such as container wall thickness, closure geometry, surface area to volume ratio, headspace to volume ratio, water vapour permeation rate or oxygen permeation rate per dosage unit or unit fill volume should be compared to select the extremes which may affect the product stability.

With justification, bracketing can be applied to studies for the same container when the closure varies. Justification could include a discussion of the relative permeation rates of the bracketed container closure systems.

1.3.2 Design Considerations and Potential Risks

If, after starting the studies, one of the extremes is no longer expected to be marketed, the study design can be maintained to support the bracketed intermediates.

Before a bracketing design is applied, its effect on the retest period or shelf life estimation should be assessed. If the stability of the extremes is shown to be different, the intermediates should be considered no more stable than the least stable extreme (i.e., the shelf life for the intermediates should not exceed that for the least stable extreme).

1.3.3 Design Example

An example of a bracketing design is given in Table 1. This example is based on a product available in three strengths and three container sizes. In this example, it should be demonstrated that the 15 ml and 500 ml high-density polyethylene container sizes truly represent the extremes. The batches for each selected combination should be tested at each time point as in a full design.

Table 1: Example of a Bracketing Design

Strength 50 mg 75 mg 100 mg

Batch 1 2 3 1 2 3 1 2 3

Container size 15 ml T T T T T T

100 ml

500 ml T T T T T T

Key: T = Sample tested

1.4 Matrixing

Matrixing is the design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations would be tested at a specified time point.

At a subsequent time point, another subset of samples for all factor combinations would be tested.

The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point. The differences in the samples for the same drug product should be identified as, for example, covering different batches, different

strengths, different sizes of the same container closure system, and possibly, in some cases, different container closure systems.

When a secondary packaging system contributes to the stability of the drug product, matrixing can be performed across the packaging systems.

Each storage condition should be treated separately under its own matrixing design.

1.4.1 Design Factors

Matrixing designs can be applied to strengths with identical or closely related formulations. Examples (same as bracketing).

With justification, matrixing designs can be applied, for example, to different strengths where the relative amounts of drug substance and excipients change or where different excipients are used or to different container closure systems.

1.4.2 Design Considerations

A matrixing design should be balanced as far as possible so that each combination of factors is tested to the same extent over the intended duration of the study and through the last time point prior to submission.

However, due to the recommended full testing at certain time points, it may be difficult to achieve a complete balance in a design where time points are matrixed.

In a design where time points are matrixed, all selected factor combinations should be tested at the initial and final time points, while only certain fractions of the designated combinations should be tested at each intermediate time point.

If full long-term data for the proposed shelf life will not be available for review before approval, all selected combinations of batch, strength, container size, and fill, among other things, should also be tested at 12 months or at the last time point prior to submission.

In addition, data from at least three time points, including initial, should be available for each selected combination through the first 12 months of the study.

For matrixing at an accelerated or intermediate storage condition, care should be taken to ensure testing occurs at a minimum of three time points, including initial and final, for each selected combination of factors.

1.4.3 Design Examples

Examples of matrixing designs on time points for a product in two strengths (S1 and S2) are shown in Table 2. The terms “one-half reduction” and “one-third reduction” refer to the reduction strategy initially applied to the full study design. For example, a “one-half reduction” initially eliminates one in every two time points from the full study design and a “one-third reduction” initially removes one in every three. In the examples shown in Table 2, the reductions are less than one-half and one-third due to the inclusion of full testing of all factor combinations at some time points as discussed in section 2.4.2. These examples include full testing at the initial, final, and 12-month time points. The ultimate reduction is therefore less than one-half (24/48) or one-third (16/48), and is actually 15/48 or 10/48, respectively. Table 2: Examples of Matrixing Designs on Time Points for a Product withTwo Strengths

“One-Half Reduction”

Time point (months) 0 3 6 9 12 18 24 36

S

t

r

e

S1 Batch 1 T T T T T T

Batch 2 T T T T T T

Batch 3 T T T T T

n

g

t

h

S2 Batch 1 T T T T T

Batch 2 T T T T T T

Batch 3 T T T T T

Key: T = Sample tested

“One-Third Reduction”

Time point (months) 0 3 6 9 12 18 24 36

S

t

r

e

n

g

t

h

S1 Batch 1 T T T T T T

Batch 2 T T T T T T

Batch 3 T T T T T T T

S2 Batch 1 T T T T T T T

Batch 2 T T T T T T

Batch 3 T T T T T T

Key: T = Sample tested

Additional examples of matrixing designs for a product with three strengths and three container sizes are given in Tables 3a and 3b. Table 3a shows a design with matrixing on time points only and Table 3b depicts a design with matrixing on time points and factors. In Table 3a, all combinations of batch, strength, and container size are tested, while in Table 3b, certain combinations of batch, strength and container size are not tested.

Tables 3a and 3b: Examples of Matrixing Designs for a Product with Three Strengths and Three Container Sizes

3a Matrixing on Time Points

Strength S1 S2 S3

Container size A B C A B C A B C

Batch 1 T1 T2 T3 T2 T3 T1 T3 T1 T2

Batch 2 T2 T3 T1 T3 T1 T2 T1 T2 T3

Batch 3 T3 T1 T2 T1 T2 T3 T2 T3 T1

3b Matrixing on Time Points and Factors

Strength S1 S2 S3

Container size A B C A B C A B C

Batch 1 T1 T2 T2 T1 T1 T2

Batch 2 T3 T1 T3 T1 T1 T3

Batch 3 T3 T2 T2 T3 T2 T3

Time-point (months)

0 3 6 9 12 18 24 36

T1 T T T T T T T

T2 T T T T T T

T3 T T T T T T

S1, S2, and S3 are different strengths. A, B, and C are different container sizes.

1.4.4 Applicability and Degree of Reduction

The following should be considered when a matrixing design is contemplated:

knowledge of data variability

expected stability of the product

availability of supporting data

stability differences in the product within a factor or among factors

number of factor combinations in the study

In general, a matrixing design is applicable if the supporting data indicate predictable product stability and also when the supporting data exhibit only small variability. However, where the supporting data exhibit moderate variability, a matrixing design should be statistically justified.

If the supportive data show large variability, a matrixing design should not be applied.

1.4.5 Potential Risk

Due to the reduced amount of data collected, a matrixing design on factors other than time points generally has less precision in shelf life estimation and yields a shorter shelf life than the corresponding full design.

In addition, such a matrixing design may have insufficient power to detect certain main or interaction effects, thus leading to incorrect pooling of data from different design factors during shelf life estimation.

If there is an excessive reduction in the number of factor combinations tested and data from the tested factor combinations cannot be pooled to establish a single shelf life, it may be impossible to estimate the shelf lives for the missing factor combinations.

A study design that matrixes on time points only would often have similar ability to that of a full design to detect differences in rates of change among factors and to establish a reliable shelf life.

This feature exists because linearity is assumed and because full testing of all factor combinations would still be performed at both the initial time point and the last time point prior to submission.

2.5 Data Evaluation

Stability data from studies in a reduced design should be treated in the same manner as data from full design studies.

IMPURITY PROFILE

ICH guidelines:

Impurities Q3A Impurity Testing in New Drug Substances

Q3B Impurities in Dosage Forms: Addendum to the Guideline on Impurities in New Drug Substances

Q3C Impurities: Residual Solvents

IMPURITIES IN NEW DRUG SUBSTANCES

1. PREAMBLE This document is intended to provide guidance for registration applications on the content and qualification of impurities in new drug substances produced by chemical syntheses and not previously registered in a region or member state. It is not intended to apply to new drug substances used during the clinical research stage of development. The following types of drug substances are not covered in this guideline:

biological/biotechnological peptide, oligonucleotide, radiopharmaceutical, fermentation product and semi-synthetic products derived there from, herbal products, and crude products of animal or plant origin.

Impurities in new drug substances are addressed from two perspectives:

Chemistry Aspects include classification and identification of impurities, report generation, listing of impurities in specifications, and a brief discussion of analytical procedures; and

Safety Aspects include specific guidance for qualifying those impurities that were not present, or were present at substantially lower levels, in batches of a new drug substance used in safety and clinical studies.

2. CLASSIFICATION OF IMPURITIES

Impurities can be classified into the following categories:

Organic impurities (process- and drug-related)

Inorganic impurities

Residual solvents Organic impurities can arise during the manufacturing process and/or storage of the new drug substance. They can be identified or unidentified, volatile or non-volatile, and include:

Starting materials

By-products

Intermediates

Degradation products

Reagents, ligands and catalysts Inorganic impurities can result from the manufacturing process. They are normally known and identified and include:

Reagents, ligands and catalysts

Heavy metals or other residual metals

Inorganic salts

Other materials (e.g., filter aids, charcoal) Solvents are inorganic or organic liquids used as vehicles for the preparation of solutions or suspensions in the synthesis of a new drug substance. Since these are generally of known toxicity, the selection of appropriate controls is easily accomplished.

IMPURITIES IN NEW DRUG PRODUCTS

INTRODUCTION 1.1 Objective of the guideline

This document provides guidance for registration applications on the content and qualification of impurities in new drug products produced from chemically synthesised new drug substances not previously registered in a region or member state.

1.2 Scope of the guideline

This guideline addresses only those impurities in new drug products classified as degradation products of the drug substance or reaction products of the drug substance with an excipient and/or immediate container closure system.

Impurities arising from excipients present in the new drug product or extracted or leached from the container closure system are not covered by this guideline.

This guideline also does not apply to new drug products used during the clinical research stages of development.

The following types of products are not covered in this guideline: biological/biotechnological products

Peptides

Oligonucleotides

Radiopharmaceuticals

fermentation products and semi-synthetic products derived therefrom

herbal products, and crude products of animal or plant origin. 2. RATIONALE FOR THE REPORTING AND CONTROL OF DEGRADATION PRODUCTS The applicant should summarise the degradation products observed during manufacture

and/or stability studies of the new drug product. This summary should be based on impurities arising from the interaction with excipients

and/or the immediate container closure system. In addition, the applicant should summarise any laboratory studies conducted to detect

degradation products in the new drug product.

3. ANALYTICAL PROCEDURES The registration application should include documented evidence that the analytical

procedures have been validated and are suitable for the detection and quantitation of degradation products.

In particular, analytical procedures should be validated to demonstrate specificity for the specified and unspecified degradation products.

As appropriate, this validation should include samples stored under relevant stress conditions: light, heat, humidity, acid/base hydrolysis, and oxidation.

The quantitation limit for the analytical procedure should be not more than () the reporting threshold.

Degradation product levels can be measured by a variety of techniques, including those that compare an analytical response for a degradation product to that of an appropriate reference standard or to the response of the new drug substance itself.

Reference standards used in the analytical procedures for control of degradation products should be evaluated and characterised according to their intended uses. The drug substance can be used to estimate the levels of degradation products.

4. REPORTING DEGRADATION PRODUCTS CONTENT OF BATCHES Analytical results should be provided in the registration application for all relevant

batches of the new drug product used for clinical, safety, and stability testing, as well as batches that are representative of the proposed commercial process.

Quantitative results should be presented numerically. For each batch of the new drug product described in the registration application, the

documentation should include:

Batch identity, strength, and size

Date of manufacture

Site of manufacture

Manufacturing process

Immediate container closure

Degradation product content, individual and total

Use of batch (e.g., clinical studies, stability studies)

Reference to analytical procedure used

Batch number of the drug substance used in the new drug product

Storage conditions for stability studies

5. LISTING OF DEGRADATION PRODUCTS IN SPECIFICATIONS The specification for a new drug product should include a list of degradation products

expected to occur during manufacture of the commercial product and under recommended storage conditions.

Stability studies, knowledge of degradation pathways, product development studies, and laboratory studies should be used to characterize the degradation profile.

The selection of degradation products in the new drug product specification should be based on the degradation products found in batches manufactured by the proposed commercial process.

Those individual degradation products with specific acceptance criteria included in the specification for the new drug product are referred to as "specified degradation products" in this guideline.

Specified degradation products can be identified or unidentified.

A rationale for the inclusion or exclusion of degradation products in the specification should be presented.

This rationale should include a discussion of the degradation profiles observed in the safety and clinical development batches and in stability studies, together with a consideration of the degradation profile of batches manufactured by the proposed commercial process.

In summary, the new drug product specification should include, where applicable, the following list of degradation products:

Each specified identified degradation product

Each specified unidentified degradation product

Any unspecified degradation product with an acceptance criterion of not more than () the identification threshold

Total degradation products.

6. QUALIFICATION OF DEGRADATION PRODUCTS Qualification is the process of acquiring and evaluating data that establishes the

biological safety of an individual degradation product or a given degradation profile at the level(s) specified.

The level of any degradation product present in a new drug product that has been adequately tested in safety and/or clinical studies would be considered qualified.

Therefore, it is useful to include any available information on the actual content of degradation products in the relevant batches at the time of use in safety and/or clinical studies.

Degradation products that are also significant metabolites present in animal and/or human studies are generally considered qualified.

Degradation products could be considered qualified at levels higher than those administered in safety studies based on a comparison between actual doses given in the safety studies and the intended dose of the new drug product.

Justification of such higher levels should include consideration of factors such as: (1) the amount of degradation product administered in previous safety and/or clinical studies and found to be safe; (2) the increase in the amount of the degradation product; and (3) other safety factors, as appropriate.

REFERENCE: 1. ICH HARMONISED TRIPARTITIE GUIDELINES www.ich.org 2. Drug Stability: Principles and Practices, 3rd Edition, edited by Jens T. Carstensen and C.

T. Rhodes; chapter-13 & 17. 3. Remington, The Science and Practice of Pharmacy; 21st Edition, volume-1, chapter- 4. Stability of drugs and dosage forms by Sumie yoshika & valentio stella; chapter- 6; page

no- 205 5. 17. Food and Drug Administration for immediate release consumer media: 888-Info-

FDA. May 6, 1998. 6. Chemical Works of Gedeon Richter Ltd., P.O.B. 27, H-1475 Budapest, Hungary(Talanta 44

(1997) 1517-1526)