STABILITY STUDIES ICH Guidelines Q1A-Q1F

STABILITY STUDIES ICH Guidelines Q1A-Q1F

Drug Stability

“A measure of how pharmaceutical products maintains its quality attribute over a time.”

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”

Scope of Stability Testing

•         Provide evidence as to how the quality of the drug product varies with time.

•         Establish shelf life for the drug product.

•         Determine recommended storage conditions.

•         Determine container closure system suitability.

Rationale of Stability Studies

•         Chemical degradation of the product leads to lowering of the concentration of the drug in the dosage form.

•          Toxic products may be formed, due to chemical degradation of the active ingredient.

Advantage of Stability Studies

•         Assurance to the patient

•         Economic considerations

•         Legal requirement

Variables that might affect the stability

•         Formulation

•         Packaging

•         Site and method of  manufacture

•         API

•         Finished product

•         Batch size

•         Batch-to-batch variability

•         Process validation

•         Quality risk management

•         Container labelling

•         Changes to product

Adverse effect of Instability of Drugs

Loss of active drug (e.g. aspirin hydrolysis, oxidation of adrenaline)

Loss of vehicle (e.g. evaporation of water from o/w creams, evaporation of alcohol from alcoholic mixtures)

Loss of content uniformity (e.g. creaming of emulsions, impaction of suspensions)

Loss of elegance (e.g. fading of tablets and colored solutions)

Reduction in bioavailability (e.g. ageing of tablets resulting in a change in dissolution profile)

Production of potential toxic materials (e.g.  Breakdown products from drug degradation)

Types of Stability

A Drug must possess following types of stability

•       CHEMICAL: Each active ingredient retains its chemical integrity and labeled potency within the specified limit.

•       PHYSICAL: The  physical stability properties includes appearance, palatability, uniformity, dissolution and suspend ability are retained.

•       MICROBIOLOGICAL: Sterility or resistance to microbial growth is retained according to specified requirement.

•       THERAPEUTIC: Therapeutic activity remains unchanged.

•       TOXICOLOGIC: No significant increase in toxicity occurs.

Stability studies are incorporated at all stage of the drugs product life cycle, can be segregated into 6 different stages:

STAGE 1– Early stage stress and accelerated testing with drug substances.

STAGE 2– Stability on pre-formulation batches.

STAGE 3– Stress testing on scale-up batches.

STAGE 4– Accelerated and long term testing for registration purposes.

STAGE 5– On-going stability testing

STAGE 6– Follow-up stabilities

Stability Testing

Development studies

•         Characterise compatibility with common excipients.

•         Characterise stability profile of API (E.g. susceptibility to acid, base, light, oxygen etc)

•         Characterise stability profile of early formulations (Especially susceptibility to heat, humidity & light)

Confirmatory studies

•
Long term & accelerated studies on the
product as it  is to be registered

ICH Guideline for Stability Testing

The ICH has so far released six guidelines for

Terminologies Adapted from ICH 2006

•         Production batch

•         Pilot scale batch

•         Re-test period(API)

•         Accelerated testing

•         Intermediate testing

•         Stress testing

•         Bracketing

•         Matrixing

Climatic Zones

•         Partition of the world into four temperature classes based on kinetic averaging of monthly temperatures,

•         Zones (Futscher & Schumacher 1972):

I Temperate (21^oC/45%RH)

II Subtropical (25^oC/60%RH with possibly high RH) 

III Hot & dry (30^oC/35%RH)

IV Hot & wet (30^oC/70%RH)

•         The temperatures above are kinetic averages.

The Zone Concept

Stability Testing of New Drugs Substances and Product Q1A (R2)

Current step 4 version dated 6 February 2003

Stability Testing of API

•         General

•         Stress Testing

•         Selection of Batches

•         Container Closure System

•         Specification

•         Testing Frequency

•         Storage Conditions

•         Stability Commitment

•         Evaluation

•         Statements/Labelling

General

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

Stress Testing

Main tool that predict the stability problems.

Foundation for developing and validating analytical methods.  For an API the following approaches may be used:

When available, it is acceptable to provide relevant data published in the scientific literature to support the identified degradation pathways and products.

When no data is available, stress testing should be performed.

The nature of the stress testing will depend on the individual active substance and the type of pharmaceutical product involved.

The Role of Stress Testing

Stress testing of the active substance can help in

Identification of degradants

Identification of degradation pathways

Determination of which type(s) of stress affect the molecule:

◦      Photo-stability

◦      High Temperature

◦      Low Temperature

◦      Oxidation

◦      pH extremes

◦      Water

Oxidation:

Typically done by placing the drug substance in aqueous solution of hydrogen peroxide.

Goal is significant degradation (typically 10-30% of API)

◦      Can identify degradants

◦      Determine whether protective packaging is required

◦      Determine if an antioxidant should be considered for the drug product formulation.

pH:

Typically done by adding drug substance to buffered aqueous solutions at pH values from 1-10

◦      Decide if the molecule will survive passage through the stomach

–      Is enteric coating necessary?

–      Should the drug be given by injection?

Typical Stress Conditions

Selection of Batches

Data from formal stability studies should be provided on at least three primary batches of the active 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.

Container Closure System

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

Specification

•        Stability studies should include testing of those attributes of the drug substance that are susceptible to change during storage and are likely to influence quality, safety, and/or efficacy.

•         The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes. e.g. appearance, assay, degradation.

Testing Frequency

For long term studies:
Year 1: every 3 months

Year 2: every 6 months Subsequent years: annually

At accelerated storage conditions: (6 month study) Minimum three points including t₀ and t_final,

e.g. 0     3      6

(initial) (final)

At intermediate storage conditions: (12 month study) Four points including t₀ and t_final,

e.g. 0     3      6      12

(initial)                (final)

Storage Condition

A drug substance should be evaluated

•         To test its thermal stability

•         Its sensitivity to moisture(if applicable)

•         The long-term testing (minimum of 12 months) on at least 3  primary batches at the time of submission and

•        Should be continued for a period of time sufficient to cover the proposed re-test period.

General Case

If long-term studies are conducted at 25°C ± 2°C/60% RH ± 5% RH  and “significant change” occurs at any time during six months’ testing  at the accelerated storage condition, additional testing at the  intermediate storage condition should be conducted and evaluated  against significant change criteria.

Significant change – failure to meet its specification

Drug Substances Intended for Storage in a Refrigerator

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.

Drug Substances Intended for Storage in a Freezer

In the absence of an accelerated storage condition for active substances intended to be stored in a freezer, testing on a single batch at an elevated temperature (e.g. 5°C ± 3°C or 25°C ± 2°C or 30°C ± 2°C) for an appropriate time period should be conducted to address the effect of short term excursions outside the proposed label storage condition.

e.g., during shipping or handling

Stability Commitment

•         When available long-term stability data does not cover the proposed re-test period, a commitment should be made to continue stability studies in order to firmly establish the re-test period.

•         Where the data submitted is from fewer than 3 production batches, a commitment should be made to continue the long-term studies with additional production batches, to a total of at least 3.

•         If the submission does not include stability data on production batches, a commitment should be made to place the first 3 production batches on long-term studies through the proposed re- test period.

Evaluation

Minimum of 3 batches of drug substance is tested.

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.

The analyst must found the batch to batch variability & if it is small than only it is accepted & it can be done by different statistical test’s (P value for level of significance for rejection).

Where the data show so little degradation and so little variability then it is normally unnecessary to go through the statistical analysis; providing a justification for the omission should be sufficient.

Statements/Labelling

A storage statement should be established for the labelling based on the stability evaluation of the active substance.

Where applicable, specific instructions should be provided, particularly for active substances that cannot tolerate freezing. Terms such as “ambient conditions” or “room temperature” must be avoided.

Stability Testing of Drug Products

•         General

•         Selection of Batches

•         Container Closure System

•         Specification

•         Testing Frequency

•         Storage Conditions

•         Stability Commitment

•         Evaluation

•         Statements/Labelling

General

The design of the formal stability studies for the pharmaceutical product should be based on knowledge of the behavior and properties of the active substance, from stability studies on the active substance, and on experience gained from clinical formulation studies.

Selection of Batches

Data from stability studies should be provided on at least three primary batches of the pharmaceutical product.

The primary batches should be of the same formulation and packaged in the same container closure system as proposed for marketing.

Two of the three batches should be at least pilot scale batches and the third one can be smaller, if justified.

Stability studies should be performed on each individual strength and container size of the drug product unless bracketing or matrixing is applied.

Container Closure System

Stability testing should be conducted on the dosage form packaged in the container closure system proposed for marketing (including, as appropriate, any secondary packaging and container label).

Specifications

The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes, preservative content (e.g. antioxidant, antimicrobial preservative).

Analytical procedures should be fully validated, and stability indicating.

Testing Frequency

For long term studies:
Year 1: every 3 months

Year 2: every 6 months Subsequent years: annually

At accelerated storage conditions: (6 month study)

Minimum three points including t₀ and t_final,

e.g.  0    3       6

(initial)   (final)

At intermediate storage conditions: (12 month study) Four points including t₀ and t_final,

e.g.  0    3      6      12

(initial)                  (final)

Storage Conditions

A drug substance should be evaluated

To test its thermal stability

Its sensitivity to moisture or potential for solvent loss (if applicable)

The storage conditions and the lengths of studies chosen should be sufficient to cover storage, shipment, and subsequent use with due regard to the climatic zone(s) in which the product is intended to be marketed.

Photostability testing should be conducted on at least one primary batch of the pharmaceutical product if appropriate.

General Case

If long-term studies are conducted at 25°C ± 2°C/60% RH ± 5% RH and “significant change” occurs at any time during 6 months’ testing at the accelerated storage condition, additional testing at the intermediate  storage condition should be conducted and evaluated against significant change criteria

In general, “significant change” for a drug product is defined as:

•         A 5% change in assay from its initial value;

•         Any degradation product’s exceeding its acceptance criterion;

•         Failure to meet the acceptance criteria for appearance, physical  attributes, and functionality test (e.g., color, phase separation,  resuspendibility, caking, hardness, dose delivery per actuation); however, some changes in physical attributes (e.g., softening of  suppositories, melting of creams) may be expected under accelerated conditions; and, as appropriate for the dosage form:

•         Failure to meet the acceptance criterion for pH;

•         Failure to meet the acceptance criteria for dissolution for 12 dosage units.

Drug products packaged in impermeable containers:

Sensitivity to moisture or potential for solvent loss is not a concern for drug products packaged in impermeable containers.

Thus, stability studies can be conducted under any controlled or ambient humidity condition.

Drug products packaged in semi-permeable containers:

Aqueous-based products packaged in semi- permeable containers should be evaluated for potential water loss in addition to physical, chemical, biological, and microbiological stability.

This evaluation can be carried out under conditions of low relative humidity.

A 5% loss in water from its initial value is considered a significant change for a product packaged in a semi-permeable container after an equivalent of 3 months’ storage at 40°C/NMT 25% RH.

Drug Products Intended for Storage in a Refrigerator

If significant change occurs between 3 and 6 months’ testing at the accelerated storage condition, the proposed shelf life should  be based on the real time data available from the long term storage condition.

Drug Products Intended for Storage in a Freezer

For drug products intended for storage in a freezer, the shelf life should be based on the real time data obtained at the long term storage condition.

Stability Commitment

If the submission includes data from stability studies on at least 3 production batches, a commitment should be made to continue the long term studies through the proposed shelf life and the accelerated studies for 6 months.

If the submission includes data from stability studies on fewer than three production batches, a commitment should be made to continue the long term studies through the proposed shelf life and the accelerated studies for 6 months, and to place additional production batches, to a total of at least three, on long term stability studies through the proposed shelf life and on accelerated studies for 6 months.

If the submission does not include stability data on production batches, a commitment should be made to place the first three production batches on long term stability studies through the proposed shelf life and on accelerated studies for 6 months.

Evolution

A systematic approach should be adopted in the presentation and evaluation of the stability information.

Minimum of 3 batches of drug product was tested

The analyst must found the batch to batch variability & if it is small than only it is accepted & it can be done by different statistical test’s (P value for level of significance for rejection).

Where the data show so little degradation and so little variability then it is normally unnecessary to go through the formal
statistical analysis; justifying the omission should be sufficient.

Ongoing Stability Studies

Purpose: to monitor and determine that API/FPP remains within specifications under the storage conditions, within the re-test period/shelf life in all future batches.

The programme should be described in a written protocol.

The programme should include at least one production batch per year, tested at least annually.

An ongoing study should be conducted after any significant change to the synthetic route/manufacturing process or container which may impact stability.

Stability Indicating Quality Parameter

Stability studies should include testing of those attributes of the Drug product that are susceptible to change during storage and are likely to influence quality, safety and/or efficacy.

For instance, in case of tablets:

• appearance
• hardness
• friability
• moisture content
• dissolution time
• degradants
• assay
• microbial purity

Dosage form Consideration

Accelerated Stability

This stability study run under more stressful conditions than expected for long term storage to account for any changes outside the label storage conditions

The goal is to get a quick understanding of what may be expected from a long term study.

Stability Testing: Photostability Testing of New Drugs Substances and Products Q1B

Current Step 4 Version dated 6 November 1996

Photostability Testing

Photo-stability testing studies include:

(Single batch) (no photo-stability studies after administration)

•         Test on drug substance.

•         Test on exposed drug product outside the immediate pack.

•         Test on drug product in the immediate pack.

•         Test on drug product in the marketing pack.

Light source

Option 1: Artificial daylight lamp combining both visible & UV output similar to D65 & ID65.

Option 2: Cool white fluorescent & near UV lamp (320-400nm)

output similar to that specified in ISO  10977

max. energy emission  between 350-370 nm

Procedure

E.g.: Quinine chemical actinometry:  2%w/v aq.solution of quinine  monohydrochloride dihydrate

Stability Testing for New Dosage Forms Annex to the ICH Harmonised Tripartite Guideline on Stability Testing for New Drugs and Products Q1C

Current Step 4 version dated 6 November 1996

New Dosage Form

This document is an annex to the ICH parent stability guideline and addresses the recommendations on what should be submitted regarding stability of new dosage forms by the owner of the original application, after the original submission for new drug substances and products

A new dosage form is defined as a drug product which is a different pharmaceutical product type, but contains the same active substance as included in the existing drug product approved by the pertinent regulatory authority.

Stability protocols for new dosage forms should follow the guidance in the parent stability guideline in principle. However, a reduced stability database at submission time may be acceptable in certain justified cases.

Bracketing and Matrixing Design for Stability Testing of New Drug Substances and Products Q1D

Current Step 4 version dated 7 February 2002

Bracketing

It is the design of a stability schedule such that only samples on the extremes of certain design factors, e.g., strength, package size, 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. Where a range of strengths is to be tested, bracketing is applicable if the strengths are identical or very closely related in composition.

e.g.: for a tablet range made with different compression weights of a similar basic granulation.

Bracketing can be applied to different container sizes or different fills in the same container closure system.

Bracketing Design

+ indicates- Sample tested

Matrixing

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

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

The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point.

}        One half reduction

}        One third reduction

Matrixing Design

Example of Matrixing Design on Time Points for a Product with Two Strengths

Evaluation for Stability Data Q1E

Current Step 4 version dated 6 February 2003

Evaluation for Stability Data

Data Presentation-

•       Data for all attributes should be presented in an appropriate format (e.g., tabular, graphical, narrative) and an evaluation of such data should be included in the application.

•      The values of quantitative attributes at all-time points should be reported as measured (e.g., assay as percent of label claim).

•      If a statistical analysis is performed, the procedure used and the assumptions underlying the model should be stated and justified.

•      A tabulated summary of the outcome of statistical analysis and/or graphical presentation of the long-term data should be included.

Extrapolation

•       Extrapolation is the practice of using a known data set to infer information about future data (e.g. by using regression line analysis)

•       Extrapolation to extend the retest period or shelf life beyond the period covered by long-term data can be proposed in the application, particularly if no significant change is observed at the accelerated condition.

Data Evaluation for Retest Period or Shelf Life Estimation for Drug Substances or Products Intended for Room Temperature Storage

No significant change at accelerated condition

Where no significant change occurs at the accelerated condition, the retest period or shelf life would depend on the nature of the long-term and accelerated data.

Long-term and accelerated data showing little or no change over time and little or no variability

Where the long-term data and accelerated data for an attribute show little or no change over time and little or no variability, it might be apparent that the drug substance or product will remain well within the acceptance criteria for that attribute during the proposed retest period or shelf life.

The proposed retest period or shelf life can be up to twice, but should not be more than 12 months beyond, the period covered by long-term data.

Long-term or accelerated data showing change over time and/or variability

Data not amenable to statistical analysis

Where long-term data are not amenable to statistical analysis, but relevant supporting data are provided, the proposed retest period or shelf life can be up to one and-a-half times, but should not be more than 6 months beyond, the period covered by long-term data.

Data amenable to statistical analysis

If long-term data are amenable to statistical analysis but no analysis is performed, the extent of extrapolation should be the same as when data are not amenable to statistical analysis

However, if a statistical analysis is performed, it can be appropriate  to propose a retest period or shelf life of up to twice, but not more  than 12 months beyond, the period covered by long-term data,

Significant change at accelerated conditions

Where significant change occurs at the accelerated condition, the retest period or shelf life would depend on the outcome of stability testing at the intermediate condition as well as at the long-term condition.

No significant change at intermediate condition

Where no significant change occurs at the intermediate condition, the retest period or shelf life would depend on the nature of the long-term and intermediate data.

Data not amenable to statistical analysis

When the long-term data for an attribute are not amenable to statistical analysis, the proposed retest period or shelf life can be up to 3 months beyond the period covered by long-term data.

Data Amenable to Statistical Analysis

If long-term data are amenable to statistical analysis but no analysis is performed, the extent of extrapolation should be the same as when data are not amenable to statistical analysis

However, if a statistical analysis is  performed, it can  be appropriate to  propose a retest period or shelf life of up to one & half times, but not more than 6 months beyond, the period covered by long-term data,

SIGNIFICANT CHANGE AT INTERMEDIATE CONDITIONS

Where significant change observed at intermediate conditions, the proposed retest period or shelf life should not be more than period covered by long term study.

In addition a retest period or shelf life shorter than data covered by long term study may be called for.

References

THE FOLLOWING ICH GUIDELINES MAY BE CONSULTED IN THE CONTEXT OF STABILITY TESTING:

1)      ICH Q1A (R2): Stability testing of new drug substances and products (http://www.ich.org/LOB/media/ MEDIA419.pdf).

2)      ICH Q1B: Photostability testing of new drug substances and products (http://www.ich.org/LOB/media/ MEDIA412.pdf).

3)   ICH Q1C: Stability testing of new dosage forms http://www.ich.org/LOB/media/MEDIA413.pdf).

4)      ICH Q1D: Bracketing and matrixing designs for stability testing of new drug substances and products (http://www.ich.org/LOB/media/MEDIA414.pdf).

5)      ICH Q1E: Evaluation for stability data (http://www.ich.org/LOB/media/MEDIA415.pdf).

6)      V.SAI KISHORE’s Drug regulatory affairs (pg no 227-288)

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