ICH stability guidelines

Ms. Preeti Dali

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”
Variables affecting the stability-
• Formulation
• Packaging
• Site and method of manufacture
- API or
- Finished product
• Batch size
• Batch to batch variability
- Process validation
- Quality risk management
• Container labelling
• Changes to product
ADVERSE EFFECTS 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)
CLIMATIC ZONES-
• Partition of the world into four temperature classes based on kinetic
averaging of monthly temperatures,
• Zones (Futscher & Schumacher 1972):
I Temperate (21° C/45%RH)
II Subtropical (25°C/60%RH with possibly high RH)
III Hot & dry (30°C/35%RH)
IV Hot & wet (30°C/70%RH)
THE ZONE CONCEPT-
Zone I Zone II Zone III Zone IV
Temperate Subtropical Hot and Dry Hot and Humid
Kinetic average temp Kinetic average temp Kinetic average temp Kinetic average temp
21°C 25°C 30°C 30°C
Yearly average relative Yearly average relative Yearly average relative Yearly average relative
humidity humidity humidity humidity
45% RH 60% RH 35% RH 70% RH
THE ZONE CONCEPT-
Region Zone I & II Countries Zone III & IV Countries

Europe All Countries ----------

America Argentina, Canada, Barbados, Brazil,

Bolivia etc. Venezuela, Panama etc
Asia Japan, Afghanistan, Israel Bangladesh, Hong Kong,
etc India etc
Africa Egypt, South Africa, Mali, Uganda, Nigeria etc
Zimbabwe etc
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 stages of
the drug product lifecycle, 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
1. Development studies-
• Characterize compatibility with common excipients.
• Characterize stability profile of API (E.g. susceptibility to acid, base,
light, oxygen etc.)
• Characterize stability profile of early formulations (Especially
susceptibility to heat, humidity & light)
2. Confirmatory studies-
• Long term & accelerated studies on the product as it is to be registered
ICH Guidelines TITLE
Q1A Stability testing of new drug substances and products
(second revision)
Q1B Stability testing : photo stability testing of new drug
substance and products

Q1C Stability testing for new dosage forms

Q1D Bracketing and matrixing designs for stability testing
of drug substances and products

Q1E Evaluation of stability data

Q1F Stability Data Package for Registration Applications in
Climatic Zones III and IV
Q1A : Stability Testing of New Drug
Substances and Products-
• 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.
ROLL 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?
• the drug be given by injection?
TYPICAL STRESS CONDITION
Stress factor Conditions
Heat 10°C increments
Humidity 75%RH or greater
Acid 0.1N HCl
Base 0.1 NaOH
Oxidative 3%H2O2
Photolytic Xenon, Metal halide lamp or
Near UV, White florescent lamp
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 AND CLOSURE SYSTEM
• The stability studies should be conducted on the drug product
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 (initial) 3 6 (final)

• At intermediate storage conditions: (12 month study)

Four points including t 0 and t final,
e.g. 0 (initial) 6 9 12 (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-
Study Storage condition Minimum time
period covered by
data at submission
Long Term* 25º C ± 2º C 12 months
(Ambient) 60%RH ± 5%
Intermediate** 30º C ± 2º C 6 months
(controlled) 65%RH ± 5%
Accelerated 40º C ± 2º C 6 months
75%RH ± 5%
STORAGE IN REFRIGERATOR-
•Study
Study
•Storage condition
Storage condition Minimum time
•Minimum time period covered by data at submission period covered by
data at submission
Long Term 5º C ± 3º C 12 months

Accelerated 25º C ± 2º C 60%RH ± 6 months

5%
STORAGE IN A FREEZER
•Study
Study
•Storage condition
Storage condition Minimum time
•Minimum time period covered by data at submission period covered by
•Study
•Storage condition data at submission
•Minimum time period covered by data at submissionStudy
•Storage condition
•Minimum time period covered by data at submission
Long Term -20º C ± 5º C 12 months
EVALUATION-
• Minimum of 3 batches of drug substance/ product 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 find 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.
STATEMENT/LABELING-
• 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.
• For drug product, “store at or below 25°C or 30°C”
• Excursions permitted between 15°C to 30°C…….
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
ACCELARATED 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
Q1B: PHOTOSTABILITY TESTING OF NEW
DRUG SUBSTANCES AND PRODUCTS-
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)
Q1C: Stability Testing for New Dosage
Forms-
• 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.
Q1D:(Bracketing and Matrixing Designs for Stability
Testing of New Drug Substances and Products)-
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-
+ = samples tested

Pack Type Label strength and batch numbers (X,Y,Z)

10 mg 20 mg 30 mg
X Y Z X Y Z X Y Z
Alu/Alu blister + + + - - - + + +
cards of 10 tablets

HDPE pack of 30 + + + - - - + + +
tablets
HDPE pack of 100 - - - - - - - - -
tablets
HDPE pack of + + + - - - + + +
1000 tablets
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.
MATRIX DESIGN-
• Sample of Matrixing Design on Time Points for a Product with Two
Strengths – one half reduction
Time points 0 3 6 9 12 18 24 36
(months)
S1 Batch 1 + + - - + - + +

Batch 2 + - + + + - + +

Batch 3 + - + - + + - +

S2 Batch 1 + - + + + + - +

Batch 2 + + - - + + - +

Batch 3 + + - + + - + +
Q1E: EVALUATION OF 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. Dataset - Run1-10a.M3
Observed vs. Predicted $Time [Last comp.] (Aligned)

• The values of quantitative attributes at all time points should be

300

reported as measured (e.g., assay as percent of label claim). 200

• If a statistical analysis is performed, the procedure used and the

100

assumptions underlying the model should be stated and justified. 0

• A tabulated summary of the outcome of statistical analysis and/or

-100

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230 240 2
$Time (normaliz ed)

graphical presentation of the long-term data should be included

SIMCA-P+ 11.5 - 05/02/2007 23:17:07
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.
Q1F: Stability Data Package for Registration
Applications in Climatic Zones III and IV
• Describes harmonized global stability testing requirements in order to
facilitate access to medicines by reducing the number of different
storage conditions.
• WHO conducted a survey amongst their member states to find
consensus on 30°C/65% RH as the long term storage conditions for
hot-dry and hot-humid regions.
TEST PARAMETERS FOR
DIFFERENT DOSAGE FORMS
• TABLETS: appearance, color, odor, assay, weight variation test,
disintegration or dissolution, friability or hardness testing.
• CAPSULE: appearance, color, odor ,assay, disintegration or
dissolution , microbial growth.
• ORAL POWDERS: appearance, color, odor, moisture and re
constitution time
• SUPPOSITORY: appearance, color, particle size, assay, dissolution,
microbial growth
 EMULSION: appearance, color, odor, assay , viscosity, microbial
growth.
 SUSPENSION: particle size, appearance, color, odor, preservative
content, microbial growth, re-dispersibility.
 SOLUTIONS: appearance, color, odor, pH, viscosity, microbial
growth, sterility.
 PARENTERALS: appearance, color, assay, sterility (pyrogenicity or
bacterial endotoxin), impurities.
• IMPLANTS: total drug substance content, in-vitro drug release rate,
sterility.
• TRANSDERMAL: appearance, assay, leakage, microbial growth, drug
release rate.
References
• Guidelines on cGMP and quality of pharmaceutical products by S.Iyer.
• Futscher, N.; Schumacher ,P.; Pharm. Ind. 34, 479 - 483 (1972)
• Grimm, W.; Krummen, K.; Stability Testing in the EC, Japan and the USA,
• Wissenschaftiche Verlagsgesellschaft mbH, Stuttgart (1993)
• Grimm, W.; Drugs made in Germany 28, 196 - 202 (1985) and 29, 39 - 47
( 1986)
• Dietz, R.; Feilner, K., Gerst, F.; Grimm, W.; Drugs made in Germany 36, 99
- 103,(1993)
• Haynes, J.D.; J. Pharm. Sci. 60, 927 - 929 (1971)
• www.ich.org