ICH Stability Studies

ICH – International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human
Use
Now our concern is “QUALITY guideline”, in that stability
guidelines.

STABILITY: The ability of a pharmaceutical product to retain its properties within
specified limits throughout its shelf life.
To provide evidence on how the quality of pharmaceutical product varies with time under
the influence of variety of environmental factors such as temperature, humidity and light.
In order to demonstrate that the clinical effect, the quality and patient safety of the drug is
maintained during its maximal time of storage and intended use.
Aspects of stability that are to be considered includes physical, chemical, microbiological
and bio-pharmaceutical attributes.
Objectives:
To understand basic properties of the product.
To assure integrity/quality of the product.
Product development.
To recommend storage conditions.
To recommend re-test date and assigning shelf life
To review the product quality.
To full fill the requirements for dossier quality.

World divided into climatic zones
Climatic
Zone
Zone – I Zone – II Zone – III Zone – IVa Zone - IVb
Moderate Mediterranean Hot & Dry Hot & Humid
Hot & High
Humid
Temperature
(±2°C) - MKT
21 25 30 30 30
Yearly avg.
Humidity
(±5%RH)
45 60 35 65 75
European All Countries -
American Chile, Canada & US Brazil, Jamaica
Asian China, Japan & Turkey India, Srilanka & Philippines
African South Africa, Zambia & Zimbabwe Botswana, Ghana & Uganda
Australia /
Oceanic
Australia, Newzelannd Fiji, Papua & New guinea

What is Mean Kinetic Temperature?
Mean Kinetic Temperature:
“ Single calculated temperature at which the total amount of degradation over a
particular period is equal to the sum of the individual degradation that would occur at
various temperature.”

Synthesis
Stability of Pharmaceutical product
Formulations Packaging
Q: Why do pharmaceutical properties change under storage/ over time?
A: The drug substance is chemical entity with many reactive functional groups (e.g.: -OH,
-NH2, -COOH, etc…..). Similarly the excipients used in formulations are also chemicals with
reactive functional groups.
Oxidation, Reduction, Hydrolysis, Photolysis, Aggregation, Precipitation, morphology
change, Microbial Growth etc.,

Chemical Reactivity Check List
API/ExcipientFunctionalGroups
• Alcohols (-OH)
• Thiols (-SH)
• Amines (-NH2)
• Halides (-X = Cl, Br, F, I)
• Carboxylic acid (-COOH)
• Esters, Lactones (-COOR)
• Amides, Peptides, Lactam (-COONRR’)
• Imines, Ethers (-C=N-R, R-O-R)
• Aldehydes (-COH)
• α-β unsaturated ketones (-C=C-COR)
• Chiral Centers (-C*-)
• Double bond (C=C, N=N)
Reactivitythatcanaffectstability
• Oxidation, Esterification, Etherification
• Disulphide formation
• Addition rxn, N-Oxidation, Q-ium-salts
• Alkylation
• Decarboxylation, Esterification
• Hydrolysis, trans-esterification
• Hydrolysis
• Hydrolysis
• Reaction with amines (Schiff’s base)
• Additions, adduct formation.
• Racemisation
• Oxidation
• ---Rearrangements, Polymerization

Drug Instability could lead to………
Results
• Reduction of labeled quantity.
• Sub-potent drug products.
• Super-potent drug products.
• Change in content uniformity.
• Change in Bio-availability.
• Toxicity due to degradation.
• Loss of Container closure integrity.
• Loss of Microbial integrity / sterility.
• Loss of Cosmetic aspects.
• Loss of Functional aspects.

Stability during various stages of drug development
Development
Phase
CMCActivitiesObjectives
Pre-IND
Preclinical Research
Phase – I
Phase – III
(File NDA)
Phase – II Phase – IV
* API
* Drug Product
* Analytical Development
(Medicinal / Process
Chem)
* Process Development
- API
- Drug Product
* Scale-up / Validation
- API
- Drug Product
* Post approval
- CMC commitments
- CMC Changes
- Line extensions
* Provide material for
Pharm/Tox Studies
* Preliminary CMC
development (API – AM)
* API/Solution Stability
* Provide Phase – I & II Clinical
supplies
* Understand & Optimize
-- API process
-- Formulation
-- Analytical Methods
* Developmental Stability
-- API
-- Drug Product
* Provide Phase – III
Clinical supplies
* Develop Commercial
-- API process
-- Formulation
-- Analytical Methods
* NDA Stability (ICH)
-- API, Drug Product
* Set API/DP specs, Retest
date, Shelf Life
* CMC Comments
-- Post approval stability
-- Annual stability
* CMC Changes
-- Improvement in process,
Scale, Site, Vendors etc.,
-- API/DP
* Stability (ICH)
-- API/DP
*New dosage forms
Development & Stability

Clinical Studies - Phases
Each clinical trial is conducted in four phases. The Food and Drug Administration (FDA) must approve
each phase before the study can continue.
Phase I: In this phase, a new drug or treatment is tested on a small group of healthy people to
determine safe dosage, study how the drug works in the body, and see if it has any side effects. The
overall safety of the drug is not known during this phase.
Phase II: The drug or treatment can now be tested on a larger group of people to see if it is effective
and to further test its overall safety. Rating scales are developed and used to record data during this
phase.
Phase III: Now the drug or treatment is ready to be tested on even larger numbers of people. The study
will look even more closely at the drug's effectiveness, if it has any side effects, overall safety, and how it
can improve a person's quality of life. Most drugs that reach this phase are considered for FDA approval.
Phase IV: Once given FDA approval, the trial can enter into the final phase, which involves monitoring
the drug after it has been released to the public. In this phase, researchers look for additional information
such as risks, benefits, and optimal or additional uses of the drug. In some cases this phase is used to
test the drug on a sub-group of people (such as patients over a certain age).

Stability Specification (Test – Method – Limit) – Attributes investigated
DRUG SUBSTANCE
Physical Properties:
Color / Appearance / pH / Solubility
/ Melting Pt. / Optical Rotation /
Density / Viscosity
Particle Size / Morphology
Crystal Structure, etc.,
Chemical Properties:
Reactivity / Solvent content / Purity
/ Degradation products, etc.,
Microbial Properties:
Sterility, Microbial limits
***** Validated analytical method
should be used.
DRUG PRODUCT
Color / Appearance / pH /
Viscosity, etc.,
Assay / Moisture content /
Degradation products, etc.,
Microbial Properties:
Sterility, Microbial limits
Functional Properties:
Dissolution / Disintegration /
Brittleness / Preservative content /
Wt. loss / Dose uniformity, etc.,
***** Validated analytical method
should be used.
CONTAINER CLOSURE
Moisture / Vapor transmission /
Light permeation / Adhesion /
Scaling / Elasticity / Fragility /
Corrosion, etc.,
Chemical interaction / Degradation
/ Extraction & leaching of additives
/ Chemicals into drug product

Q1A (R2) – Stability Testing of New Drug Substances and Products
Key Features:
-- Covers stability information needed for marketing application in EU, Japan & USA. (Zone – I & II)
-- Outlines the core stability data package for New drug substances and products.
Major points:
-- Stress testing ( to understand the degradation pattern, intrinsic stability and defining SIM)
-- Number of batches / Selection of batches / Storage conditions.
-- Amount of data required at the time of filing.
SIM – Stability indicating method:
A validated method that can accurately and precisely quantitate the decrease in the quantity of drug
substance due to degradation.
Specification:
It is a list of tests, reference to analytical procedures and proposed acceptance criteria, addressed based
on ICH – Q6A, Q6B, Q3A, Q3B & Q5C

Testing Conditions:-
Accelerated Testing:
Studies designed to increase the rate of chemical degradation or physical change of a pharmaceutical
product by using exaggerated storage conditions as part of the formal stability studies.
Intermediate Testing:
Studies designed to moderately increase the rate of chemical degradation or physical change for a drug
substance or drug product.
Long-term Testing:
Stability studies under the recommended storage condition for the re-test period of shelf life period for
labeling.
Shelf-Life: The time period during which a drug product is expected to remain within the approved shelf-
life specification.
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.

General Case (Drug Substances / Products
Label Storage
Condition
Stability Studies Study Condition
Minimum Data
required for Filing
Room Temperature
(General customary
requirements)
Long Term
25±2°C / 60±5%RH
or
30±2°C / 65±5%RH
12 Months
Intermediate 30±2°C / 65±5%RH 6 Months
Accelerated 40±2°C / 75±5%RH 6 Months
Refrigerator
Long Term 5±3°C 12 Months
Freezer Long Term -20±5°C 12 Months

For Aqueous-Based Drug Products (Packaged in Semi-permeable Containers)
Label Storage
Condition
Stability Studies Study Condition
Minimum Data
required for Filing
Room Temperature
(General customary
requirements)
Long Term
25±2°C / 40±5%RH
or
30±2°C / 35±5%RH
12 Months
Intermediate 30±2°C / 65±5%RH 6 Months
*** No intermediate condition for Refrigerator storage condition.
*** No accelerated condition for Freezer storage condition.
*** Storage below -20°C should be treated case-by-case.

NUMBER OF BATCHES and SELECTION OF BATCHES
Material Number of Batches / Scale Formulation
API At least 3 batches / Pilot scale N/A
Drug Product
At least 3 batches
2 of them should be pilot scale
3rd can be smaller
Same as proposed commercial product
(Pilot Scale = 10% of production scale; or 1,00,000 units, which ever is larger for solid orals)
Process: API and Drug Product should be manufactured by a process representative of commercial process.
Container Closure: Same as proposed commercial packaging.
Testing Frequency:
Long-term testing: 0, 3, 6, 9, 12, 18, 24 months, then yearly (36M).
Intermediate testing: 0, 6, 9 & 12 months.
Accelerated testing: 0, 3 & 6 months.

Significant Change in Drug substance
• Failure to meet in specification
Significant Change in Drug Product
• 5% change in assay value from its initial value.
• Any degradation product exceeding its acceptance criteria.
• Failure to meet the acceptance criteria for dissolution 12 units.
• Failure to meet the acceptance criteria for pH.
• Failure to meet the acceptance criteria for appearance, physical attributes and functional tests.
Significant Change in Pharmaceutical Product packed in semi-permeable container
• 5% water loss from its initial value.

Pharmaceutical product packed in semi-permeable container – Water loss
Low-Humidity
testing conditions
Alternative testing
conditions
Ratio of water
loss rates
Calculation Formula
R A RWL RWL = (100-R)/100-A)
25°C / 40% RH 25°C / 60% RH 1.5 (100 – 40)/(100 – 60)
30°C / 35% RH 30°C / 65% RH 1.9 (100 – 35)/(100 – 65)
30°C / 35% RH 30°C / 75% RH 2.6 (100 – 35)/(100 – 75)
40°C / NMT 25% RH 40°C / 75% RH 3.0 (100 – 25)/(100 – 75)
Ex., at 40°C the calculated rate of water loss during storage at NMT 25% RH is the rate of
water loss measured at 75% RH multiplied by 3.0.

Stability Commitment – Drug Substance and Product
Primary Batches
• If the submitted data do not cover the proposed shelf life at the time of approval, commitment
should be made to continue the studies to firmly establish the shelf life.
Production scale batches
• No Commitment required if full term production scale data provided.
• If production scale batch on stability but full term data not provided, commitment to continue studies.
• If data provided on less than 3 production scale batches, commitment to add additional batches to
study.*
• If no production scale data, commitment to put first 3 production scale batches.*
• ***For drug substance = Long term stability.
• ***For drug product = Long term and accelerated stability.

Limiting Factors
• Pharmaceutical products that cannot tolerate
refrigerating.
Additional labeling
statement, where relevant
freezing.
• Light-sensitive pharmaceutical products.
• Highly hygroscopic pharmaceutical products.
excessive heat.
• “Do not keep in refrigerator or freeze”.
• “Do not freeze”.
• “Protect from light”.
• “Store in dry condition”
• “Store & transport always below 30°C”.
Labeling

Q1B – Photo Stability Testing of New Drug Substances and Products
Key Features:
-- Covers the photo stability information for application.
-- Photo stability testing conditions for exposing drug substance and products. (Photo sensitivity)
Major points:
-- Light sources
-- Photo stability conditions.
-- Study Design.
-- Number of batches.
Light Sources:
-- Option – 1: Artificial daylight (out put similar to D65 [outdoor daylight] & DI65 [indoor indirect daylight])
combining visible and UV outputs, Xenon or metal halide lamp.
-- Option – 2:
(a) Cool white fluorescent lamp. (b) Near UV Fluorescent lamp with spectral distribution between 320 –
400 nm, Emax emission between 350 – 370 nm.

Photo stability conditions:
-- Fluorescent light: Minimum 1.2 million lux hours at 25°C / 60% RH.
-- UV light: Minimum 200 Watts hours per square meter.
Study design and Number of batches
Material
Forced Photo
degradation
study
Confirmatory Studies
No. of Batches * Conditions
Drug Substance YES 1 1.2 Million lux hours:
Near-UV energy of ≥
200 watts hours / sq.
meterDrug Product ** NO 1
•* Two additional batches should be studied if the results are equivocal.

Photo stability conditions:
-- Fluorescent light: Minimum 1.2 million lux hours at 25°C / 60% RH.
-- UV light: Minimum 200 Watts hours per square meter.
A B C
D E F
G H I
Calibration - Calculation:
Fluorescent light: with Lux meter
Avg lux = (A + B + C + D + E + F + G + H + I) / 9
Light Exposure for Fluorescent light = 1.2 X 1000000 hrs
Avg.Lux
UV light: with Radio meter
Avg lux = (A + B + C + D + E + F + G + H + I) / 9
Light Exposure for UV light = 200 X 1000000
Avg.Lux X 10000

Drug
Product
Immediate
Pack
Market
Pack
Photo stability study of
Drug Product **

Q1C – Stability Testing of New Dosage Forms
Key Features:
-- Covers 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.
New Dosage Form:
A pharmaceutical product, containing the same active substance as include in the existing approved drug
product, differing in
-- rout of administration (e.g., oral to parenteral).
-- new functionality / delivery systems (e.g., IR to MR).
-- dosage form / same administration (e.g., capsule to tablet, solution to suspensions).
****
A reduced stability database at submission time (e.g., 6 months accelerated and 6 months long term data
from ongoing studies) may be acceptable in certain justified cases.

Q1D – Bracketing and Matrixing designs for Stability Testing
of New Dosage Forms
Key Features:
-- Provides guidance on bracketing and matrixing study designs to stability studies.
Bracketing:
Design of a stability schedule whereby 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, assuming that the
stability of any intermediate levels is represented by the stability of the extremes tested.
Matrixing:
Design of a stability schedule where testing is performed on a selected subset of samples for one
time point and or another subset of samples for a subsequent time point.
** Effect on retest date and shelf life should be checked before going to reduced study design.
STUDY DESIGN
REDUCED
BRACKETING MATRIXING
FULL

of New Dosage Forms
Bracketing
Applicable
Multiple Strengths
of identical or
closely related
formulations.
Same container
closure system (if
only size & fill
varies)
Bracketing
Not Applicable
Drug Substances
Different strengths
with different
excipients
Matrixing
Applicable
Different Batches /
Strengths / size of
same container
closure system. (in
some cases
different)
Multiple Strengths
of identical or
closely related
formulations
Matrixing
Not Applicable
Limited utility for
Drug Substance.
Supporting data
with more
variability.

of New Dosage Forms
Example for Bracketing Design
Strength S1 = 50 mg S2 = 75 mg S3 = 500 mg
Batch B1 B2 B3 B1 B2 B3 B1 B2 B3
Container
Size (C)
15 ml T T T T T T
100 ml
500 ml T T T T T T
T = Samples tested
C1 – S1 – B1 C3 – S1 – B1 C1 – S3 – B1 C3 – S3 – B1
C1 – S1 – B2 C3 – S1 – B2 C1 – S3 – B2 C3 – S3 – B2
C1 – S1 – B3 C3 – S1 – B3 C1 – S3 – B3 C3 – S3 – B3

of New Dosage Forms
Example for Matrixing Design – “One-Half reduction”
Time points (M) 0 3 6 9 12 18 24 36
S1
B1 T T T T T T
B2 T T T T T T
B3 T T T T T
S2
B1 T T T T T
B2 T T T T T T
B3 T T T T T
T = Sample Tested

of New Dosage Forms
Example for Matrixing Design – “One-Third reduction”
Time points (M) 0 3 6 9 12 18 24 36
S1
B1 T T T T T T
B2 T T T T T T
B3 T T T T T T T
S2
B1 T T T T T T T
B2 T T T T T T
B3 T T T T T T
T = Sample Tested

of New Dosage Forms
For Product with three strengths and three container sizes
“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

of New Dosage Forms
For Product with three strengths and three container sizes
“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
Key
Time Point (M) 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

Q1E – Evaluation of Stability Data
Key Features:
-- How to propose a retest period for drug substance and shelf life for drug product in the registration
application.
-- When and how a extrapolation beyond available data can be considered.
General Principles:
The purpose of a stability study is to establish, based on testing a minimum of three batches of the drug
substance or product, a retest period of shelf life and label storage instructions applicable to all future
batches manufactured and packaged under similar circumstances.
Presentation and evaluation of the stability information.
Physical, chemical, biological and microbiological tests. Mass balance should be considered.
Single vs. multifactor designs and full vs. reduced design studies.
Data from formal stability studies & supporting data - critical quality attributes.
Appendix – A: Decision Tree.
Appendix – B: Statistical approach.

General Principles (Contd.,):
Quantitative critical attributes – Assay, Degradation products, Preservative content.
Qualitative attributes are not amenable to statistical analysis.
Statistical analysis is not intended to imply when it can be justified to be unnecessary
Data presentation:
Data of all attributes should be presented in an appropriate format: Tabulated, Graphical , Narrative.
Extrapolation:
Extrapolation is the practice of using a known data set to infer the information about a future data.
-to extend retest period / shelf life beyond the period covered by long term data.
Mass Balance:
The process of adding the assay value and levels of degradation products to see how closely those add
up to 100% of the initial value, with due consideration of the margin of analytical error.

1. No Significant change in accelerated condition data within 6 months
1.1 Long term & Accelerated data showing little or no variability / change over time
Room temperature Y = up to “2X”, NMT “X + 12”
Refrigerator temperature Y = up to “1.5X”, NMT “X + 6”
1.2 Long term & Accelerated data showing variability / change over time
1.2.1 Data not amenable to statistical analysis.
Room temperature Y = up to “1.5X”, NMT “X + 6”
Refrigerator temperature Y = up to “X + 3”
1.2.2 Data amenable to statistical analysis.
Room temperature Y = up to “2X”, NMT “X + 12”
Refrigerator temperature Y = up to “1.5X”, NMT “X + 6”
Data evaluation for RTP / SL estimation for Pharmaceutical product

2. Significant change in accelerated condition data within 6 months
2.1 Intended to be stored in refrigerator.
No Extrapolation, shorter RTP / SL.
2.2 Significant change at intermediate condition
No Extrapolation, shorter RTP / SL.
2.3 No significant change at intermediate condition
2.3.1 If long term data amenable to statistical analysis.
Y = up to “1.5X”, NMT “X + 6”
2.3.2 If long term data amenable to statistical analysis.
Y = up to “X + 3”
Y = Proposed RTP /SL X = Period covered by Long term data
Data evaluation for RTP / SL estimation for Pharmaceutical product

No significant change at Accelerated condition within 6 months
General case: The proposed retest period / shelf life can be up to twice, but should be NMT 12
months beyond the period covered by long term data.
Long Term (X) 9 M 12 M 18 M 24 M 36 M
Formula (Y = ) 2X 2X X + 12 X + 12 X
SL / RTP 18 M 24 M 30 M 36 M 36 M
Refrigerated case: The proposed retest period / shelf life can be up to one and half times, but
should be NMT 6 months beyond the period covered by long term data.
Long Term (X) 9 M 12 M 18 M 24 M 36 M
Formula (Y = ) 1.5X 1.5X X + 6 X + 6 X
SL / RTP 13.5 M 18 M 24 M 30 M 36 M
No extrapolation after 36 months

Significant change at Accelerated condition within 6 months
General case: The proposed retest period / shelf life can be up to one and half times, but
should be NMT 6 months beyond the period covered by long term data.
Long Term (X) 9 M 12 M
Formula (Y = ) 1.5X 1.5X
SL / RTP 1.35 M 18 M
Refrigerated case: The proposed retest period / shelf life can be up to 3 months beyond the
period covered by long term data.
Long Term (X) 9 M
Formula (Y = ) X + 3
SL / RTP 12 M
If accelerated stability data for 6 months is not ok, consider intermediate condition as long-term.
If any significant change occur at any time during 6 months testing at the accelerated storage condition,
additional testing at the intermediate storage condition should be conducted and evaluated.

Statistical Methods
A Linear regression analysis (Y = mX + C)
B
Poolability tests:
Pooling the data from several batches to estimate a RTP / SL.
ANCOVA – Analysis of Co-variance method.
C Statistical modeling
These procedures can be used in the analysis of stability data that are amenable to statistical
analysis for a quantitative attribute for which there is a proposed criterion.
Statistical approaches for RTP / SL estimation for Pharmaceutical product

Changes in ICH – Q1A parent guideline
Case Q1A Q1A (R) Q1A(R2) Remarks
Testing Frequency
(Accelerated Condition)
0, 1, 2, 3 & 6
months
0, 3 & 6
months
0, 3 & 6
months
5 point study to
3 point study
Stability
storage
condition
Long Term
25±2°C /
60±5%RH
25±2°C /
60±5%RH
25±2°C /
60±5%RH
(or) 30±2°C /
65±5%RH
Decision is left to
applicant
Intermediate
30±2°C /
60±5%RH
30±2°C /
60±5%RH
30±2°C /
65±5%RH
-
Nov - 2000
Feb - 2003
Feb - 2003

Stability challenge for Zone – III & IV
Withdrawn in June 2006 - Reasons
Several countries / regions have revised their own stability testing guidelines for larger safety margin (e.g.,
30°C / 75%RH a long term storage condition).
Respective regions and WHO responsible for defining of storage conditions.
Impact on ICH Q1A (R2)
Intermediate testing condition is unchanged: 30°C / 65% RH.
30°C / 75% RH is acceptable, should the applicant decide to use them.
ICH – Q1F - Stability Data Package for Registration in Climatic Zones III & IV
Stability Study Long Term Accelerated
Condition 30±2°C / 65±5% RH 40±2°C / 75±5%
Data Required 12 months 6 months
Stress Condition: 50°C at ambient humidity to cover extremely hot & dry conditions; 25°C / 80%
RH to cover extremely high humidity condition.

Conclusion
Pharmaceutical stability is a critical quality
attribute. Any deviation from the established
stability profile could affect the quality, safety
and efficacy.
Through understanding of the stability of the
pharmaceutical product is important to build
the quality in
-- Design the optimal pharmaceutical product, define
efficient API / DP process and establish appropriate
specifications and Expiry dates.
-- Successful development, registration and
commercialization.

ICH Stability Studies

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