Solid state stability and shelf-life assignment, Stability protocols,reports and ICH guidelines

1. SOLID STATE STABILITY AND SHELF-LIFE ASSIGNMENT,
STABILITY PROTOCOL, REPORTS AND ICH GUIDELINES
GUIDED BY:
K.SRINIVASA REDDY
M.PHARM.,( Ph.D. ) PRESENTED BY:
G.DURGA BHAVANI
M.PHARM-1st
YEAR
PHARMACEUTICS
18IS1SO314
JAWAHARLAL NEHRU TECHNOLOGICAL UNIVERSITY-
KAKINADA
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2. CONTENTS:
SOLID STATE STABILTY
SELF-LIFE ASSIGNMENT
STABILITY PROTOCOL, REPORTS
ICH GUIDELINES
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3. STABILITY:
 The USP defines the stability of a product or drug substance as “The extent to which a product or drug substance
retains within specified limits of identity, strength, quality and purity throughout its period of storage and use(i.e.,
shelf-life)and the same properties and characteristics that it possessed at the time of its manufacturer.
(or)
 Stability of pharmaceutical product may be defined as the capability of a particular formulation in a specified
container /closer system to remain within its physical, chemical, microbiological, therapeutic and toxicological
specifications.
 It is investigated throughout the various stages of development process i.e., first assessed in the preformulation stage
which will be determined by pharmaceutical scientists.
 Stability/compatibility with various solvents, buffered, solutions and excipients considered for formulation
development.
 It is the responsibility of the pharmacist via the information of the manufacture to instruct the patient in the proper
storage and the handling of the drug product.
NEED TO MAINTAIN STABILITY:
 Provide an evidence on how the quality of a product or drug substance varies with time under the influence of a
variety of environmental factors such as temperature, humidity and light.
 Establish a re-test period for the drug substance or a shelf-life for the drug product and recommended storage
conditions.
 Because physical, chemical or microbiological changes might impact the efficiency and security of the final product.
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4. WHAT ARE THE CHANGES:
 Physical changes: appearance, melting point, clarity, color of solution, moisture, crystal modification, particle size.
 Chemical changes: increase in degradation, decrease of assay.
 Microbial changes
TYPES:
STABILITY CONDITIONS MAINTAINED THROUGHOUT THE SHELF-LIFE OF THE DRUG
PRODUCT
Physical The original physical properties, including appearance, palatability, uniformity, dissolution and
suspend ability are retained.
Chemical Each active ingredient retains its chemical integrity and labelled potency within the specified limits.
Microbiological Sterility or resistance to microbial growth is retained according to the specified requirements.
Antimicrobial agents retain effectiveness within specified limits.
Therapeutic The therapeutic effect remains unchanged.
Toxicological significant increase in toxicity occurs.
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5.  Ideally any commercial pharmaceutical product should have a shelf-life of 5 yrs and shouldn’t fail below 90-95%
potency under recommended storage.
 In designing a solid dosage form, it is necessary to know the inherent stability of drug substance, excipients to be used,
formulation procedure.
 For a drug substance, we need to study 3 categories of stabilities:
1. Solid state stability of drug only.
2. Compatibility studies(drug+excipients).
3. Solution phase stability.
SOLID STATE STABILITY:
 The primary objective of these studies are:
-Identification of stable storage conditions for drug in the solid state.
-Identification of compatible excipients for a formulation.
 It includes both physical and chemical stability.
 Physical changes caused by Polymorphic transitions, amorphous form, Hydrate formation, crystallization material.
 Chemical changes such as oxidation, photolysis, temperature, light, humidity.
Solid drug substances undergo the physical transformations, as given below:
1. POLYMORPHIC TRANSITION:
 In the manufacture, metastable form of drug substance is preferred. During the storage, the meta-stable form may be
transferred into stable form.
 The mechanism of transformation is diffusion controlled interaction. The moisture may diffuse into the layer of
metastable polymorph, solubilize and crystallize to stable polymorph.
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6. TECHNIQUES OF DETERMINING POLYMORPHS
Analytical techniques.
X-Ray powder diffraction [XRPD].
Differential Scanning Calorimeter [DSC].
These analytical techniques have been use for quantitative and qualitative analysis of polymorphs.
2. HYDRATES FORMATION:
Hydrate is a special class of solvate form where the solvent molecule in the crystal structure is water.
In higher relative humidity [RH] drug substance can form hydrate.
TECHNIQUES OF DETERMINING HYDRATES
Humidity-controlled thermo-gravimetric analysis (TGA).
Near-infrared (NIR) Spectroscopy.
3. AMORPHOUS FORM:
Solid can occur either in crystalline form or amorphous form.
The chemical stability in crystalline form differ from amorphous form. In most of cases, amorphous form are stable than
the crystalline forms under the same condition.
Moisture promote the conversion of amorphous form to crystalline form.
Amorphous substance are preferred for the production of dosage form. These are high energy substances and readily
converted to crystalline state at elevated temperature
Eg. Novobiocine an antibiotic available in amorphous and crystalline form , amorphous form of this drug have greater
solubility and higher dissolution rate than the crystalline form.
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7. ANALYTICAL TECHNIQUES FOR STABILITY STUDIES OF AMORPHOUS
Molecular level spectroscopy.
FT-IR.
 DRIFT FT-Raman Solid-state NMR Near infrared spectroscopy (NIR)
4. CRYSTALINE MATERIAL:
Physical changes of crystalline drug substances may includes :
-Loosening of intermolecular interactions Non-covalent bonds [hydrogen bonding, van der Waals force]
-effect of environmental factors (e.g., heat, light, mechanical forces, solvent, and moisture) defects on crystal
surface.
-Nucleation of new phase Homogeneous or heterogeneous.
-Crystal growth and formation of new form.
FACTORS INFLUENCING DRUG STABILITY:
The degradation of pharmaceutical product can be treated as zero order reaction, first order reaction.
(1) Zero Order Reaction
The reaction rate is independent on concentration of the reacting substance.
(2) First Order Reaction
The rate of reaction is directly proportional to the concentration of the reacting substance.
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8. (3) Influence of pH on Degradation
The magnitude of rate of hydrolytic reaction catalysed by hydrogen and hydroxyl ions can vary with pH .
Hydrogen ion catalysis predominates at lower pH range.
Hydroxyl ion catalysis at higher pH range.
Most of the drugs are stable at pH 4 – 8.
Weakly acidic and basic drugs are most soluble in ionized form and instability is likely as they are charged
(4) Influence of Temperature on Degradation
 High temperature accelerate oxidation, reduction and hydrolysis reaction which leads to drug degradation.
In order for the rate constant or velocity of the degradation to be of use in the formulation of pharmaceutical product, it
is necessary to evaluate the temperature dependency of the reaction.
Elevated temperature studies
Tests are usually performed at 40°,50°,60°C in conjunction with ambient humidity.
Higher temperatures are also used, samples kept at highest temperature examined for chemical and physical changes at
weekly intervals- if no change is seen after 30 days at 60°C Stability prognosis is excellent.
Arrhenius Treatment is used to determine the degradation rate at lower temperature
(5)Influence of Moisture on degradation:
Water catalyses chemical reactions as oxidation, hydrolysis and reduction reaction.water promotes microbial growth.
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9. (6) Influence of Dehydration on Degradation
In physical dehydration processes water removal does not create new bonds but often changes the crystalline structure
of the drug.
Since anhydrous compounds have different dissolution rates compared to their hydrated, dehydration reaction
involving water of crystallization may potentially affect the absorption rate of the dosage form.
(7) Influence of Hydrolysis on Degradation
Drugs with functional group such as ester, amide, lactones may be susceptible to hydrolytic degradation.
It is probably the most commonly encountered mode of drug degradation because of the prevalence of such group in
medicinal agents.
(8) Influence of Photolysis on Degradation
Photolysis is the process by which the light sensitive drug or excipient molecules are chemically degraded by light,
room light, or sunlight.
The variation of degradation depends on the wavelength of light.
In this process, light may be initiator while the reaction may be oxidation, polymerization or ring rearrangement.
Photolysis followed by a thermal reaction since light energy converted into heat energy.
(9)Influence of optical isomerization on degradation
A change in the optical activity of the drug may result as a change in its biological activity. Racemization is its main
type of optical isomerization which effects drug molecule and it occurs when the optical form of the drug is converted
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10. into its enantiomorphs.
 Racemization continues until 50% of the original drug has been converted into its enantiomorph.
 In most cases the enantiomorph has less therapeutic effect than the original drug.
(10)Influence of drug incompatibility on degradation
 Reactions between components of pharmaceutical dosage forms itself or between these components and cover of the
container.
STRATAGIES TO IMPROVE THE STABILITY:
Degradation process Method of protection
Hydrolysis adjusting the ph 3-4 using buffer
removing the contact of water
removing moisture ( use of dry desiccant )
lowering the water activity
eliminating substance having hygroscopicity
changing excipients that poses problem
using solid dosage form
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11. Oxidation removing the contact of oxygen ( use of nitrogen and carbon dioxide or helium gas).
adjusting the ph 3-4 using buffer
adding antioxidants ( ascorbic acid and sulphates )
adding chelating agents for reducing the influence of metal ion ( EDTA )
photolysis protecting from light appropriate
packaging the product appropriate
temperature keeping the product in refrigerator at 4°c
storing the product in cool place ≤ 15°c
SHELF-LIFE ASSIGNMENT
DEFINITION:
Shelf-life of a drug product is defined as the time at which the average drug characteristic (e.g. Potency) remains
within an approved specification after manufacture.
(or)
Shelf life is the time required for 10% of the material to disappear; it is the time at which it has decreased up to 90% of
its initial concentration. 11

12. t 90 =(a-0.9a)/K 0 =0.1a/ K
where, a=initial concentration
K 0 =specific rate constant for zero order reaction
NEED FOR SHELF LIFE DETERMINATION :
 Expiry date is defined as the time in which a drug product in a specific packaging configuration will remain stable
when stored under recommended conditions.
 Expiry date is expressed in terms of months & years and is clearly indicated on the primary (immediate) pack as well
as the secondary pack.
 Shelf life values are normally given to the product rather than a batch .
FACTORS AFFECTING SHELF-LIFE OF DRUGS:
 Moisture, hydrolysis and ph
 Oxygen and oxidation
 Light
 Temperature
 Microbes
 API and excipient
 Physicochemical properties like hygroscopic nature, crystalline or amorphous state, polymorphism, vapour pressure
etc.,
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13. TYPES OF SHELF LIFE STUDY
1. Real time stability study.
2. Accelerated stability study.
1. REAL TIME STABILITY STUDY
 In real-time stability testing, a product is stored at recommended storage conditions and monitored until it fails the
specification.
Real time stability testing is normally performed for longer duration of the test period in order to allow significant
Product degradation under recommended storage conditions.
PROCESS:
A product stored at recommended storage condition andmonitored for a period of time until it fail the specification.
↓
During the testing, data is collected at an appropriate frequency.
↓
The reliability of data interpretation can be increased by including a single batch of reference material for which stability
characteristics have already been established.
↓
Its performed for longer duration the shelf life is determine by testing of product at different time intervals
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14.  It is also required that at least three lots of material be used in stability testing to capture lot-to-lot variation, an
important source of product variability.
2.ACCELERATED STABILITY STUDY
The preparation is stored at different elevated stress conditions like temp. to accelerate the degradation.
↓
samples are withdrawn at different time intervals.
↓
The order of reaction is determine by plotting the graph between concentration against time and linear relationship is
determined.
↓
similarly graphs are drawn for different elevated temp.
↓
K-value for each temp. calculated by using Arrhenius equation log k values are plotted against reciprocal of absolute
temp. from this energy of activation can be calculated.
↓
extrapolate the straight line to room temp. (k25) read the log k value on y-axis.
↓
substitute the k value in equation to get shelf life of product.
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15.  The concept of accelerated stability testing is based upon the Arrhenius equation and modified Arrhenius equation
Log K=log A+∆E/RT
Where, K=Degradation rate.
A=frequency factor.
∆E=activation energy(kj/mole)
R=universal gas constant(0.00831kj/mole)
T=absolute temperature
CONDITIONS TO DETERMINE THE SHELF-LIFE OF DRUG:
Test conditions ICH guidelines WHO guidelines
Accelerated 40 °C±2°C, 75% RH ± 5% for 6 months. 40 °C±2°C, 75% RH ± 5% for 6 months for zone
4 countries.
40 °C±2°C, 75% RH ± 5% for 3 months for zone
2 countries
Real time 25 °C±2°C, 60% RH ± 5% for 12 months,
assurance to be provided for continuity of the test
up to the end of expected shelf-life.
25 °C±2°C, 60% RH ± 5% for zone 2 countries.
Data for 6 months min. shall be provided at the
time of registration.
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16. STABILITY PROTOCOL AND REPORT
 The ongoing stability programme should be described in a written protocol and results formalized as a report.
 The stability protocol used for long-term studies for the stability commitment should be the same as that for the
primary batches, unless otherwise scientifically justified.
 The design of the stability studies for the product should be based on knowledge of the behaviour and properties of the
drug substance and dosage form.
 Stability protocol is prepared according to the ICH guidelines.
 A typical stability protocol for a drug substance include:
-Stress testing
-Selection of batches
-General information
-Container/closure system
-Literature and supporting data
-stability-indicating analytical methods
-Testing plan
-Test parameters
-Test results
-Other requirements(post approval commitments)
-conclusion
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17. STRESS TESTING IN API
 It can help identify the degradation products, which, in turn, can help establish the degradation pathway, any may be
carried out on a single batch of the API.
 It should include the effect of temperature, humidity.
SELECTION OF BATCHES
 Batch number
 Manufacturing g date
 Manufacturing size
-Lab scale
-Pilot scale
-Exhibit scale
 Batch size
-1kg,100kg, 1000kg
STORAGE CONDITIONS TESTING PERIOD
pH± 2,room temperature 2 weeks
pH± 7,room temperature 2 weeks
pH± 10-12,room temperature 2 weeks
H2O2, 0.1-2% at neutral pH, room temperature 2 weeks
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18.  Container closure
API BATCH NUMBER
 stability studies at developmental stages are generally carried out on a single batch while studies intended for
registration of new product or unstable established product are done on first three production batches.
 The selection of batches should constitute a random sample from the population of pilot or production batches.
 For conventional dosage forms and when the drug substances are known to be stable, stability data on at least two pilot
scale batches are acceptable whereas for critical dosage forms or when the drug substances are known to be unstable,
stability data on three primary batches are to be provided. Two of the three batches should be at least of a pilot scale;
the third batch may be smaller.
GENERAL INFORMATION
FOR DRUG SUBSTANCE
GENERAL
 Information on the stability of the drug substance is an integral part of the systematic approaches to stability
evaluation.
FORMAL STUDIES
 Primary stability studies are intended to show that the drug substance will remain with in specification during the re-
test period if stored under recommended storage conditions.
SELECTION OF BATCHES
 Stability information from accelerated and long term testing is to be provided on at least three batches. The long term
testing should cover a minimum of 12 months duration on at least three batches at the time of submission.
.
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19. TEST PROCEDURE AND TEST CRITERIA
 The testing should cover those features susceptible to change during storage and likely to influence safety, quality,
efficacy.
 Stability information should cover as necessary the physical, chemical and microbiological test characteristics.
 Validated stability indicating testing methods must be applied. The need for the extent of replication will depend on the
results of validation studies.
SPECIFICATION
 Limits of acceptability should be derived from the profile of the material as used in the pre clinical and clinical batches.
STORAGE CONDITIONS
 Long term testing 25˚c±2ºc/60%RH±5% for 12months
 Accelerated testing 40˚c±2ºc/75%RH±5% for 6months
TESTING FREQUENCY
 Frequency of testing should be sufficient to establish the stability characteristics of the drug substance.
 Testing under the defined long term conditions will normally be every 3 months, over the first year, every 6 months
over the second year and then annually .
PACKAGING/CONTAINER
 The containers to be used in the long term, real time stability evaluation should be the same as or simulate the actual
packaging used for storage and distribution.
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20. EVALUATION
 The design of the stability study is to establish, based on testing a minimum of three batches of the drug substance and
evaluating the stability information.
LABELING
 A storage temperature range maybe used in accordance with regional requirements Drug substances cannot tolerate
freezing.
FOR DRUG PRODUCT
GENERAL
 The design of the stability program for the finished product should be based on drug substance.
SELECTION OF BATCHES
 Stability information from accelerated and long term testing is to the provided on three batches of the same
formulation and dosage form in the containers and closure proposed for marketing.
TEST PROCEDURE AND TEST CRITERIA
 The testing should cover those features susceptible to change during storage and likely to influence quality, safety,
efficacy.
SPECIFICATION
 Limits of acceptance should relate to the release limits, to be derived from consideration of all the available stability
information.
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21. STORAGE TEST CONDITIONS
 Long term testing 25˚c±2ºc/60%RH±5% for 12months
 Accelerated testing 40˚c±2ºc/75%RH±5% for 6months
TESTING FREQUENCY
 Testing will normally be every 3months over the first year, every 6 months over the second year and then normally.
PACKAGING MATERIAL
 The testing should be carried out in the final packaging proposed for marketing.
EVALUATION
 Evaluation of the stability information should cover necessary physical chemical, biological, microbiological quality
characteristics including properties of the dosage form.
LABELING
 A storage temperature range maybe used in accordance with regional requirements Drug substances cannot tolerate
freezing.
CONTAINER/CLOSURE SYSTEMS
 The containers should be tested in all directions i.e. up right ,inverted ,on the side positions.
 This is done for long term and accelerated stability testing.
 This is to ensure that there are no adverse effects from any interaction is produced.
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22.  In this, generally considered moisture-impermeable containers include glass ampoules, aluminium/aluminium blisters,
High Density Polyethylene (HDPE) or glass bottles fitted with metal or HDPE closures.
STABILITY-INDICATING ANALYTICAL METHODS
 One method of assessment is an analysis of variance (ANOVA). TESTING FREQUENCY
TESTING FREQUENCY
 The frequency of testing at the long term storage condition should normally be every 3 months over the first year, every
6 months over the second year, and annually thereafter through the proposed shelf life Reduced designs, i.e., matrixing
or bracketing.
STUDY STORAGE CONDITION MAX. TIME PERIOD
COVERED BY DATA
SUBMISSION
Accelerated 40ºc±2ºc/75%RH±5%RH 6 months
Intermediate 30ºc±2ºc/65%RH±5%RH 6 months
Long term 25ºc±2ºc/60%RH±5%RH or
30ºc±2ºc/65%RH±5%RH
12 months
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23. SPECIFICATION(Testing Parameter )
 list of tests, reference to analytical procedures, and proposed acceptance criteria, including the concept of different
acceptance criteria for release and shelf-life specifications.
 The testing should cover, as appropriate, the physical, chemical, biological and microbiological attributes,
preservative content and functionality tests.
1.Tablets
 Tablets should be evaluated for appearance, odour, colour, assay, degradation products, dissolution, moisture and
hardness/friability.
2. Emulsions
 An evaluation should include appearance , odour, assay, degradation products, pH, viscosity, microbial limits,
preservative content, and mean size and distribution of dispersed globules.
3. Capsules
 Hard gelatin capsules should be evaluated for appearance, odour of content, assay, degradation products,
dissolution, moisture and microbial content.
 Testing of soft gelatin capsules should include appearance, colour, and odour of content, assay, degradation
products, dissolution, microbial content, pH, leakage, and pellicle formation. In addition, the fill medium should be
examined for precipitation and cloudiness.
.
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24. 4. Metered-dose Inhalations and Nasal Aerosol
 Dose content uniformity, labelled number of medication actuations per container, aerodynamic particle size
distribution, microscopic evaluation, water content, leak rate, microbial limits, valve delivery (shot weight) and
extractables /leachables from plastic and elastomeric components. Samples should be stored in upright and inverted/on-
the-side orientations.
5. Suppositories
 Suppositories should be evaluated for appearance, colour, assay, degradation products, particle size, softening range,
dissolution (at 37oC) and microbial limits.
6. Freeze-dried Products
 Appearance of both freeze-dried and its reconstituted product, assay, degradation products, pH, water content and rate
of solution.
STABILITY RESULTS
 A storage statement should be proposed for the labelling (if applicable), which should be based on the stability
evaluation of the API.
 A re-test period should be derived from the stability information, and the approved re-test date should be displayed on
the container label.
 An API is considered as stable if it is within the defined/regulatory specifications when stored at 30 2˚c and 65 5% RH
for 2years and at 40 2 ˚c and 75 5%RH for 6 months.
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25. EVALUATION
 Evaluation A systematic approach should be adopted in the presentation and evaluation of the stability information,
which should include, as appropriate, results from the physical, chemical and microbiological tests, including particular
attributes of the dosage form (for example, dissolution rate for solid oral dosage forms).
API ORAL SUSPENSION
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26. ICH GUIDELINES
WHAT DOES ICH STANDS FOR:
 The complete name of ICH is the “INTERNATIONAL CONFERENCE ON HARMONIZAT ION” of technical
requirements for registration of pharmaceuticals for human use.
BIRTH OF ICH:
 The birth of ICH took at a meeting in April 1990 hosted by the EFPIA in Brussels. The meeting held by representatives
of regulatory agencies and industry associations of Europe ,Japan and USA .Topic selected for harmonization would
divided into safety, Quality and Efficacy which are basis for approving and authorizing new drug product.
PURPOSE OF ICH
 The objective of ICH is to increase international harmonization of technical requirements to ensure that safe, effective
& high quality medicines are developed and registered in the most efficient & cost- effective manner.
 To eliminates of duplication in the development and registration process i.e., eliminate the duplications of clinical trials,
evaluations of safety, quality ,efficacy and other technical requirements.
GOAL OF ICH
 To promote international harmonisation by bringing together the representatives from the three region(EU, Japan, USA)
to established a common guidelines.
 TO make the information available on ICH,ICH activities and guidelines to any country or company that request the
information and facilitate harmonization processes related to ICH guidelines regionally and globally.
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27. STRUCTURE OF ICH
 It is a joint initiative involving both regulators bodies & research- based industry as equal partners .
 The parties involved from the European Union, Japan & the USA are:
1.European Commission ( EC )
2.European Federation of Pharmaceutical Industries & Association ( EFPIA )
3.Ministry of Health, labour & Welfare ( MHLW ),Japan
4.Japan Pharmaceutical Manufacturers Association ( JPMA )
5.US Food & Drug Administration ( FDA )
6.Pharmaceutical research & manufacturers of America. ( PhRMA )
 Three observers which represent non-ICH countries and regions are:
1.World Health Organization (WHO)
2. European Free Trade Area ( EFTA )
3.Canada
ICH GUIDELINES
 ICH has developed over 45 harmonized guidelines which are divided into 4 major categories :
1.QUALITY TOPICS
2.SAFETY TOPICS
3.EFFICACY TOPICS
4.MULTIDISCIPLINARY TOPICS
27

28. 1.QUALITY TOPICS
 Q1A(R2) : Stability Testing of New Drug substances &Drug Product.
 Q1B : Photo stability Testing of New Drug Substances & Product.
 Q1C : Stability Testing of New Drug Forms.
 Q2 : Analytical Validation.
 Q3A : Impurities in New Drug Substances.
 Q3B : Impurities in New Drug Products.
 Q4 : pharmacopoeias
 Q5c : Stability Testing of Biotechnological Biological Product.
 Q6: Specifications
 Q7: Good manufacturing practice
 Q8: Pharmaceutical Development
 Q9: Quality Risk Management
 Q10: Pharmaceutical Quality system
2. SAFETY TOPICS – related to in vivo & in vitro pre clinical studies.
 eg. S1- Carcinogenicity testing.
S2- Genotoxicity testing.
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29. 3. ‘E’ EFFICACY TOPICS- related to clinical studies in human subject.
 eg. E4- Dose response studies.
E5- Carcinogenicity testing.
E6- Good clinical practices. (GCP).
4. ‘M’ MULTIDISCIPLINARY TOPICS
 M1- Medical technology.
 M2- Electronic standards for transmission of regulatory information.
 M3- Timing of pre clinical studies in relation to clinical trials.
 M4- Common technical documents.
 M5- Data elements & standards for drug dictionaries.
STABILITY DATA GENERATION
 The key step in the data generation is writing a stability protocol. A properly designed test protocol contains in general
the following information:
-Type, size & no. of batches.
-Type, size & source of containers & closures.
-Container storage orientation.
-Test parameters.
-Test methods.
-Acceptance
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30. GLOBAL CLIMATIC ZONE
 Havens gathered the climatic data in major cities around the world & proposed division of the world into 4 climatic
zone.
DISTRIBUTION OF WORLD NATIONS INTO DIFFERENT ZONES
CLIMATIC ZONE DEFINITION STORAGE CONDITIONS
I TEMPERATE CLIMATE 21˚C/45 % R.H
II SUBTROPICAL AND MEDITERRANEAN CLIMATE 25˚C/60 % R.H
III HOT , DRY CLIMATE 30˚C/35 % R.H
IV HOT , HUMID CLIMATE 30˚C / 70% R.H
REGIONS ZONE 1&2 COUNTRIES ZONE 3&4 COUNTRIES
EUROPE All countries -
AMERICA Argentina, Bolivia, Canada, USA Brazil, Columbia, Cuba
ASIA Afghanistan, China, Iran, Israel, Japan, Nepal Bangladesh, India, Indonesia, Iraq,
Srilanka
AFRICA Egypt, Algeria, South Africa Ethiopia, Ghana, Kenya, Nigeria
AUSTRALIAN/OCEANIC Australia, New Zealand Fiji, Society Island, New Guinea
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31. PRINCIPLES OF THE GUIDELINE
1.Purpose of stability testing is to provide evidence how quality varies with time under influence of
- temperature
- humidity
-Light
2.Establish re-test period for drug substances
-RETEST PERIOD: the period after which samples of the drug substance should be examined to ensure that the
material is still in compliance with the specification, and thus suitable for use in manufacturing.
-A retest period should be proposed on the basis of stability results and may be extended to five years (e.g.,
Ethambutol 2HCl, or Isoniazid).
3.Establish shelf life for drug products
-SHELF LIFE: (EXPIRY DATE/EXPIRATION DATING PERIOD):The period of time during which a
pharmaceutical product, if stored correctly, is expected to comply with the specification as determined by stability
studies on a number of batches of the product.
-The shelf-life is used to establish the expiry date of each batch.
4.Recommends storage conditions.
5.Gives Test conditions based on analysis of effects of climatic conditions in the three regions of the EU, Japan, USA.
6. Gives mean kinetic temperature which is derived from climatic data . 31

32. 7.Divided world into four climatic zone I-IV - This guideline addresses climatic zones I and II
8. And the Stability information generated in one of the three regions is mutually acceptable to the other two provided:
- information is consistent with this guideline,
- labelling is in accord with national/ regional requirements
OBJECTIVES OF A GUIDELINE Q1-A(stability studies)
 The ICH (International Conference on Harmonization) Guidelines Q1A(R2) “Stability testing of new drug substances
and products” is the “gold standard” for conducting stability studies. This is valid for “new drug substances or drug
products” that are sufficient for a registration application.
 This guideline is a revised of the ICHQ1A –stability data package for new drug substance /DRUG PRODUCT .
 To define stability data package that sufficient for a registration application within the 3 regions of EU ,JAPAN &
USA.
 To maintain the quality of drug products, in relation to safety , efficacy & acceptability throughout the propose shelf
life.
NOTE: It does not cover testing for registration of drug substance or product intended for import or export to other areas
of the world.
Q1A(R2)-new drug substances and products
 The guide line primarily addresses the information required in registration applications for new molecular entities and
associated drug products .
 It seeks to exemplify the stability data package required for new drug substances and products .
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33.  It is not always necessary to follow this when there are scientifically justifiable reasons for using alternative
approaches.
Q1B-photostability testing of new drug substances and products
 The guide line primarily addresses the generation of photo stability information for submission in registration
applications for new molecular entities and associated drug products .
 The guide line on stability testing of new drug substances and products notes that light testing should be an integral
part of stress testing .
 This document is an annex to the parent guide line and addresses the recommendations for photo stability testing.
Q1C-stability testing for new dosage forms
 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.
 Such pharmaceutical product types include products of different administration route (e.g., oral to parenteral ), new
specific functionality/delivery systems (e.g., immediate release tablet to modified release tablet) and different dosage
forms of the same administration route (e.g., capsule to tablet, solution to suspension).
 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 (e.g., 6 months accelerated and 6 months long term data
from on-going studies) may be acceptable in certain justified cases
Q1D- Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products
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34.  This guide line is intended to address recommendations on the application of bracketing and matrixing to stability
studies conducted in accordance with principles out lined in the ICH Q1A(R) guide line on stability testing of new drug
substances and products.
 This document provides guidance on bracketing and matrixing study designs.
 Specific principles are defined in this guideline for situations in which bracketing or matrixing can be applied.
 Sample designs are provided for illustrative purposes, and should not be considered the only, or the most appropriate,
designs in all cases.
Q1E- Evaluation of Stability Data
 This guide line addresses the evaluation of stability data that should be submitted in registration applications
for new molecular entities and associated drug products.
 The guide line provides recommendations on establishing retest periods and shelf lives for drug substances and
drug products intended for storage at or below “Room temperature
Q1F- Stability Data Package for Registration Applications in Climatic Zones III and IV
 ICH Q1F stability data package for registration applications in climatic zones III and IV defined storage
conditions for stability testing in countries located in climatic zones III(hot and dry) and IV (hot and humid).
 ICH Q1F described harmonised global stability testing requirements in order to facilitate access to medicines by
reducing the number of different Storage conditions.
 WHO states to find consensus on 30˚C /65% RH as the long term storage conditions for hot and humid regions.
 30˚C /65% RH was defined as the long term storage condition for climatic zone III and IV countries in ICH Q1F
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35. Outline the changes made in Q1A(R)
 The intermediate storage condition has been changed from 30°C ± 2°C/60% RH ± 5% RH to 30°C ± 2°C/65% RH ±
5% RH in the following sections:
-Drug Substance - Storage Conditions - General Case
-Drug Product - Storage Conditions - General Case
-Drug products packaged in semi-permeable containers
 30°C ± 2°C/65% RH ± 5% RH can be a suitable alternative long-term storage condition to 25°C ± 2°C/60% RH ± 5%
in the following sections:
-Drug Substance - Storage Conditions - General Case
-Drug Product - Storage Conditions - General Case
 30°C ± 2°C/35% RH ± 5% RH has been added as a suitable alternative long-term storage condition to 25°C ±
2°C/40% RH ± 5% and the corresponding example for the ratio of water-loss rates has been included in the following
section:
-Drug products packaged in semi-permeable containers
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36. CONCLUSION:
Stability testing is now the key procedural component in the pharmaceutical development program for a
new drug as well as new formulation, no drug can be introduced into market without a stability study
which is ongoing.
Variability and time trends of stability data must be evaluated by the manufacturer in order to propose a
re-test date or expiry date.
Stability tests are carried out so that recommended storage conditions and shelf life can be included on the
label to ensure that the medicine is safe and effective throughout its shelf life.
Therefore, the stability tests should be carried out following proper scientific principles and after
understanding of the current regulatory requirements and as per the climatic zone and the stability studies
should be based on the basis of pharmaceutical R&D and regulatory requirements.
ICH plays an important role in maintaining the quality, efficacy and safety of the drug throughout its
storage period.
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37. REFERENCES:
Statistical evaluation of stability data: criteria for change-over-time and data variability (PDA journal of
pharmaceutical science and technology, vol. 57. no.5, Sep./Oct. 2003,pp. 369-377).
Edited by jens T. carstensen and C. T. Rhodes, Data stability principles and practices, 3rd
edition, 2008,
PP.145-190.
L.Lachman and H.Lieberman, The theory and practice of industrial pharmacy, CBS publishers and
distributors PVT LTD,2009, PP.760-803.
Remington, The science and pharmacy practice, 21st
Edition, vol.1, pp.1025-1038.
ICH guidelines www.ich.org
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