DRUG STABILITY

Stability of drugs
Stability: is the capacity of a drug product to remain
within specifications established to ensure its
identity, strength quality and purity.
 Stability of drugs

Undesired
change in
performance

Instability

Causing Substantial changes in

physical appearance of
product failures the dosage form
Stability of drugs
Types of stability studies

chemical

physical microbiology

stability
 Physical stability
Physical stability implies that:
The formulation is totally unchanged throughout its shelf life
and has not suffered any changes by way of appearance,
organoleptic properties, hardness, brittleness, particle size
etc.

It is significant as it affects:
pharmaceutical elegance
drug content uniformity
drug release rate.
Physical stability
 Chemical stability

Chemical stability implies:

The lack of any decomposition in the chemical that is

incorporated in the formulation as the drug, preservatives
or any other excipients.

This decomposition may influence the physical and

chemical stability of the drug
 Chemical stability

Hydrolysis

Chemical
Isomerization Oxidation
stability

Photolysis
 Microbiological stability

Microbiological stability implies that:

The formulation has not suffered from any

microbiological attack and is meeting the standards
with respect to lack of contamination/sterility.
Microbiological stability
Sources of Microbial Contamination:

Water gram-negative groups: Pseudomonas,

Xanthamonas, Flavobacterium

Air Mould spores: Penicillium, Aspergillus

Bacterial spores: Bacillus spp. Yeasts

Raw materials Micrococci

Starches Coliforms
Pigments Salmonella
 Sources of Microbial Contamination

Gums Actinomyces

Animal products Salmonella, Coliforms

Personnel Coliforms, Staphylococci, Sterptococci

 To prevent contamination to the
formulation during storage

(1) suitable designing the containers

(2) usually using single dose containers

(3) sticking to proper storage conditions

(4) adding an antimicrobial substance as

preservative.
 Preservatives used in
pharmaceutical preparations:
Preparation Preservative Concentration
% w.v
Injections Phenol 0.5
Cresol 0.3
Chlorocresol 0.1
Eye drops Chlorhexidine 0.01
acetate 0.01
Benzalkonium
chloride
Mixtures Benzoic acid 0.1
Methyl paraben 0.1
Alcohol 12-20
 Preservatives used in
pharmaceutical preparations:

Preparation Preservative Concentration

% w.v

Creams Parabens 0.1-0.2

Chlorocresol 0.1
Tablets Methylparaben 0.1
 Packaging And Stability :

The immediate container and closure are particularly

important in affecting product stability.
 Packaging And Stability:

Glass
- Glass is resistant to chemical and physical change and is the most
commonly used material.

Limitations Overcome
1. Its alkaline surface use of Borosilicate glass

2. Ions may precipitate the use of buffers

insoluble crystals from the glass

3- Permits the transmission of Amber coloured glass

light which may accelerate
decomposition.
 Packaging And Stability :

Plastics
The problems with plastic are:
1.Migration of the drug through the plastic into the
environment.
2.Transfer of environmental moisture, oxygen, and other
elements into the pharmaceutical product.
3.Leaching of container ingredients into the drug.
4.Adsorption of the active drug or excipients by the
plastic.
 Packaging And Stability :

Metals
- Various alloys and aluminium tubes may be utilized
as containers for emulsions, ointments, creams and
pastes.

- Limitation: They may cause corrosion and

precipitation in the drug product.

- Overcome: Coating the tubes with polymers may

reduce these tendencies.
 Packaging And Stability :

Rubber
- Rubber also has the problems of extraction of drug
ingredients and leaching of container ingredients.

- The pretreatment of rubber vial stoppers and

closures with water and steam reduces potential
leaching.
 What are changes?
Physical changes
Appearance
Melting point
Clarity and color of solution
Water
Crystal modification (Polymorphism)
Particle size
Chemical changes
Increase in Degradation products
Decrease of Assay
Microbial changes
Growth of microorganism
 Stability studies at different stages

1. Stress-and accelerated Testing with drug

substances
2. Stability on pre-formulation batches
3. Stress testing on scale-up Batches
4. Accelerated and long term testing for
registration
5. On-going Stability testing
6. Follow-up Stabilities
Climatic Zones / Storage
conditions
 Countries of climatic
zone I and II
Europe : all countries
Americas : Argentina, Bolivia, Chile, Canada,
Peru, USA, Uruguay
Asia : Afghanistan, Armenia, China, Iran,
Aserbaidschan, Georgia, Israel,
Japan, Corea(north & south), Nepal,
Lebanon, Syria, Turkey ..
Africa : Egypt, Algeria, Libya, Marocco, Namibia,
Ruanda, Sambia, Simbabwe, South Africa,
Tunesia
Australia : Australia, New Zeeland
 Countries of climatic
zone III and IV
Americas : Bahamas, Barbados, Belize, Brasilia,
Costa Rica, Ecuador, Guatemala,
Colombia, Nicaragua
Asia : Bahrain, Bangladesh, India, Laos,
Indonesia, Iraq, Cambodia, Qatar, Kuwait,
Malaysia, Myanmar, Pakistan, Philippines,
Singapore, Thailand, UAE, Vietnam ..
Africa : Angola, Ethiopia, Benin, Botswana, Burkina
Faso ..
Oceania : Fiji, Marshall Islands, Micronesia, Papua
New-Guinea .
 ICH and Guidelines overview
ICH stands for International Conference on Harmonization of
Technical Requirements for Registration of Pharmaceuticals for
Human use

Objectives of ICH
Harmonization of registration applications within the three regions of
the EU, Japan and the United States.
ICH is a joint initiative involving both regulators and industry as equal
partners in the scientific and technical discussions of the testing
procedures which are required to ensure and assess the safety,
quality and efficacy of medicines
 ICH Guidelines
Quality Guidelines Q (chemical and pharmaceutical QA)

Safety Guidelines S (in vitro and in vivo pre-clinical studies)

covering Carcinogenicity Testing, Genotoxicity Testing,
Toxicokinetics and Pharmacokinetics .. etc.
Efficacy Guidelines E (clinical studies in human subject)
Covering clinical safety, Dose Response Studies, Good Clinical
Practices, Clinical evaluation . etc.
Multidisciplinary Guidelines M
Covering Medical Terminology, Electronic Standards for
Transmission of Regulatory Information etc.
Important for Stability !
Guideline M4: The Common Technical Document (CTD)
ICH Q-Guidelines (Quality)
 Guidelines
ASEAN* Guidelines
Stability Studies of Drug products
Validation of Analytical Procedures
Common Technical Dossier (ACTD) for the registration of
pharmaceuticals
WHO
WHO TRS 863, Annex 5: Guidelines for stability testing of
pharmaceutical products containing well established drug substances in
conventional dosage forms
USP (US Pharmacopeia)
USP 29 <1150> Pharmaceutical Stability

EMEA (European Agency for the Evaluation of Medicinal Product)

Note for Guidance on Stability Testing of existing active substance
and Related Finished products (Draft), February 2002
 ICH Q1A Guideline
Objectives
Define common principles valid for both Drug Substances and
Products
Ensures that all data derived from DS can be used for further
development of DP
Scope
Adresses the information to be submitted in registration
applications for
new molecular entities (NMEs) and
Associated drug products
Dedicated to climatic Zone I and II
Does not currently seek to cover the information to be submitted
for
abbreviated or abridged applications
variations
clinical trial applications
Structure / Sections
 Section 1 -General
Drug Substance
Information on the stability of the drug substance is an integral
part of the systematic approach to stability evaluation
Drug Product
The design of the stability studies should be based on knowledge
of the
behavior and
properties of the drug substance and from
stability studies on the drug substance and on
experience gained from clinical formulation studies.
The likely changes on storage and the rationale for the selection
of attributes to be tested in the formal stability studies should be
stated
 Section 1 -General
Drug Substance
carried out on a single batch
Should include the effect of temperatures (in 10C increments
above that for accelerated testing), humidity (e.g., 75% RH or
greater) where appropriate, oxidation, and photolysis
Should evaluate the susceptibility to hydrolysis across a wide range
of pH values when in solution or suspension
Examining degradation products under stress conditions is useful
in establishing degradation pathways and developing and
validating suitable analytical procedures.
Photostability testing should be an integral part of stress testing
Drug Product
Photostability testing should be conducted on at least one batch
Conditions are described in ICH Q1B.
 Section 3 -Selection of Batches
Drug Substance
At least three primary batches of the drug substance.
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.
Drug Product
At least three primary batches of the drug product
The manufacturing process used for primary batches should simulate that to be
applied to production batches and should provide product of the same quality
and meeting the same specification as that intended for marketing
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.
Batches should be manufactured by using different batches of drug substance
Stability studies should be performed on each individual strength and container
size of the drug product unless bracketing or matrixingis applied ICH Q1
Section 4 -Container Closure System
Drug Substance
Container closure system should be the same as for
storage and distribution (or should be able to simulates
the packaging proposed)
Drug Product
Tested dosage form should be packaged in the container
closure system proposed for marketing
Including any secondary packaging and container label
Studies carried out on the drug product outside its immediate
container or in other packaging materials can form a useful part
of the stress testing of the dosage form or can be considered as
supporting information, respectively.
 Section 5 -Specifications
Drug Substance and Drug Product
Stability studies should include testing of
attributes that are susceptible to change
during storage and are likely to influence
quality, safety, and/or efficacy
Analytical procedures should be validated
and stability indicating
References: ICH Q2, ICH Q3A/B, ICH Q6
 Drug Product

The testing should cover, as appropriate, the physical, chemical, biological,

and microbiological attributes, preservative content (e.g., antioxidant,
antimicrobial preservative), and functionality tests (e.g., for a dose delivery
system).

Shelf life acceptance criteria should be derived from consideration of all

available stability information.

It may be appropriate to have justifiable differences between the shelf life and
release acceptance criteria based on the stability evaluation and the changes
observed on storage.

A single primary stability batch of the drug product should be tested for
antimicrobial preservative effectiveness (in addition to preservative content) at
the proposed shelf life for verification purposes, regardless ofwhether there is
a difference between the release and shelf life acceptance criteria for
preservative content
 Section 5 -Specifications /
Significant change
Drug Substance
failure to meet its specification

Drug Product
5% change in assay from its initial value
Any degradation products 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, etc
Failure to meet the acceptance criterion for pH
Failure to meet the acceptance criteria for dissolution for 12
dosage unit
 Section 6 -Testing Frequency
Long term Storage condition
Frequency should be every 3 months over the first year, every 6 months over the
second year, and annually thereafter through the proposed retest period (For
drug substances with a proposed re-test period of at least 12 months)

Accelerated storage condition

a minimum of three time points, including the initial and final time points (e.g.,
0, 3, and 6 months), from a 6-month study is recommended

Intermediate storage condition

When testing at the intermediate storage condition is called for as a result of
significant change at the accelerated storage condition, a minimum of four time
points, including the initial and final time points (e.g. 0, 6, 9, 12 months), from a
12-month study is recommended

Reduced designs, (matrixing or bracketing) where the testing frequency is

reduced or certain factor combinations are not tested at all, can be applied, if
justified (Q1D)
Section 7 -Storage Conditions
Storage should be evaluated under storage conditions
that test thermal stability and, if applicable, sensitivity to
moisture
The storage conditions and the lengths of studies
chosen should be sufficient to cover storage, shipment,
and subsequent use
The long term testing should cover a minimum of 12
months duration on at least three primary batches
Data from the accelerated storage condition and, if
appropriate, from the intermediate storage condition can
be used to evaluate the effect of short term excursions
outside the label storage conditions (e.g. during
shipping)
The general case applies if the DS / DP is not
specifically covered by a subsequent section. Alternative
storage conditions can be used, if justified.
 Storage conditions
Drug Product
Stability testing of the drug product after constitution or dilution, if
applicable, should be conducted to provide information for the
labeling on the preparation, storage condition, and in-use period
of the constituted or diluted product.
This testing should be performed on the constituted or diluted
product through the proposed in-use period on primary batches
at initial and final time points and, if full shelf life long term data
will not be available before submission, at 12 months or the last
time point for which data will be available.
Additional data accumulated during the assessment period of the
registration application should be submitted to the authorities if
requested.
 Storage Conditions
Climatic Zones III & IV
 Special transportation and climatic conditions outside the
storage conditions recommended in this guideline should
be supported by additional data. For example, these
data can be obtained from studies on one batch of drug
product conducted for up to 3 months at 50C/ambient
humidity to cover extremely hot and dry conditions and
at 25C/80% RH to cover extremely high humidity
conditions.

Stability testing at a high humidity condition, e.g.,

25C/80% RH, is recommended for solid dosage forms
in water-vapour permeable packaging, e.g., tablets in
PVC/aluminum blisters, intended to be marketed in
territories with extremely high humidity conditions in
Zone IV. However, for solid dosage forms in primary
containers designed to provide a barrier to water vapour,
e.g. luminum/aluminum blisters, stability testing at a
storage condition of extremely high humidity is not
considered necessary.
 Section 8 -Stability Commitment
If Submission includes stability data from three production
batches covering the proposed re-test period / shelf life,
a post approval commitment is not necessary.

Otherwise a commitment should be made

Study dont cover proposed re-test period / shelf life :
Continue through the proposed re-test period / shelf life
Less than three production batches used:
Enlarge studies with additional production batches, to a total of at
least three
No production batch used:
Commitment to place the first three production batches on stability
through the proposed re-test period / shelf life and on accelerated
studies for 6 months.
 Section 9 -Evaluation
Determine the time at which the 95 one-sided
confidencelimit for the mean curve intersects the
acceptance criterion
Calculation of re-test period (DS)
Calculation of shelf life (DP)
If the batch-to-batch variability is small, it is
advantageous to combine the data into one overall
estimate
If it is inappropriate to combine data from several
batches, theoverall shelf life should be based on the
minimum time a batch can be expected to remain within
acceptance criteria
Any evaluation should cover not only the assay, but also
the levels of degradation products and other appropriate
attributes.
Reference: ICH Q1E
 Section 10 Statements /
Labeling
General
A storage statement should be established for the labeling in
accordance with relevant national/regional requirements
Statement should be based on the stability evaluation of the
drug substance / drug product
Terms such as ambient conditionsor room temperatureshould
be avoided.
Drug Substance
Retest date should be displayed on the container label if
appropriate.
Drug Product
There should be a direct link between the label storage statement
and the demonstrated stability of the drug product.
An expiration date should be displayed on the container label
 Submission
At Submission you need at least the
following stability data of the Drug product
Based on three primary batches
Derived from same formulation as proposed or
marketing
packaged in the same container closure system as
proposed for marketing
Studi Stabilitas

CPOB
 STUDI STABILITAS
Hendaklah dirancang program uji stabilitas
untuk menilai karakteristik stabilitas obat
dan untuk menentukan kondisi
penyimpanan yang sesuai dan tanggal
daluwarsa
STUDI STABILITAS
CPOB
 Program tertulis hendaklah dipatuhi
dan mencakup:
a. Jumlah sampel dan interval pengujian
berdasarkan kriteria statistis untuk tiap atribut yang
diperiksa untuk memastikan estimasi stabilitas;
b) kondisi penyimpanan;
c) metode pengujian yang dapat diandalkan,
bermakna dan spesifik;
d) pengujian produk dalam bentuk kemasan yang
sama dengan yang diedarkan; dan
e) pengujian produk untuk rekonstitusi, dilakukan
sebelum dan sesudah rekonstitusi. (in-use stability,
beyond on use expired date)
 Studi stabilitas hendaklah dilakukan
dalam hal berikut
a. produk baru (biasanya dilakukan pada bets pilot);
b. kemasan baru yaitu yang berbeda dari standar yang
telah ditetapkan;
c. perubahan formula, metode pengolahan atau
sumber/pembuat bahan awal dan bahan pengemas
primer
d. bets yang diluluskan dengan pengecualian misalnya
bets yang sifatnya berbeda dari standar atau bets yang
diolah ulang; dan
e. produk yang beredar.
 Bracketing and Matrixing
ICH Q1D
Full Design
A full study design is one in which samples for every
combination of all design factors are tested at all time
points
Reduced Design
A reduced design is one in which samples for every factor
combination are not all tested at all time points
Before a reduced design is considered, certain
assumptions should be assessed and justified.
 A reduced design can be a suitable alternative
to a full design when multiple design factors are
involved.
Any reduced design should have the ability to
adequately predict the retest period or shelf life.
Before a reduced design is considered, certain
assumptions should be assessed and justified.
The potential risk should be considered of
establishing a shorter retest period or shelf life
than could be derived from a full design due to
the reduced amount of data collected.
 Bracketing
Design of a stability schedule such that
only samples on the extremes of certain
design factors (e.g., strength, container
size and/or fill) are tested at all time points
as in a full design.
The design assumes that the stability of
any intermediate levels is represented by
the stability of the extremes tested
Bracketing
 Matrixing
Design of a stability schedule such that a selected
subset of the total number of possible samples for all
factor combinations would be tested at a specified time
point.
At a subsequent time point, another subset of samples
for all factor combinations would be tested.
The design assumes that the stability of each subset of
samples tested represents the stability of all samples at
a given time point
 Matrixingis applicable, if you (have)
good knowledge of data variability
expect high stability of the product
supporting data available
In general, a matrixing design is applicable if the
supporting data indicate predictable product
stability
Matrixing is appropriate when the supporting
data exhibit only small variability
STABILITY DATA PACKAGE
FOR
REGISTRATION APPLICATIONS
IN
CLIMATIC ZONES III AND IV

Q1F
 Objectives of the Guideline
This guideline describes an approach to broader
use of the ICH guideline Q1A(R) Stability
Testing of New Drug Substances and Products
(hereafter referred to as the parent guideline)
and outlines the stability data package for a new
drug substance or drug product that is
considered sufficient for a registration
application in territories in Climatic Zones III and
IV1, 2.
 Mechanisms Of Degradation

1- Hydrolysis:
Hydrolysis means splitting by water
 Some Functional Groups Subject to
Hydrolysis

Drug type Examples

Esters Aspirin, alkaloids
Dexmethasne sodium phosphate
Nitroglycerin
Lactones Pilocarpine
Spironolactone
Amides Chloramphenicol

Lactams Penicillins
Cephalosporins
 Some Functional Groups Subject to
Hydrolysis

Drug type Examples

Imides Glutethimide

Malonic ureas Barbiturates

 Mechanisms Of Degradation

2- Oxidation
Oxidation of inorganic and organic compounds is
explained by a loss of electrons and the loss of a
molecule of hydrogen.
 Some Functional Groups Subject to
Autoxidation

Functional group Examples

Catechols Catecholamines (dopamine)
Ethers Diethylether

Thiols Dimercaprol (BAL)

Thioethers Chlorpromazine
Carboxylic acids Fatty acids
 Mechanisms Of Degradation

3- Photolysis
It means: decomposition by light

e.g. Sodium nitroprusside is administered by

intravenous infusion for the management of acute
hypertension.
If the solution is protected from light, it is stable for at
least 1 year; if exposed to normal room light, it has a
shelf life of only 4 hours.
 Mechanisms Of Degradation

Relationship between wavelength and associated energy of

various forms of light.

Type of radiation Wavelength Energy

U.V. 50 400 Kcal mol-1

Visible 400 750 287 72

I.r. 750 10,000 36 - 1

Conventional tungsten filament light bulbs are safe and

do not contribute to photolysis.
 Mechanisms Of Degradation

Photolysis is prevented by:

1- suitable packing in amber coloured bottles
2- cardboard outers
3- aluminium foil over wraps
 Factors Affecting Rates Of
Degradation
1- pH
The acidity or the alkalinity of a solution has a
profound influence on the decomposition of drug
compound.
- Aspirin buffered solution is maximum stable at a pH
of 2.4, above a pH of 10 the decomposition rate
rapidly increases.

pH can also influence the rate of oxidation.

- The system is less readily oxidized when the pH is
low.
Factors Affecting Rates Of
Degradation
2- Complexation
Complex formation reduces the rate of hydrolysis and
oxidation.
e.g. caffeine complexes with local anesthetics, such as
benzocaine, procaine and tetracaime to cause a
reduction in their rate of hydrolytic degradation.
Factors Affecting Rates Of
Degradation
3- Surfactants
Nonionic, cationic and anionic surfactants when
added to solutions containing drugs form micelle and
the drug particles become trapped in the micelle.

The hydrolytic groups such as OH cannot penetrate

this micelle cover and reach the drug particles,
hence hydrolysis rate is decreased.
Factors Affecting Rates Of
Degradation
4- Presence of heavy metals
Heavy metals, such as copper, iron, cobalt and nickel
increase the rate of formation of free radicals and
enhance oxidative decomposition.

5- Light and humidity

Light, especially ultraviolet light enhances photolysis
and humidity enhances hydrolytic decomposition.
 Stabilization of drugs against hydrolysis,
oxidation and photolysis

1- Temperature
All the drug products are stored at suitable
temperatures to avoid thermal acceleration of
decomposition. Three varieties of temperatures are
suggested for storage of drug products. Room
temperature, cool storage and cold storage.

2- Light
Light sensitive materials are stored in ambered
colour bottles.
Stabilization of drugs against hydrolysis,
oxidation and photolysis

3- Humidity
Packing materials are chosen (usually glass and
plastic) to prevent exposure of drug products to high
humid condition.

4- Oxygen
Proper packing keeping the oxygen content of the
solution less and leaving very little head space in the
bottle above the drug products are methods to fight
against oxidation.
Stabilization of drugs against hydrolysis,
oxidation and photolysis

Antioxidants commonly used for

Aqueous systems Oil systems
Sodium metabisulfite Ascorbyl palmitate
Sodium thiosulfate Butylaled hydroxy toluene
Ascorbic acid Butylated hydroxy anisole
Stabilization of drugs against hydrolysis,
oxidation and photolysis

5- Chelating Agents
Chelating agents form complexes with heavy metal
ions and prevent them from catalyzing oxidative
decomposition.
e.g. ethylenediamine tetracetic acid (EDTA) derivatives
and salts, citric acid and tartaric acid.

6- Solvents
By the addition of a suitable solvent hydrolysis rate
may be decreased.
 Testing scope for TABLETS

Physical-chemical properties
Appearance
Mean mass
Water content
Hardness
Disintegration
Dissolution
Chemical properties
Assay
Degradation products
Microbial properties
Microbial purity
Container closure system properties
Functionality tests (e.g. extraction from blister
 Testing scope for CAPSULES

Physical-chemical properties
Elasticity
Mean mass
Mean filling mass
Water content (Capsule and content)
Disintegration
Dissolution
Chemical properties
Assay
Degradation products
Microbial properties
Microbial purity
Container closure system properties
Functionality tests (e.g. extraction from blister)
 Testing scope for
ORAL LIQUID FORMS
Physical-chemical properties
pH
Color & clarity of solution
Loss on weight
Viscosity
Particle size distribution (for oral suspensions only)
Chemical properties
Assay
Degradation products
Content preservatives
Degradation preservatives
Content antioxidants
Microbial properties
Microbial purity
Container closure system properties
Functionality tests
Testing scope for LIQUID FORMS for
inj. and PARENTERALS
Physical-chemical properties
pH
Loss on weight
Color & clarity of solution
Chemical properties
Assay
Degradation products
Content preservatives
Degradation preservatives
Content antioxidants
Microbial properties
Microbial purity
Container closure system properties
Functionality tests
 Testing scope for
SEMI LIQUID FORMS
Physical-chemical properties
Appearance, odor, homogeneity, consistency
Loss on weight
Viscosity
Content uniformity (within the container)
Chemical properties
Assay
Degradation products
Content preservatives
Degradation preservatives
Content antioxidants
Microbial properties
Microbial purity
Container closure system properties
Functionality tests