wjpmr, 2016,2(3), 99-103. SJIF Impact Factor: 3.

535
Review Article
Reddy et al. WORLD JOURNAL OF PHARMACEUTICAL
World Journal of Pharmaceutical and Medical Research
ISSN 2455-3301
AND MEDICAL RESEARCH
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ACCELERATED STABILITY TESTING OF DOSAGE FORMS AS PER

INTERNATIONAL CONFERENCE OF HORMONIZATION (ICH) GUIDELINES

Dr A. Sambasivarao1, Dr. Chandra Sekhara Rao Baru2, M. Hareesh Reddy3*

1
Principal & Professor- Sri Indu College of Pharmacy- Hyderabad.
2
RGR Siddhanthi College of Pharmacy, Secunderabad, Telangana.
3
Associate professor – Shadan College of Pharmacy – Hyderabad.

*Corresponding Author: M. Hareesh Reddy

Associate professor – Shadan College of Pharmacy – Hyderabad.

Article Received on 01/04/2016 Article Revised on 20/04/2016 Article Accepted on 10/05/2016

ABSTRACT
Objectives of accelerated stability studies are linked to the establishment assurance of safety, quality and efficiency
of drug product from early phase development through the drug product. The stability data for the drug substance
are used to determine optimal storage and packaging conditions for bulk lots of material. In order to assess
stability, the appropriate physical, chemical, biological and microbiological testing must be performed.
Pharmaceutical companies estimate the shelf life (Expiration date) of a drug in order to determine the amount of
time the drug is at acceptable potency, color, etc., levels. The pharmaceutical company or the food and drug
administration set the acceptable levels. The process in which the shelf-life is determined is called a stability
analysis. During the shelf-life, a drug can stay on the shelf without degrading to unacceptable levels.

KEYWORDS: Accelerated stability, Shelf- life, Potency, Safety, Quality, Efficiency.

INTRODUCTION If the slope of this line is determined from the results of

temperature by extrapolation, the k value obtained. And
The method of accelerated stability testing of
this k value is substituted in appropriate order of reaction
pharmaceutical products is based on the principles of
allows the amount of decomposition after a given time.
chemical kinetics, more specifically on the Arrhenius
Preliminary experiments are there for necessary to
plot. According to this technique, the k values for the
determine this order.
decomposition of the drug in solution at various elevated
temperatures are obtained, and the logarithms of these k
K=Ae-Ea/RT
values are plotted against the reciprocals of the absolute
Log K=Log A - Ea/2.303*RT
temperatures (in Kelvin’s). The resulting line is then
Where, K= rate constant
extrapolated to room temperature ( 5c 98 K). The
R= gas constant =1.987 cal/mole
k 5 c is used to obtain a measure of the drug under
T = absolute temperature
ordinary shelf conditions.[1-3]
A = frequency factor
Ea = energy of activation
Prediction of shelf life from accelerated stability data
T10% = (2.303/K)*(log100/90)
Based on the principle of chemical kinetics demonstrated
T90% = (2.303/K)*(log100/10)
by
1) Garret and Carper method
GARRET AND CARPER METHOD
2) Free and Blythe method
1. Keep several samples of the drug product at least
Shelf Life Determination Based on Arrhenius Plot three temperatures, such as 40 C, 50 C and 60 C.
(Garret and Carper method) 2. Determine the drug content at all three storage
The mathematical prediction of shelf life is based on the points by taking a number of samples and take the
application of the Arrhenius equation, which indicates mean drug content. We do this for a few weeks.
the effect of temperature on the rate constant, k, of a 3. At each temperature we plot a graph between time
chemical reaction of thermodynamic temperature, 1/T, is and log percent drug remaining. If the
a straight line. decomposition is first order this gives a straight line.
If it is zero order, percent drug remaining versus
time will give a straight line.[4-6]

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Reddy et al.
4. Next we take the log K or log of reaction constant
on axis and T x 0-3 on X axis and draw a best
fit line. This line is the Arrhenius Plot, extrapolate
this line to get k at 5 C and from this we calculate
the shelf-life.
Arrhenius plot for predicting drug stability at room
temp.
If the reaction is following zero-order Expiration date at
5 C Initial potency – minimum potency / reaction rate
at 25°C
tx =Yo - Yx/ Ko
If the reaction is following first order Expiration date at
5 C (tx) Log initial potency – log minimum
potency reaction rate at 5 C
tx =log Yo – log Yx / K1
Where Yo = initial potency
Yx = final potency
Ko = zero order constant
K1 = first order constant
Pharmaceutical products can deteriorate with time,
through both chemical decomposition of the active
principles and excipients and sometimes also through
microbiologically induced degradation. Therefore, all
pharmaceutical products are required by law to display
an expiry date on the packaging. Stability testing is the
primary tool used to assess the expiration dating and
storage conditions for pharmaceutical products. Many
protocols have been used for stability testing, but most in
the industry are standardizing on the recommendations of
the international conference on Harmonization (ICH).[7-
11]
Product changes in accelerated stability studies.
Physical changes- appearance, Melting point, Clarity
and color of solution, Moisture, Crystal Modification
(Polymorphism), particle size.
Chemical changes – Increase in degradation, decrease
of assay.
Microbial changes.
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 program involving both
regulatory and industry as equal partners in the scientific
and technical discussions of the testing procedures which
required ensuring and assessing the safety, quality and
efficacy of medicines.[12-15]
Tripartite guideline in the stability testing of new drug
substance and product (Q1A) IN 1993 has become
standard for stability evaluation in Japan, US, Europe.
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World Journal of Pharmaceutical and Medical Research
ICH Guidelines-
Quality guidelines “Q” (Chemical and Pharmaceutical
QA)
Safety guidelines “S” (In vitro and in vivo pre-clinical
studies)-
Covering carcinogenicity testing, Genetic toxicity
testing, toxic kinetics and pharmacokinetics.
Efficiency guidelines “E” (Clinical studies in human
subject)-
Covering clinical safety, Dose response studies, good
clinical practices, Clinical evaluation.
Multidisciplinary guidelines “M”
Covering Medical Technology, electronic standards for
transmission of regulatory information.
Guideline M4-The common technical document.(CTD)
Accelerated stability studies
1. Storage condition of40 c and relative humidity of
75% has been recommended for all the four zones
for drug substances and drug products.
2. Studies carried out for 6 months
3. Accelerated storage conditions must be at least 5 c
above the expected actual storage temperature and
appropriate relative humidity.
Protection against hydrolysis:
Good packaging practices like moisture resistant
packing. Eg- Strip pack stored in controlled humidity
and temperature conditions, even using desiccant such as
silica gel.
Buffering agent for pH control.
Alteration of Dielectric constant.
Use of surfactants, Good refrigeration.
Addition of complexing agent like caffeine.
Protection against oxidation:
Incorporation of Antioxidants such as BHA, BHT,
Propyl gallate, tocopherol.
Chelating agents using EDTA, Citric acid, Tartaric acid.
Use of inert gases like nitrogen
Protection from light by use of amber colored container.
Storage at low temperature.
Type, size, No .of batches (ICH/WHO Guidelines)
At least 3 primary batches of drug product should be of
the same formulation, packed in same container as
proposed for marketing.
2 out of 3batches should be pilot scale batches.
Stability to be performed on each strength, container
size.
Long term stability studies
1. Stability is performed at 5 c 60% or 30 c 65%
2. Ideally 12 months date is to be generated, but 6
months date is also acceptable in circumstances for
submission of registration dossier, continued till end of
shelf-life.
3. For parenteral stability has to carried out at 2-8 c. For
drugs to be stored in freezer testing should be done at -
0 c.
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Reddy et al. World Journal of Pharmaceutical and Medical Research

Chemical properties Limitations of Accelerated stability study

Assay 1. Stability predictions are based on Arrhenius’
Degradation equation, which has limitation for energy of
activation for validation of thermal decomposition,
Microbial properties which lies in the range of 10-30 Kcal/mole.
Container clouser system properties –Functionality test. 2. Functionality test
Testing seep Liquid dosage forms for injections and Testing seep for semisolid dosage form
parenteral–
Physical-chemical properties - PH Physical-chemical properties -
Loss of weight Appearance
Color & clarity of solution Color
Homogeneity
Chemical properties Consistency
Assay Loss of weight
Degradation products Content uniformity
Degradation preservatives Viscosity
Microbial properties - Chemical properties -
Pyrogen testing Assay
Container clouser system - Degradation products
Functionality test Degradation preservatives
Leakage test
Antioxidants.
Testing seep for oral liquid form Microbial properties –
Physical-chemical properties - PH Container clouser system -
Viscosity
Color & clarity of solution 3. At accelerated conditions some new reactions may
Particle size distribution (For oral suspension only) take place, which usually do not take place at normal
Chemical properties - storage conditions. Therefore, obtaining correct
Assay information is difficult.
Degradation products 4. Order of reaction may also differ in some cases with
Degradation preservatives accelerated conditions.
Antioxidants 5. Accelerated testing cannot be used for
Microbial properties microbiological decomposition and also for handling
during transport.
Testing seep for solid dosage forms 6. Thermolabile materials and products are not suitable
Physical-chemical properties –Appearance, Elasticity, candidates for accelerated stability study.
Moisture, Hardness, Disintegration, Dissolution 7. Some products appear stable at higher temperature
Container clouser system than at normal storage conditions.
Functionality test. % of Relative humidity (RH) = Water-vapour
pressure in atmosphere/Saturated water-vapour
pressure x 100

ICH Summary of Stability Parameters

Study Storage conditions Minimum time period
General case 5 C (± C) at 60 % RH (± 5 %RH) 12 Months
Long term 30 C (± C) at 65 % RH (± 5 %RH) 12 Months
Intermediate 30 C (± C) at 65 % RH (± 5 %RH) 6 Months
Accelerated 35 C (± C) at 70 % RH (± 5 %RH) 6 Months
Refrigeration
Long term 5 C (±3 C) 12 Months
Accelerated 5 C (± C) at 60 % RH (± 5 %RH) 6 Months
Freezen
Long term - 0 C (± 5 C) 12 Months

Product Characteristics Affecting Shelf-Life
Spoilage – Microbial spoilage occurs in products that
provide an environment that supports microbial growth,
or are subjected to contamination during storage. The
leaching of chemicals, or similar reactions, promoted by
long- term contact with packaging materials leads to
chemical spoilage.
Flavors – Off-flavors’ developed during storage are
often due to chemical reactions or microbial growth.

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Reddy et al. World Journal of Pharmaceutical and Medical Research

Rancidity occurs as a result of oxidative reactions and Functionality - A product is considered unacceptable and
produces off-flavors. Texture – Products containing unusable when it loses its functional properties such as a
similar ingredients do not necessarily exhibit similar vitamin-fortified product losing its potency.
textures. Water contributes greatly to a product’s texture.
Stalling, breakdown of gel structures, phase separation, Climatic zones for stability studies. Climatic conditions
water activity, moisture migration and crystallization, all prevalent in different countries, mentioning of ambient
contribute to textural changes during storage. temperature may be relevant here. For this purpose, four
climatic zones are proposed as listed here.
Appearance - An unacceptable appearance in colour
resulting in browning or fading is caused by fat and/or Temperate zone C (45%RH)
moisture migration and chemical reactions. Other Mediterranean 5 C (60%RH)
processes affecting appearance making the product Tropical moist 30 C (70%RH)
undesirable during storage include surface crystal Desert zone 30 C (35%RH)
formation, phase separation, syneresis and caking.

Overview of storage conditions and storage period for solid, semisolid and liquid dosage forms.

Stability Storage
Dosage form Storage condition
investigation period
Solid Storage in open container until equilibrium
1-2 weeks
at 5 C 60%,30 C 70%, 40 C 75%.
5C
Organoleptic and 4 weeks
>- 0 C
photochemical Semisolid 4 weeks
5 C -40 C Temperature cycle within 4
stability 2 weeks
hrs.
5C 4 weeks
Liquid
>- 0 C 4 weeks
Photo stability All Xenon lamp 48 hrs
Solid 40 C, 50 C, 60 C, 70 C. 3 months
Chemical stability Semisolid 30 C, 40 C, 50 C. 3 months
Liquid 40 C, 50 C, 60 C, 70 C. 3 months

Addition of overages and then placed at room temperature again for 24 hours.
1. Excess amount of the drug can be added to the The sample is analyzed for significant changes. This
preparation to maintain 100% of the labeled amount completes one cycle. If, after three cycles of freeze-thaw
during the shelf-life of the product. testing, no significant changes are observed, you can be
2. Overages are calculated from the accelerated confident that the stability of your product is sufficient
stability studies and added to the preparation at the for transport.
time of manufacture.
3. They should be within the limits compatible with the CONCLUSION
therapeutic requirement.
Knowledge of stability of a formulation is very important
4. Addition of overages doubles the shelf-life of the
for three primary reasons.
product.
1) A pharmaceutical product must appear fresh, elegant
5. Overages are added in multi-vitamin preparations.
and professional for as long as it remain on the shelf.
2) Since some products are dispensed in multiple dose
Freeze thaw stability testing
container uniformity dose of the active ingredient
Freeze-thaw cycle testing is a part of stability testing that
over time must be ensured.
allows you to determine if your formula will remain
3) The active ingredient must be available to the patient
stable under various conditions. This type of test puts
throughout the expected shelf-life of the preparation.
your sample through a series of extreme, rapid
A break down in the physical system can lead to non
temperature changes that it may encounter during normal
availability or of the medication to the patient.
shipping and handling processes. Freeze-thaw stability
testing is highly recommended, especially for liquid-
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