Expiry Date Calculation

Presented by:
Jagtap Uddhav Anjiram
Roll no. – 190609013
M Pharm Semester I

Guide:
Dr. Swapnil J. Dengale
Assistant Professor – Senior scale

DEPARTMENT OF PHARMACEUTICAL QUALITY ASSURANCE

MANIPAL COLLEGE OF PHARMACEUTICAL SCIENCES
MAHE, MANIPAL

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 CONTENTS
Sr. Contents Pg. No
No
1 Introduction 3
2 Need and Objective 3
3 Factors affecting shelf - life 3
4 Method to determination Order of Reaction 5
5 Methods for Shelf-life Study 5
6 Prediction of Shelf - life/ Expiration date 8
7 Stability Study by ICH Guideline 11
8 Accelerated Test for Photochemical Stability 12
9 Accelerated Test for Moisture Absorption 12
10 Accelerated Test for Emulsion 12
11 Accelerated Test for Suspension 12
12 Limitation of Accelerated Stability Testing 12
13 Reference 13

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INTRODUCTION:
Stability is the ability of a pharmaceutical product to retain its physical, chemical, microbial
and biopharmaceutical properties within the specified limits throughout the shelf life.
OR
Stability is officially defined as the “time lapse during which a drug or dosage form retain the
same properties and characteristics that are possessed at the time of manufacture.’’
The principle of reaction kinetics is applied for predicting the stability of drugs. Stability of
dosage form is expressed technically as shelf - life and denoted by expiry period.
Expiration period is a valuable quality attribute for all dosage form, while the term retest is
used in case of drug substances.
Expiry date is date which a consumable product such as food or medicine should not be used
because it may be spoiled, damaged or ineffective.
Shelf life is the period of time, from the date of manufacturing that a drug product is expected
to remain within its approved product specification while stored under defined conditions.

Need for shelf life determination:

 For patient safety
 Drug activity
 Legal requirements
 Effects on the manufactures image
 Patients economy

Objective:
 To determine maximum expiry date.
 To provide better storage condition.
 To determine packing component.
 To gather information during preformulation stage to produce a stable product.

Factors Affecting Shelf - life:

Primary Factor Affecting Stability:
1. Temperature
2. Moisture
3. Light
4. Concentration
5. pH
6. Oxygen

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 1. Temperature:
High temperature accelerates oxidation, reduction and hydrolysis reaction which lead to drug
degradation.

2. Moisture:
Water catalyses’ reaction as oxidation, hydrolysis and reduction.

3. Light:
It affects drug stability through its energy or thermal effect which lead to oxidation.

4. Concentration:
Rate of drug degradation is constant for solutions of the same drug with different
concentration. So, ratio of the degraded part to the total amount of drug in diluted solution is
bigger than the concentrated solution.

5. pH:
Acidic and alkaline pH influences the rate of the decomposition of most of the drugs. Many
drugs are stable between pH 4-8. Weekly acidic and basic drugs show good solubility when
they are ionized and they also decompose faster when they are ionized.

6. Oxygen:
Photo-degradation is also influenced by the presence of oxygen.

Major Factors Affecting Drug Stability:

1. Particle size (Suspension and Emulsion)
2. Additive
3. Molecular binding
4. Diffusion of drugs and excipients

Order of Reaction:
Order X axis Y axis Half life Shelf life
Zero Time (a-x) a/2k 0.1A0/k0
First Time log(a-x) 0.693/k 0.105/k1
Second Time 1/(a-x) 1/ka -
(a=b)
Second Time log b(a-x)/a(b-x) 1/ka -
(a≠b)
third Time 1/(a-x)2 3/2ka2 -

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Method to determination Order of Reaction:
1. Substitution Method
2. Initial Rate Method
3. Data Plotting Method
4. Half-life Method

1. Substitution Method:
The data accumulated in a kinetic study may be substituted in the integrated form of the
equations which describes the various orders. When the equation is found in which the
calculated k values remain constant the reaction is considered to be of that order.

2. Initial Rate Method:

Fig. Curve for different types of reaction

Graphs are plotted of rate of reaction against concentration and the initial rate determined θ
from the gradient at time = 0. If it is a straight line the reaction is first order. If a curve is
obtained then we can say it is second order reaction. A which is independent on
concentration is zero order.

3. Data Plotting Method:

Plot of conc. against time is if linear then it is zero order reaction. Plot 1/c against time is
linear then second order. Plot of In c against time is linear then first order reaction.

4. Half - life determination Method:

The relationship in general between half-life of a reaction in which the concentration of all
reactants are identical, is t1/2 ∞ 1/an-1, where n is the order of reaction. Thus, if two reactions
are run at different initial concentrations, a1 and a2 with their respect half-life and putting
them in above equation in logarithmic form we finally get
n = log (t1/2(1) / t1/2(2)) / log (a2 – a1) + 1

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Methods for Shelf-life Study:
1. Real Time Stability Study
2. Accelerated Stability Study
3. Retained Sample Stability Testing
4. Cyclic Temperature Stress Study

1. Real Time Stability Study:

 In real time stability testing, a product is stored at recommended storage condition
and monitored until it fails the inspection.
 It is normally performed for longer duration of the test period in order to allow
significant product degradation under recommended storage condition.
 It is mainly done for new drug substances and new drug formulations.

2. Accelerated Stability Study:

 In accelerated stability testing, a product is stressed at several high (warmer than
ambient) temperatures and the amount of heat input required to cause product failure
is determined.
 This is done to subject the product to a condition that accelerates degradation. This
information is then projected to predict shelf life or used to compare the relative
stability of alternative formulation.
 This is usually provides an early indication of the product shelf life and thus
shortening the development schedule.
 In addition to temperature, stress conditions applied during accelerated stability
testing are moisture, light, agitation, gravity, pH and package.
 In accelerated stability testing the samples are subjected to stress, refrigerated after
stressing, and then assayed simultaneously. Because the duration of the analysis is
short, the likelihood of instability in the measurement system is reduced in
comparison of the unstressed product with stressed material is made within the same
assay and the stressed sample recovery is expressed as percent of unstressed sample
recovery.
 For statistical reason, the treatment in accelerated stability projection is thermolabile
and proteinaceous components, relatively accurate stability projections are obtained
when denaturing stress temperature are avoided.
 A product may be released based on accelerated stability data but the real time testing
should be done in parallel to confirm the results of the shelf-life prediction.
 Temperature is the most common acceleration factor used for chemicals,
pharmaceuticals and biological products since its relationship with degradation rate is
well characterized.

Arrhenius Equation:
Reaction rates are proportional to the no. of collision per unit (of reactant molecule).
The no. of collision increases as the temperature increases. Therefore, the reaction rate
increases as temperature increase.

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According to Arrhenius Equation:
In k = In Ae - △E/RT
K = Degradation rate / Reaction rate constant
A = frequency factor constant i.e. maximum no. of collision at infinite temperature
△E = Activation energy
R = Universal gas constant
T = Absolute temperature(K)
Although the drugs stability at room temperature is of primary interest, a stability study at
room temperature would take too long to be useful as a screening procedure for new
formulations.
There such screening studies are done at elevated temperature in accordance with the
Arrhenius equation.
Therefore, log k = log a – Ea/2.303
Graph of log k vs 1/T gives straight line with slope Ea/2.303 and intercept at t = 0. Ea
represents energy required by molecule to react and undergo reaction. Higher is value of Ea
higher is dependency on temperature.
Rate constant at different temperature can be obtained by
log (K2/K1) = Ea (T2 – T1) R (T2*T1)
With help of k at different temperature we can be predict t10%
T90% = 0.105/k (For first order only)
t90% = 0.105/k1 (For zero order only)

3. Retained Sample Stability Testing:

 This is usual practice for every marketed product for which stability data are required.
 In this study, stability samples, for retained storage for at least one batch a year are
selected. If the no. of batches marketed exceeds 50, stability sample from two
batches are recommended to be taken.
 At the time of first introduction of the product in the market, the stability samples of
every batch may be taken, which may be decreased to only 2% to 5% of marketed
batches at a later stage.
 In this study, the stability sample are tested at predetermined interval i. e. if a product
has shelf life of 5 years, it is conventional to test samples at 3,6,9,12,18,24,36,48 and
60 months.
 This conventional method of obtaining stability data on retained storage sample is
known as constant interval method.
 Stability testing by evaluation of market samples is a modified method which involves
taking samples already in the market place and evaluation stability attributes. This

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 type of testing is inherently more realistic since it challenges the product not just in
the idealized retained sample storage conditions, but also in the actual market place.

4. Cyclic Temperature Stress Study:

 This is not a routine testing method for marketed products.
 In this method, cyclic temperature stress tests are designed on knowledge of the
product so as to mimic likely conditions in market place storage.
 The period of cycle mostly considered is 24 hours since the diurnal rhythm on earth is
24 hours, which the marketed pharmaceuticals are most likely to experience during
storage.
 The minimum and maximum temperatures for the cyclic stress testing is
recommended to be selected on a product by–product basis and considering factors
like recommended storage temperature for the product and specific chemical and
physical degradation properties.
 It is also recommended that the test should normally have 20 cycles.

Prediction of Shelf- life/ Expiration date:

 Prepare 5 portions stored at different temperature 40°, 50°, 60°, 70° and 80°.
 Samples are withdrawn at different intervals.
 Order of reaction is determined by the methods explained above.
 Now we know the order of reaction. We will plot graph for either first order or zero
order, as required.

For First Order Reaction:

If first order law is obeyed then a graph of log (a-x) v/s time t will give straight line with
slope of –k/2.303 and an intercept of log a at t = 0.

K = 2.303/t log (a/a-x)

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For Zero Order Reaction:

 Now from the given graph calculate k40, k50, k60, k70 and k80.
 The k value that you require is the temperature at which the pharmaceutical product is
to be stored. In general we take 25°c as temperature for storage conditions.
 Now with the help of Arrhenius equation we will plot a graph between the log k value
and 1/T.

Extrapolate graph to 25°c:

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  Find the log k value and then
log k = x
k = antilog x
so, we get the k25 value.
 Shelf - life calculation is done by putting the k25 value in the required equation of the
specific order.
 We therefore get the shelf life value at which the drug concentration degrades to 90%
of its initial concentration.

Calculation for overages:

 Plot the graph of time (Days) vs. conc. remaining ὠ
 Extrapolate line from Taxis, at 90% to the x axis.
 The intersect point will give shelf - life ὠ
 To maintain or increase the shelf life as per need (from a to b as shown in fig).
 Draw a parallel w line from Y to that of X, the intersect point at Y axis will
give the value of overages per 100 units.
 As shown in the figure, the value of overages is 20%. So need to add 20 unit
drugs to preexisting formulation. As per European guidelines the maximum
amount of overages is 30%.

Based on 10% degradation, overages added to the product during the manufacturing in order
to maintain the 100% labelled dose.

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Stability Study by ICH Guideline:
The whole world is divided into 4 climatic zones in order to harmonize and simplify stability
testing.

Worldwide zones / Temperature and Humidity Conditions:

Zones Condition Temperature Relative
Humidity
Zone 1 Temperate 20°c 42
Zone 2 Mediterranean/subtropical 22°c 52
zone
Zone 3 Hot & Dry 27.9°c 35
Zone 4a Hot & Humid 27.4°c 65
Zone 4b Hot & High Humid 27.4°c 75

Worldwide zones and Countries:

Zones Countries
Zone 1 Japan, United Kingdom, Northern Europe,
Canada, Russia
Zone 2 US, Japan, Southern Europe
Zone 3 Iran, Iraq, Sudan
Zone 4 Brazil, Ghana, Indonesia, Philippines

Stability Test Storage conditions for Drug Product:

Intended Storage Stability Test Test Period
Condition Method Temperature (Month)
and Humidity
1. Room Long term studies 25°C ± 2°C/60% 12 months
Temperature RH ± 5% RH or
30°C ± 2°C/65%
RH ± 5% RH
Intermediate 30°C ± 2°C/65% 6 months
studies RH ± 5% RH
Accelerated studies 40°C ± 2°C/75%
RH ± 5% RH 6 months

2. Refrigerator Long term 5°C ± 3°C 12 months

Accelerated 25°C ± 2°C/60% 6 months
RH ± 5% RH
3. Freezer Long term - 20°C ± 5°C 12 months

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Accelerated Test for Photochemical Stability:
 It can be done by inducing rapid decomposition by using artificial light source.
 The intensity of light is proportional to photo degradation of formulation.
 To overcome photochemical degradation, the formulation must be packed in amber
colored containers and extra protection from light is provided by placing the container
in carbon box.

Accelerated Test for Moisture Absorption:

 In these the products are placed in small cabinets containing different saturated salt
solution which maintain high relative humidity and controlled temperature.
 The formulations are kept in packed and unpacked forms and are checked for physical
and chemical stability.
 It indicates the product is susceptible to, moisture or not.

Accelerated Test for Emulsion:

 For emulsion we cannot perform accelerated test by increasing temperature because at
higher temperature, the emulsion will break.
 So we perform centrifugation instead of increasing temperature.
 By centrifugation we accelerate the rate of creaming. Ultracentrifuges used with
60,000 rpm.
 Rate of creaming is proportional to speed of centrifuge.
 The emulsion is subjected to different centrifugal speeds and separation of phases is
observed at different time periods.
 Bad emulsion separate oil instantly.
 Good emulsion does not exhibit detectable separation of oil phase until certain time
period.

Accelerated Test for Suspension:

 Cake formation is accelerated by centrifugation, hence high speed centrifugation is
not performed. So low speed centrifugation is used to study physical stability.
 A freeze – Thaw cycling technique is one of the stress testing.

Freeze – Thaw Method:

A freeze - Thaw cyclic technique is one of the stress testing. This cyclic treatment
promotes particle size, particle size distribution and crystal habit.

Limitation of Accelerated Stability Testing:

 Carried out only at final package container.
 Prediction is not possible at climatic conditions.
 Valid only when the break down/ degrade with increase in temperature.
 The energy of activation obtained in the study should be between 10 – 30 kcal/mole.
 It is not useful when degradation is due to:
 Microbial contamination

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  Photochemical reactions
 Diffusion
 Excessive agitation
 When the product loses its physical integrity at higher temperature.
 When the order changes at elevated temperature.

Expected Shelf – life of various dosage forms:

Sr. No. Dosage forms Shelf life
1. Tablets 2 – 3 yrs.
2. Capsules 2 – 3 yrs.18 months or 2 yrs.
3. Oral liquids 18 months or 2 yrs.
4. Parenteral 2 yrs.
5. Ointment and Gels 3 – 4 yrs.
6. Ophthalmic Unopened – 2 yrs.
Opened – 30 days
7. Dental product 4 – 5 yrs.
8. Ayurvedic formulations 5 yrs.

Reference:
 Sanjay Bajaj, Dinesh Singla and Neha Sakhuja, Stability Testing on Pharmaceutical
Products jspsonline.com; Available from
http://japsonline.com/admin/php/uploads/409_pdf.pdf

 Ulrich Markens, Conducting Stability Studies – Recent change in climatic zone IV;
Available on
https://www.sgs.com/~/media/global/documents/technical%20documents/sgs%20stabi
lity%20studies-en-09.pdf

 Order of Reaction and Their Applications in Predicting Shelf life of Pharmaceutical

Formulations (Under stability study); Available from
http://pharmaquest.weebly.com/uploads/9/9/4/2/9942916/order_of_reaction.pdf

 Dr. A. Sambasivarao, Dr. Chandra Sekhara Rao Baru, M. Hareesh Reddy,

Accelerated Stability Testing of Dosage Forms As Per International Conference of
Hormonization (ICH) Guidelines; Available
from www.wjpmr.com/download/article/14042016/1463225274.pdf

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