. SHELF LIFE DETERMINATION BY: VIDYA DHONDE M.

PHARM SEM-1
PHARMACEUTICS GUIDED BY: DR.SHRUTI SHRIKHANDE 1
2. CONTENTS: DEFINATION NEED FOR SHELF LIFE DETERMINATION FACTORS
AFFECTING ON SHELF LIFE DETERMINATION ARRHENIUS EQUATION ICH
CONCLUSION REFERENCE 2
3. 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
(FDA, 1987). Shelf life is the time required for 10%of the material to disappear; it is the time
at which a has decreased to 90% of its initial conc. 3
4. 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 condions. Expiry date is expressed in terms of months & years and is clearly
indicated on the primary (immediate) pack as well as the seconday pack. Shelf life values
are normally given to the product rather than a batch. 4
5. FACTORS AFFECTING SHELF LIFE OF DRUGS Moisture, hydrolysis and PH 
Oxygen and oxidation Light Temperature Microbes  API’s and excipients 
physicochemical properties like hygroscopic nature, crystalline or amorphous state,
polymorphism, vapor pressure etc. 5
6. FACTORS AFFECTING DRUG STABILITY  Temperature: high temperature accelerate
oxidation, reduction and hydrolysis reaction which lead to drug degradation  PH: acidic and
alkaline PH influence the rate of decomposition of most drugs. Many drugs are stable
between ph 4 and 8. Weekly acidic and basic drugs show good solubility when they are
ionized and they also decompose faster when they are ionized.  Sometimes PH can have a
very serious effect on decomposition. As little as 1 PH unit change in cause a change of ten
fold in rate constant. So when we are formulating a drug into a solution we should carefully
prepare a PH decomposition profile 6
7. CONTND  Moisture: water catalyses chemical reactions as oxidation, hydrolysis and
reduction reaction. Water promotes microbial growth  Light: affects drug stability through its
energy or thermal effect which lead to oxidation  Pharmaceutical dosage forms: solid
dosage forms are more stable than liquid dosage forms for presence of water. 
Concentration: rate of drug degradation is constant for the solutions of the same drug with
different concentration. So, ratio of degraded part to total amount of drug in diluted solution is
bigger than of concentrated solution. 7
8. CONTND  Drug incompatibility: reactions between components of pharmaceutical
dosage forms it self or between these components and cover of the container .  oxygen:
exposure of drug formulations to oxygen affects their stability 8
9. TYPES OF SHELF LIFE STUDY Real time stability study. Accelerated stability study. 9
10. 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. 10
11. METHOD • In real-time stability tests, a product is stored at recommended storage
conditions and monitored for a period of time.(Ttest) • Product will degrade below its
specification, at some time, denoted ts, and we must also assure that ts is less than or equal
to Ttest. The estimated value of ts can be obtained by modeling the degradation pattern. •
Good experimental design and practices are needed to minimize the risk of biases and
reduce the amount of random error during data collection. • Testing should be performed at
time intervals that encompass the target shelf life and must be continued for a period after
the product degrades below specification. • 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. 11
12. ACCELERATED STABILITY TESTING • In accelerated stability tests, a product is stored
at elevated stress conditions (such as temperature, humidity, and PH). • Degradation at the
recommended storage conditions can be predicted using known relationships between the
acceleration factor and the degradation rate. • A product may be released based on
accelerated stability data, but the real-time testing must be done in parallel to confirm the
shelf-life prediction. 12
13.  Sometimes the amount of error of the predicted stability is so large that the prediction
itself is not useful. Design your experiments carefully to reduce this error. It is recommended
that several production lots should be stored at various acceleration levels to reduce
prediction error. Increasing the number of levels is a good strategy for reducing error.
Temperature is probably the most common acceleration factor used for chemicals,
pharmaceuticals, and biological products since its relationship with the degradation rate is
well characterized by the arrhenius equation. 13
14. CONTND… • The concept of accelerated stability testing is based upon the arrhenius
equation and modified arrhenius equation : Log K= log A+ΔE/RT Where K= degradation
rate/s, A= frequency factor/s, ΔE=activation energy (kJ/mol), R = universal gas constant
(0.00831kJ/mol), T=absolute temperature 14
15. Stability study as per USP Physical stability. Chemical stability. Microbiological
stability. Therapeutic stability. Toxicological stability. 15
16. 16
17. 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 minimum shall be
provided at the time of registration. 17
18. ARRHENIUS EQUATION • When a new drug product is being formulated, it is desirable
to determine the stability of the drug entity in the drug product so that a shelf life or expiration
date may be assigned to the product. • The shelf-life is the length of time required for the
product potency to be reduced to some percentage of its original value. • For most products,
this is the tor time at which the product 90 18 retains 90% of its original potency.
19. ARRHENIUS EQUATION • Although the drug's 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. • Therefore, such screening studies are conducted at
elevated temperatures in accordance with the arrhenius equation. 19
20. ARRHENIUS EQUATION K= ae-ea/RT • A = arrhenius / frequency factor,(no. Of effective
collisions). • R = gas constant (1.987 calories/deg mole) • T = absolute temperature. 20
21. ARRHENIUS EQUATION 21 Log K1/K2 = Ea T2 - T1 ------x ---- ------- 2.303R T 1T2
22. 22 ORDER 1ST RATE LAW RATE K[A] INTEGRATED RATE LAW LN[A]T=−KT+LN[A]0
INTEGRATED RATE EQUATION LOG A/A-X = K /2.303 XT STRAIGHT-LINE PLOT LN[A]
VS. T SLOPE −K HALF-LIFE (T1/2) 0.693/K UNITS OF K /SECOND = SECOND-1
23. ICH The estimate of shelf life, using ICH Q1E methodology, depends on  sample size
 Level of confidence.  While no explicit quality statement is provided, the intent of the ICH
q1E strategy is to establish the storage time during which the critical attribute(s) will be
considered acceptable for all "future batches manufactured, packaged, and stored under
similar circumstances. 23
24. ICH  A stability study is a designed experiment where the pharmaceutical product is
stored in environmental chambers and followed for a prescribed amount of storage time. 
Periodically, the product is sampled to measure a series of stability limiting properties from
these data, an estimate of the true product shelf life is obtained.  In general, this estimate of
the true product shelf life is called the estimated shelf life or the estimated product shelf life
24
25. ICH Current industry procedure for determining the labeled Shelf life for a new drug
product assess “ICH shelf life” based on long term data, accelerated data and if applicable
intermediate condition data against the ICH decision tree perform statistics if applicable,
Test for pool ability of slopes and intercepts.  Pool slopes and intercepts as applicable. 
Use the pooled mean square error calculated from all Batches. 25
26. CONCLUSION Pharmaceutical products are assigned a shelf-life which determines the
time when a product is considered to be safe and effective under a relevant storage
condition.  Accelerating the aging process allows the development and production of
pharmaceutical products without waiting for the entire shelf-life to elapse before assigning a
value. Factors as temperature and relative humidity can be used to accelerate these
processes effectively allowing for accurate and precise predictions. 26
27. REFERENCES Drug shelf-life estimation, jun shao and shein-chung chow university of
wisconsin and statplus, inc.  ICH guidelines www.Ich.Org Terrence tougas, david
christopher, dennis sandell, suntara cahya on behalf of the PQRI stability shelf life working
group. 27
28. 28