stability testing of dosage form and shelf life estimation with storage conditions

1. DRUG STABILITY
Manish kumar sharma
MAIP jaipur

2. “A measure of how pharmaceutical product
maintains its quality attribute over a time”

3. Stability
The USP defines the stability of a
pharmaceutical product as “ extent to which a
product retains , with in specified limits, and
throught out its period of storage and use i.e its
shelf life, the same properties and
characteristics that it possesed at the time of its
manufacture”.

4. Stability is used to determine
quality of a drug substance or drug product
 shelf life for the drug product
Recommended storage conditions

5. Why stability testing is necessary-
Chemical degradation may lead lowering of
concentrataion of drug in dosage form
toxic product may form due to degradation of
active ingridients

6. Advantages of stability studies
Assurance to the patient
Economic consideration
Legal requirements

7. Types of stability
Chemical
Physical
Microbiological
Therapeutical
Toxicological

8. Stability evaluation for different
formulations
1.Tablets
odour
colour
 assay
 degradation
products
 dissolution
moisture
 hardness/friability.

9. 2. Capsules
appearance (including brittleness)
colour
odour of content,
 assay,
 degradation products,
dissolution,
 moisture and microbial content.

10. 3. Emulsions
appearance (including phase separation),
colour,
odour,
assay,
pH, viscosity, microbial limits,
preservative content, and mean size and
distribution of dispersed globules.

11. 4. Oral Solutions and Suspensions
Additionally for suspensions, redispersibility,
rheological properties
 mean size and distribution of particles should be
considered.
5. Oral Powders for Reconstitution
moisture and reconstitution time.

12. 6.Metered-dose Inhalations and Nasal Aerosols
appearance (including content, container, valve, and
its components),
Dose content uniformity
labeled number of medication actuations per
container meeting
aerodynamic particle size distribution,
microscopic evaluation,
water content,
leak rate,
microbial limits

13. 7.Topical & Ophthalmic and Preparation
-Topical preparations
clarity, colour,odour, pH, resuspendability
(for lotions), consistency,
viscosity,
 preservative and antioxidant content (if
present), microbiallimits/sterility and weight
loss (when appropriate).

14. -Evaluation of ophthalmic or (e.g., creams, ointments,
solutions,and suspensions)
Sterility
particulate matter, and extractable.
-Evaluation of non-metered topical aerosols
delivery rate,
microbial limits,
spray pattern,
 water content, and particle size

15. 8. Suppositories
 softening range, dissolution (at 37 C)
Microbial limits.
9. Small Volume Parenterals (SVPs) & Large
Volume Parenterals (LVPs)
particulate matter, pH, sterility and
pyrogen/endotoxin.

16. 10. Transdermal Patches
in-vitrorelease rates,
leakage,
microbial limits/sterility, peel and adhesive forces, and
the drug release rate.
11. Freeze-dried Products
Appearance of both freeze-dried and its reconstituted
product, assay,
degradation products, pH, water content and rate of
solution.

17. Shelf life estimation

18. What is shelf life ??
Shelf life (t0.9)
It is defined as the time necessary for the drug
to decay to 90% of its original concentration.

19. Accelerated analysis for chemical stability
Based on the principles of chemical kinetics
Test are carried out at different elevated
temperature that enables prediction of the
effective life of the preparation at normal
temperature

20. Arrhenius equation
Reaction rates are proportional to the number of collisions
per unit time (of reactant molecules). The number of
collisions increases as the temperature increases. Therefore,
the reaction rate increases as the temperature increases
according to Arrhenius equation.

21. K = reaction rate constant
A = frequency factor constant i.e maximum number of
collisions at infinite temperature
Ea = Energy of activation
T = absolute temperature (Kelvin)

22. Arrhenius plot:

23. 1.According to the Garrett and carper “the k value for
decompostion of a drug in solution at various elevated
temperature are obtained by plotting some function of
concentration against time”.
2.The log of specific rates of decomposition are than
plotted aginst the reciprocal of the absolute temperature
and the resulting line are extraplotted to room
temperature.

24. Predicting drug stability at room temperature by Arrhenius
plot

25. 3. Free and Blythe suggested a similar method in which
the fractional life period is plotted against reciprocal
temperature, and the time in days required for the drug
to decompose to some fraction of its original potency at
R.T is obtained.
4.The log % of the drug remaining is plotted against
time in days and the time for the potency to fall to 90%
of the original value i.e t90 is read from the graph. The
log time to 90% is then plotted against 1/T and the time
at 25 degree c gives the shelf life of the product in days

26. Time in days required for drug ptency at fall 90% t90 are than plotted on a log
scale

27. Limitations of accelerated analysis
Carried out only at final package container
Prediction is not possible at all climatic
conditions
Limited to the product formulations
Only apply to the those which degrade with
increase in temperature

28. Long term stability studies

29. 2 side 95%
confidence
limit

30. Overage
It is over loading the dosage form with more
drug than 100% (i.e 110% or more) to give more time to get 90% potency
i.e. shelf life is longer.
Rational
 Shelf lives are usually a maximum of 5 years and it takes a product
up to 2 years to reach customer
 Reduced shelf lives are seen in liquid products e.g, antibiotics and
ophthalmics because they are unstable in presence of moisture
 Some drugs are inherently unstable e.g, vitamins. Therefore, they are
over loaded.

31. ICH guidelines…………………
ICH stands for International Conference on
Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human use.
Objective
 Harmonization of registration application within the
three regions of the EU, Japan and the United States.

32.  ensure and assess the safety, quality and efficacy of
medicines.
The zone concept-
The whole world is divided into 4 climatic zones in order
to harmonize and simplify stablity testing:

33. Stability Studies are preformed on
Drug Substances Drug Products
 Stress Testing
 Selection of Batches
 Container Closure System
 Specification
 Testing Frequency
 Storage Conditions
 Stability Commitment
 Evaluation
 Statements/Labeling

34. Drug substance General case
Study Storage condition
Minimum time period
covered by data at
submission
Long term 25°C ± 2°C / 60% ± 5%
r.h or
30°C ± 2°C / 65% ± 5%
r.h.
12 months
Intermediate 30°C ± 2°C / 65% ± 5%
r.h.
6 months
Accelerated 40°C ± 2°C / 75% ± 5%
r.h.
6 months

35. Drug substances intended for storage in a freezer
Study Storage condition Minimum time period
covered by data at
submission
Long term -20°C ± 5°C 12 months

36. Drug substances intended for storage in a refrigerator
Study Storage condition Minimum time period
covered by data at
submission
Long term 5°C ± 3°C 12 months
Accelerated 25°C ± 2°C / 60% ± 5%
r.h.
6 months

37. Drug product general case
Study Storage condition Minimum time period
covered by data at
submission
Long term 25°C ± 2°C / 40% ± 5%
r.h. or
30°C ± 2°C / 35% ± 5%
r.h.
12 months
Intermediate 30°C ± 2°C / 65% ± 5%
r.h.
6 months
Accelerated 30°C ± 2°C / 65% ± 5%
r.h.
6 months

38. Storage in refrigerator
Study Storage condition Minimum time period
covered by data at
submission
Long term 5°C ± 3°C 12 months
Accelerated 25°C ± 2°C / 60% ± 5%
r.h.
6 months

39. THANK
YOU