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
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.
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)
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.
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
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