Stability testing and shelf life estimation
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stability testing of dosage form and shelf life estimation with storage conditions
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- DRUG STABILITY Manish kumar sharma MAIP jaipur
- A measure of how pharmaceutical product maintains its quality
attribute over a time
- 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.
- Stability is used to determine quality of a drug substance or
drug product shelf life for the drug product Recommended storage
conditions
- 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
- Advantages of stability studies Assurance to the patient
Economic consideration Legal requirements
- Types of stability Chemical Physical Microbiological
Therapeutical Toxicological
- Stability evaluation for different formulations 1.Tablets odour
colour assay degradation products dissolution moisture
hardness/friability.
- 2. Capsules appearance (including brittleness) colour odour of
content, assay, degradation products, dissolution, moisture and
microbial content.
- 3. Emulsions appearance (including phase separation), colour,
odour, assay, pH, viscosity, microbial limits, preservative
content, and mean size and distribution of dispersed globules.
- 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.
- 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
- 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).
- -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
- 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.
- 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.
- Shelf life estimation
- 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.
- 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
- 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.
- 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)
- Arrhenius plot:
- 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.
- Predicting drug stability at room temperature by Arrhenius
plot
- 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
- Time in days required for drug ptency at fall 90% t90 are than
plotted on a log scale
- 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
- Long term stability studies
- 2 side 95% confidence limit
- 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.
- 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.
- 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:
- 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
- Drug substance General case Study Storage condition Minimum
time period covered by data at submission Long term 25C 2C / 60% 5%
r.h or 30C 2C / 65% 5% r.h. 12 months Intermediate 30C 2C / 65% 5%
r.h. 6 months Accelerated 40C 2C / 75% 5% r.h. 6 months
- Drug substances intended for storage in a freezer Study Storage
condition Minimum time period covered by data at submission Long
term -20C 5C 12 months
- Drug substances intended for storage in a refrigerator Study
Storage condition Minimum time period covered by data at submission
Long term 5C 3C 12 months Accelerated 25C 2C / 60% 5% r.h. 6
months
- Drug product general case Study Storage condition Minimum time
period covered by data at submission Long term 25C 2C / 40% 5% r.h.
or 30C 2C / 35% 5% r.h. 12 months Intermediate 30C 2C / 65% 5% r.h.
6 months Accelerated 30C 2C / 65% 5% r.h. 6 months
- Storage in refrigerator Study Storage condition Minimum time
period covered by data at submission Long term 5C 3C 12 months
Accelerated 25C 2C / 60% 5% r.h. 6 months
- THANK YOU