Stability testing

DRUG STABILITY

INDEX

Introduction

Advantages

Types

Stability evaluation for different formulations

Shelf life estimation

Overage calculation

ICH guidelines

“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 pateint

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

(ointments, creams, lotions, paste, gel,solutions and non-metered aerosols forapplication to the skin)

-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 &

overage calculation

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 equationReaction 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”.

Accelerated breakdown of a drug in solution at various elevated temperature

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.

Log plot of t90 against reciprocal temperature

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 25°C ± 2°C / 60% ± 5% r.h or30°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

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

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

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. or30°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

Storage in refrigeratorStudy 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

THANK YOU