INDEXIntroductionAdvantagesTypesStability evaluation for different formulationsShelf life estimationOverage calculationICH guidelines
“A measure of how pharmaceutical productmaintains 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 ofconcentrataion of drug in dosage formtoxic product may form due to degradation ofactive ingridients
Advantages of stability studies Assurance to the pateint Economic consideration Legal requirements
Types of stability Chemical Physical Microbiological Therapeutical Toxicological
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 aerosolsforapplication 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
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 ofcollisions per unit time (of reactant molecules).The number of collisions increases as thetemperature increases. Therefore, the reactionrate increases as the temperature increasesaccording to Arrhenius equation.
K = reaction rate constantA = frequency factor constant i.e maximumnumber of collisions at infinite temperatureEa = Energy of activationT = absolute temperature (Kelvin)
Arrhenius plot: Click to edit Master text styles Second level Third level Fourth level Fifth level
1.According to the Garrett and carper “thek value for decompostion of a drug insolution at various elevated temperature areobtained by plotting some function ofconcentration against time”.
Accelerated breakdown of a drug in solution at various elevated temperature
2. The log of specific rates ofdecomposition are than plotted aginst thereciprocal of the absolute temperature andthe resulting line are extraplotted to roomtemperature
Predicting drug stability at room temperature by Arrheniusplot
3. Free and Blythe suggested a similarmethod in which the fractional life period isplotted against reciprocal temperature, andthe time in days required for the drug todecompose to some fraction of its originalpotency at R.T is obtained.
Log plot of t90 against reciprocal temperature
4. The log % of the drug remaining isplotted against time in days and the timefor the potency to fall to 90% of theoriginal value i.e t90 is read from the graph.The log time to 90% is then plotted against1/T and the time at 25 degree c gives theshelf life of the product in days
Time in days required for drug ptency at fall 90% t90 are than plotted on a logscale
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 Click to edit Master text styles Second level Third level Fourth level Fifth level
2 side 95%confidencelimit
OverageIt is over loading the dosage form with moredrug 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.
Click to edit Master text styles Second level Third level Fourth level Fifth level
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 onDrug 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 Minimum time period Storage condition covered by data at Study submissionLong term 25°C ± 2°C / 60% ± 5% 12 months r.h or 30°C ± 2°C / 65% ± 5% r.h.Intermediate 30°C ± 2°C / 65% ± 5% 6 months r.h.Accelerated 40°C ± 2°C / 75% ± 5% 6 months r.h.
Drug substances intended for storage in a freezerStudy Storage condition Minimum time period covered by data at submissionLong term -20°C ± 5°C 12 months
Drug substances intended for storage in a refrigeratorStudy Storage condition Minimum time period covered by data at submissionLong term 5°C ± 3°C 12 monthsAccelerated 25°C ± 2°C / 60% ± 5% 6 months r.h.
Drug product general caseStudy Storage condition Minimum time period covered by data at submissionLong term 25°C ± 2°C / 40% ± 5% 12 months r.h. or 30°C ± 2°C / 35% ± 5% r.h.Intermediate 30°C ± 2°C / 65% ± 5% 6 months r.h.Accelerated 30°C ± 2°C / 65% ± 5% 6 months r.h.
Storage in refrigeratorStudy Storage condition Minimum time period covered by data at submissionLong term 5°C ± 3°C 12 monthsAccelerated 25°C ± 2°C / 60% ± 5% 6 months r.h.