STABILITY TESTING OFNEW DRUG SUBSTANCES AND

PRODUCTS

Mr. AGNIMITRA DINDASCHOOL OF PHARMACEUTICAL

SCIENCESINDIA

STABILITY STUDIES :

• Stability is defined as the extent to which a product retains, within specified limits and throughout its period of storage and use (i.e., its shelf-life), the same properties and characteristics that it possessed at the time of its manufacture.

CRITERIA FOR ACCEPTABLE LEVELS OF STABILITY:

• Chemical • Physical• Microbiological• Therapeutic• Toxicological

PURPOSE OF STABILITY STUDIES IN ACTIVE INGREDIENT :

• To ascertain suitability of the active ingredient for particular product shelf life.

• To ascertain shelf life of the product.

• To determine storage condition of the product.

QUALITY OF PHARMACEUTICAL PREPARATION TO BE ASSESSED :• The active ingredient content; • Product safety (e.g. appearance of toxic

degradation products); • Physical appearance of the product; • The content of other important components

of the formulation ( e.g. antimicrobial preservatives);

• Purity (limits or absence of degradation products of the active ingredient);

• Physical properties of the dosage form, Microbial properties;

• Properties of the container/closure system; • Organoleptic properties (taste, odour, etc.)

CLASSIFICATION OF CLIMATIC ZONES :

1. Tropical Humid Climates- Tropical Wet: Average

temperature 26°C, Relative Humidity (RH) 70-100%

Tropical Wet and Dry : Temperature range 8-40°C, RH 50-100% RH

2. Dry climates - ♦Arid (hot and dry): Temperatures up to

50°C, RH 10-50%, ♦Semi-arid: Temperatures 10-35°C.

3. Subtropical Climates ♦Subtropical Dry: Temperatures 10-40°C,

RH 50-80% ♦Subtropical Humid: Temperatures 10-

40°C, RH higher than in Subt Dry.

4. Temperate Climates: ♦ Temperate Oceanic:

Temperatures from 0-18°C, RH 60-80%,

♦ Temperate Continental: Temperatures 12-24°C, RH 60-90%.

5. Sub Arctic Climate 6. Polar Climate: Average

temperature below 0°C. 7. Highland Climates

Mean Kinetic Temperature: • It is defined as a singled calculated

temperature at which, the degradation of an article would be equivalent to the actual degradation that would, result from temperature fluctuations during the storage period.

Climatic Conditions

Zone I Zone II Zone III Zone IV

Mean annual Temperature

20.50C 20.5 - 240C > 240C >240C

Kinetic mean Temperature

210C 260C 310C 310C

Mean annual Relative Humidity

45% 60% 40% 70%

DEGRADATION PRODUCTS :

• Identity and chemical structure- • Cross-reference to any available

information about biological effect and significance at the concentrations likely to be encountered.

• Procedure for isolation and purification. • Mechanism of formation, including order

of reaction. • Specifications and directions for testing

for their presence at the levels or concentrations expected to be present.

• Indication of pharmacological action or inaction.

STABILITY REPORT AS FDA SUGGEST:

• A. General product information: 1. Name of the drug substance/product. 2. Dosage form and strength (including

formulation). 3. Labeling.4. Composition, type and size of

container and closure

• B. Specifications and test methodology information:

1. Physical, chemical and microbiological characteristics and proposed specification.

2. Test methodology used on each sample. 3. Analytical validation data on test methods

used. 4. Description of any biological potency tests.

STABILITY REPORT AS FDA SUGGEST:

C. Study design and study conditions : 1. Description of the sampling plan including (a) Batches and number selected. (b) Container-closure and number

selected. (c) Number of dosage units selected and

whether test conducted on individual units or on a composite sample-

(d)Sampling times.2. Expected duration of the study. 3. Conditions of storage of the product under

study (temperature, humidity and light).

STABILITY REPORT AS FDA SUGGEST:

D. Stability data/information: 1. Lot number, scale of manufacture

(research, pilot, production), and date of manufacture.

2. For antibiotic products, the age of the bulk antibiotic used in the manufacture.

3. Analytical data and source of each data point (e.g. lot, container, composite, etc.).

4. Summary of information previously submitted during development.

STABILITY REPORT AS FDA SUGGEST:

E. Data analysis and conclusions: 1 Documentation of appropriate scientific

methods used and their formulas. 2. Evaluation of data, including

calculations, statistical analysis, plots and graphics.

3. Statistical analysis of biological potency estimates.

4. Proposed expiration data and its justification.

STABILITY REPORT AS FDA SUGGEST:

GUIDELINES OF ICH FOR STABILITY TESTING

(A) NEW ACTIVE DRUG SUBSTANCE

1. Formal Studies:

• Primary stability studies are done to show that drug substance will remain within specifications during the retest period if stored under recommended storage conditions.

2. Selection of Batches:

• At least 3 batches over at least 12 months under accelerated & long term (real) storage.

3. Batch Size :

• Pilot scale batch size, manufactured by the same synthetic route that simulates the final process to be used on a manufacturing scale.

4. Test Method :

• Testing should cover all aspects likely to be changed during storage and also likely to influence quality, safety & efficacy of the drug substance.

5. Specification for the Drug:• The limit of acceptance set from the

stability data. Limits of degradation products to be justified from the levels seen in clinical studies.

6. Storage Test Condition: • The length should cover storage,

shipment & subsequent use. 7. Testing Frequency: • 3 monthly for first year. • 6 monthly over the second year

and then annually.

8. Packaging Containers: • The actual packaging container used for

storage and distribution.

9. Labeling: • Specific storage temperature to be

mentioned as' Store below 30°C. , Additional warning about light exposure, humidity etc. should also be given. The use of terms such as 'ambient temperature' or 'room temperature' is unacceptable.

TESTING CONDITIONS FOR DRUG SUBSTANCE(AN EXAMPLE) :

• Where signified changes occurs during six months storage under conditions accelerated testing at 40°C + 2°C/75% RH + 5%, additional testing at an intermediate condition, e.g., 30°C + 2°C/60 + 5% RH should be conducted. Significant change, 40°C/75% RH or 30°C/60% RH is defined

as failure to meet the specifications.

Designation Conditions Minimum time storage period at submission

Long-term testing 25°C ± 2°C/60% RH ± 5% 12 months

Accelerated testing 40°C ± 2°C/75% RH ± 5% 6 months