Stability Testing Of New Drug Substances And Products

STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS Mr. AGNIMITRA DINDA SCHOOL OF PHARMACEUTICAL SCIENCES INDIA

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 ClimatesTropical Wet: Average temperature 26°C, Relative Humidity (RH) 70-100% Tropical Wet and Dry : Temperature range 8-40°C, RH 50100% 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 1040°C, RH higher than in Subt Dry.

4. Temperate Climates: ♦ Temperate Oceanic: Temperatures from 0-18°C, RH 6080%, ♦ Temperate Continental: Temperatures 12-24°C, RH 6090%. 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

STABILITY REPORT AS FDA SUGGEST: • 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(f) Sampling times. 2. Expected duration of the study.

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

STABILITY REPORT AS FDA SUGGEST: E. Data analysis and conclusions: 1 Documentation of appropriate scientific methods used and their formulas. 3. Evaluation of data, including calculations, statistical analysis, plots and graphics. 3. Statistical analysis of biological potency estimates. 4. Proposed expiration data and its justification.

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) : Designation

Long-term testing

Conditions

Minimum time storage period at submission

25°C ± 2°C/60% RH ± 5% 12 months

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

6 months

• 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.