STABILITY ?

STABILITY ? The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light, and to establish a re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions.

CLASSIFICATION OF STABILITY STUDIES ? Long term Stability Accelerated Stability Intermediate Stability

WHY - STABILITY ? To establish the i) Degradation pathways and intrinsic stability of molecules . ii) To test the attributes influencing the quality & safety of drug during storage. iii) The impact of these factors are modulated by the type of container or packaging quality.All these factors jointly attributes to the shelf life of the products. .

FREQUENCY OF VARIOUS STABILITY STUDIES For long term studies, frequency of testing should be proposed re-test period of at least 12 months, normally be every 3 months over the first year, every 6 months over the second year, and annually thereafter through the proposed re-test period. At the accelerated storage condition, a minimum of three time points, including the initial and final time points (e.g., 0, 3, and 6 months), from a 6-month study is recommended. Where an expectation exists that results from accelerated studies are likely to approach significant change criteria,increased testing should be conducted.

FREQUENCY OF VARIOUS STABILITY STUDIES When testing at the intermediate storage condition is called for as a result of significant change at the accelerated storage condition, a minimum of four time points (e.g., 0, 6, 9, 12 months), from a 12-month study is recommended.

ZONES The choice of test conditions defined,is based on an analysis of the effects of climatic conditions in the three regions of the EC, Japan and the United States. The mean kinetic temperature in any part of the world can be derived from climatic data, and the world can be divided into four climatic zones, I-IV. Dividing the world according to temperature and humidity zone Zone - I : Temperate Climatic zones Zone - II : Mediterranean/Sub tropical Climatic zones Zone - III : Hot Dry Climatic zone Zone - IV : Hot Tropical humid climatic zone

CONCEPT BEHIND ZONES ZONE - I ZONE- II ZONE-III ZONE-IV CLIMATIC CONDITION ZONE - I ZONE- II ZONE-III ZONE-IV Mean annual temp. 20.5°C 20.5°–24.0°C >24.0°C Kinetic mean 21.0° C 26.0°C 31.0°C relative humidity 45% 60% 40% 70%

STORAGE CONDITIONS FOR STABILITY STUDIES The long term studies performed at 25°C ± 2°C/60% RH ± 5% RH for minimum of 12 months’ duration and should be continued for a period of time sufficient to cover the proposed re-test period. The Accelerated studies conducted at 40°C ± 2°C/75% RH ± 5% RH 6 months Intermediate studies conducted at 30°C ± 2°C/65% RH ± 5% RH for 6 months The other storage conditions can also be followed if justified. Heat sensitive drugs are stored at alternative lower temperature conditions which eventually becomes designated long term storage condition

STORAGE CONDITIONS FOR STABILITY STUDIES The six months Accelerated testing carried out at the temperature at least 15°C above its designated long term storage temperature together with appropriate relative humidity conditions for the temperature(e.g. if a product is to be stored at refrigerated conditions 2-8°C , Accelerated testing is conducted at 25°C + 2% / 60% + 5% RH )

SELECTION OF BATCHES At least three primary production batches of the drug substance should be taken for stability studies. Thereafter one batch should be taken every year of each product from production batches.

SAMPLING METHOD / QUANTITIES Product Sampling Qty. Method Study Period The stability studies should be conducted on the drug substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution. Product Sampling Qty. Method Study Period Capsules 400 LTS, ASS & ISS LTS – 36 Months ASS – 6 Months ITS – 12 Months Tablets Injection 120 Dry Syrup 40

ACCEPTANCE CRITERIA The testing should cover, as appropriate, the physical,chemical, biological, and microbiological attributes. The possibility of identification of degradation products should be explored if some degradation product is reported (They should not be more than 5% in Assay from its initial value / Change in colour , hardness , pH, Dissolution of 12 dosage ) The stability of drug products after reconstitution or dilution according to labeling should be addressed to provide appropriate and supportive information. The stability samples should confirm to all finished product specifications. Manufacturers recommendations on these can also be an alternate criteria for acceptance .

PHOTO STABILITY Photostability testing should be conducted on at least one primary batch of the drug product if appropriate. Selection of Batches At least three primary batches of the drug product. Same formulation and packaged in the same container closure system as proposed for marketing. Manufacturing process for primary batches should same as that in production batches.

Stability studies should be performed on each individual strength and container size of the drug product unless Bracketing or Matrixing is applied.Other supporting data can be provided. Specifications : Stability studies should include testing of those attributes of the drug product that are susceptible to change during storage and are likely to influence quality, safety, and or efficacy,as appropriate, the physical, chemical, biological, and microbiological attributes, preservative content (e.g., antioxidant, antimicrobial preservative), and functionality tests (e.g., for a dose delivery system).

EVALUATION The purpose of the stability study is to establish, based on testing a minimum of three batches of the drug substance and evaluating the stability information (including, as appropriate, results of the physical, chemical, biological, and microbiological tests), applicable to all future batches of the drug substance manufactured under similar circumstances.