| OBJECTIVE | DRUG SUBSTANCE | DRUG PRODUCT | |||||||||||||||||||||||||||
2.1.1. General | Stability of the drug substance is an integral part of the systematic approach to stability evaluation | The design should be based on knowledge of the behavior and properties of the drug substance and from stability studies on the drug substance. | |||||||||||||||||||||||||||
2.1.2. Stress Testing/ Photostability Testing | To be carried out on a single batch of the drug substance including the effect of temperatures; humidity; oxidation; hydrolysis and photolysis on the drug substance | To be conducted on at least one primary batch of the drug product. (ICH Q1 B) | |||||||||||||||||||||||||||
| 2.1.3. Selection of Batches | 3 primary batches – manufactured to a minimum of pilot scale by the same synthetic route as, and using a method of manufacture and procedure that simulates the final process | 3 primary batches – of the same formulation and packaged in the same CCS | |||||||||||||||||||||||||||
| 2.1.4. Container Closure System | Testing to 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 | Testing to be conducted on the dosage form packaged in the container closure system proposed for marketing. | |||||||||||||||||||||||||||
| 2.1.5. Specification | It include testing of those attributes of the drug substance that are susceptible to change during storage and are likely to influence Q, S, E | It include testing of those attributes of the drug product that are susceptible to change during storage and are likely to influence Q, S, E | |||||||||||||||||||||||||||
2.1.6. Testing Frequency | LT – (0, 3, 6, 9, 12, 18, 24, 36) Accelerated – 0, 3 and 6-months | LT – (0, 3, 6, 9, 12, 18, 24, 36) Accelerated – 0, 3 and6-months | |||||||||||||||||||||||||||
| 2.1.7. Storage Conditions | |||||||||||||||||||||||||||||
| “Significant change” For a drug substance is defined as failure to meet its specification. For a drug product is defined as: 1. A 5% change in assay from its initial value; or failure to meet the acceptance criteria for potency when using biological or immunological procedures; 2. Any degradation product’s exceeding its acceptance criterion; 3. Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test; however, some changes in physical attributes may be expected under accelerated conditions; and, as appropriate for the dosage form: 4. Failure to meet the acceptance criterion for pH; or dissolution for 12 dosage units. If significant change occurs: – Within the first 3 months’ testing at the accelerated storage condition, a discussion should be provided. – Between 3 and 6 months’ testing at the accelerated storage condition, the proposed re-test period should be based on the real time data | 2.1.7.1 General case
2.1.7.2. Intended for storage in refrigerator
2.1.7.3. Drug substances intended for storage in a freezer
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| 2.1.8. Stability Commitment | 1. If the submission includes data from stability studies on at least three batches, a commitment should be made to continue these studies through the proposed re-test period. 2. If the submission includes data from stability studies on fewer than three batches, a commitment should be made to continue these studies through the proposed re-test period and to place additional production batches, to a total of at least three, on long term stability studies through the proposed re- test period. 3. If the submission does not include stability data on batches, a commitment should be made to place the first three production batches on long term stability studies through the proposed re-test period. | ||||||||||||||||||||||||||||
2.1.9. Evaluation | The purpose is to establish, based on testing a minimum of three batches of the drug substance and evaluating the stability information. The data may show so little degradation and so little variability | The purpose is to establish, based on testing a minimum of three batches of the drug product, a shelf life and label storage instructions applicable to all future batches of the drug product manufactured and packaged under similar circumstances. | |||||||||||||||||||||||||||
2.1.10. Statements/Labeling | The statement should be based on the stability evaluation of the drug substance. | The statement should be based on the stability evaluation of the drug product. An expiration date should be displayed on the container label. | |||||||||||||||||||||||||||
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