Significant change for a drug substance is defined as failure to meet its specification during stability testing.
Stability of a pharmaceutical product may be defined as the capability of a particular formulation in a specific container/closure system to remain within its physical, chemical, microbiological, toxicological, protective and informational specifications.
Pharmaceutical product stored under accelerated and long term condition for stability determination.
During Stability testing any changes in physical and chemical condition of pharmaceutical product will be consider as a “Significant change”.
According to ICH guideline “Significant change” for a drug product is defined as:
1. A 5 percent 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 (e.g., color, phase separation, resuspendibility, caking, hardness, dose delivery per actuation). However, some changes in physical attributes (e.g., softening of suppositories, melting of creams) may be expected under accelerated conditions.
4. Failure to meet the acceptance criterion for pH.
5. Failure to meet the acceptance criteria for dissolution for 12 dosage units.
Above up changes in Accelerated condition are considered as a significant change for drug product.
5% change in assay is absolute change in the initial result; it means direct 5% from initial value. For example ‐ if initial assay of any product is 100% then the significant change will be 95%. It will not be 5% of 100%. But if assay is analyzed by biological method, results below the acceptance criteria will be considered as significant change because biological methods have less accuracy and may produce fluctuated results.
Failure to meet the specification for related substances, physical appearance, moisture content, hardness, friability, solubility, pH and other similar tests is considered as significant change in pharmaceutical substances and products.
Significant change in dissolution test is when product fails to meet the specification in S2 stage i.e. 12 dosage units are used in analysis.
According to ICH Q1E the following physical changes can be expected to occur at the accelerated condition and would not be considered significant change that calls for intermediate testing if there is no other significant change:
1. Softening of a suppository that is designed to melt at 37ºC, if the melting point is clearly demonstrated,
2. Failure to meet acceptance criteria for dissolution for 12 units of a gelatin capsule or gel-coated tablet if the failure can be unequivocally attributed to cross-linking.
However, if phase separation of a semi-solid dosage form occurs at the accelerated condition, testing at the intermediate condition should be performed. Potential interaction effects should also be considered in establishing that there is no other significant change.