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Significant Change in Pharmaceutical Stability Testing

When the changes in results of pharmaceutical products during their stability testing are reported as significant change.
Stability of the pharmaceutical products is determined by storing the product under Accelerated and Long Term Conditions. The product is then analyzed at different time stations for any significant change in physical or chemical condition.

Significant Change“Significant Change” is an important or remarkable change in any physical or chemical condition of the pharmaceutical product. These changes may occur in product during the stability study of drug product.
According to ICH “significant change” 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 (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;
and, as appropriate for the dosage form:
4. Failure to meet the acceptance criterion for pH; or
5. Failure to meet the acceptance criteria for dissolution for 12 dosage units.

These changes in Accelerated storage conditions are considered as a significant change for drug products. For any drug substance significant change is failure of substance to meet the specification.
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 98% then the significant change will be 93%. It will not be 5% of 98%. 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.
ICH Q1E says, when gelatin capsule and gel-coated tablets fails to meet the specification of dissolution, it will not be a significant change if no other significant change is found. If phase separation of the semisolid product or liquid oral dosage forms occurs during the accelerated storage conditions, testing at intermediated storage conditions should be done.

Also see: Shelf Life Estimation of Pharmaceutical Products

Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of Pharmaceutical Guidelines, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
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atul sharma said... on 9/9/14 19:24

all these changes are for accelerated as well as long term?

Pseidy Mamani said... on 20/10/16 01:44

If I am doing accelerated test for a cream of tretinoin, and the pharmacopoeia monograph accept contains not less than 90 and no more that 120%. Are some change in the limit of 5% like a "significant change " in my study?

Unknown said... on 18/9/17 00:43

Very nice notes. Easily understandable. Thank you sir

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