Substances Intended for Storage below

Drug substances intended for storage below -20°C should be treated on a case-by-case basis. When available longterm stability data on primary batches do not cover the proposed retest period granted at the time of approval, a commitment should be made to continue the stability studies postapproval to firmly establish the retest period. 

Where the submission includes long-term stability data on three production batches covering the proposed retest period, a postapproval commitment is considered unnecessary. Otherwise, one of the following commitments should be made  

An approach for analyzing the data on a quantitative attribute that is expected to change with time is to determine the time at which the 95%, one-sided confidence limit for the mean curve intersects the acceptance criterion. If analysis shows that the batch-to-batch variability is small, it is advantageous to combine the data into one overall estimate. This can be done by first applying appropriate statistical tests (e.g., P . 25 for level of significance of rejection) to the slopes of the regression lines and the zero-time intercepts for the individual batches. If it is inappropriate to combine data from several batches, the overall retest period should be based on the minimum time a batch can be expected to remain within acceptance criteria. 

The nature of any degradation relationship will determine whether the data should be transformed for linear regression analysis. Usually, the relationship can be represented by a linear, quadratic, or cubic function on an arithmetic or logarithmic scale. Statistical methods should be employed to test the goodness of fit of the data from all batches and combined batches (where appropriate) to the assumed degradation line or curve. 

A storage statement should be established for the labeling in accordance with relevant national and regional requirements. The statement should be based on the stability evaluation of the drug substance. Where applicable, specific instructions should be provided, in particular for 

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