Re-test period

The long-term testing is required to be continued for a sufficient period beyond 12 months to cover all appropriate re-test periods. The frequency of testing should be... 

If the submission includes long-term storage data on three production batches through the proposed re-test period, no postapproval commitment is needed. Even though no further commitment is required, it is recommended that one production-sized batch be selected for stability testing annually to monitor stability of future batches over time. 

If the submission does not include long-term storage data on the primary batches through the proposed re-test date, the studies should be continued through the postapproval phase to establish the re-test period. 

If the submission includes stability data on at least three production batches, a commitment to continue testing through the proposed re-test period must be made. 

Studies that show virtually no degradation or variability will usually not require any formal statistical analysis. Under these circumstances the requested re-test period is normally granted when a complete justification for not needing a statistical analysis is part of the submission. The analysis should include all appropriate properties of the drug substance. 

The normal and acceptable statistical approach for analyzing quantitative properties that change over time is to calculate the time it takes for the 95% one-sided confidence limit for the mean degradation curve to intersect the acceptable specification limit. If the data show that batch-to-batch variability is small, it may be worthwhile to combine the data into one overall estimate. This can be done by first applying the appropriate statistical tests to the slopes of the regression lines and zero time intercepts for the individual batches. If the data from the individual batches cannot be combined, the shortest time interval any batch remains within acceptable limits may determine the overall re-test period. 

Extrapolation of the real-time data from the long-term stability condition to support a re-test period longer than the real-time data can be proposed. The proposal should be supported by the accelerated data, by knowledge of the degradation mechanism, by additional stability data from batches other than the primary batches that might be available, and the goodness of fit of the mathematical model used in the statistical analysis. 

In ICH QIA(R), data evaluation is addressed. For data that show little degradation and little variability, it is apparent from looking at them that the requested re-test period should be granted. Under these circumstances, it is... 

Limited extrapolation of the real-time data from the long-term testing storage condition beyond the observed range to extend the re-test period at approval time may be undertaken, particularly if the accelerated data are supportive. However, this assumes that the same degradation relationship will continue to apply beyond the observed data. Hence the use of extrapolation should be minimized but can be justified in an application in terms of what is known about the mechanism of degradation, the goodness of fit of any mathematical model, batch size, and existence of supportive data. 

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 enables recommended storage conditions, re-test periods and shelf lives to be established. 

Primary stability studies are intended to show that the drug substance will remain within specification during the re-test period if stored under recommended storage conditions. 

A re-test period should be derived from the stability information. 

Stability evaluation of the physical, chemical, biological and microbiological characteristics of a drug product and a drug substance, covering the expected duration of the shelf life and re-test period, which are claimed in the submission and will appear on the labelling. 

Data other than primary stability data, such as stability data on early synthetic route batches of drug substance, small scale batches of materials, investigational formulations not proposed for marketing, related formulations, product presented in containers and/or closures other than those proposed for marketing, information regarding test results on containers, and other scientific rationale that support the analytical procedures, the proposed re-test period or shelf life and storage conditions. 

A competent authority is also at liberty to request more appropriate specifications if it considers that the monograph is insufficient to assure adequate qualify of the substance. Further to the examples given above which result fi om differences in the synthesis route, additional tests may be required for particle size, polymorphic form, microbial contamination and sterility as necesseury to ensure the correct performance of the starting material in the finished medicinal product. Limits which are tighter than the pharmacopoeial specification may be imposed if appropriate for the particular product in question. In addition, the competent authority will require stability data for active substances on which to base the storage conditions for the drug substance and its re-test period (the period of time for which it is expected to remain within specification and after which it must be re-tested for compliance and used immediately). 

Full information on the batches tested and their packaging, the test methods (description and validation) and results and proposals for re-test period and shelf-life must be included in the dossier, together with details of any on-going studies. 

The maximum inspection and re-test period for a domestic electrical installation is ... 

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