Primary stability data

Where applicable, an appropriate statistical method should be employed to analyze the long term primary stability data. The purpose of this analysis is to establish, with a high degree of confidence, a shelf life during which a quantitative attribute will remain within acceptance criteria for all future batches manufactured, packaged, and stored under similar circumstances. 

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 drug substance should be adequately characterized (i.e., results of chemical, physical, and, when applicable, biological testing). Material produced at different sites should be of comparable quality. In general, 3 to 6 months of stability data on one to three site-specific drug substance batches, depending on the availability of sufficient primary stability data from another site, should be provided at the time of application submission. 

Primary Stability Data [ICH Q1 A] — Data on the drug substance stored in the proposed packaging under storage conditions that support the proposed retest date. Data on the drug product stored in the proposed container and closure for marketing under storage conditions that support the proposed shelf life. 

Supporting Stability Data [ICH Q1A] — Data other than the primary stability data, such as stability data on... 

Primary container-closure system-related data will need to cover storage, transportation, and use. The choice of materials of construction, their description, and the ability of the container-closure system to protect from moisture and/or light will need to be considered. The compatibility of the container-closure and its contents will need to consider sorption, leaching, and safety. The performance of the container-closure system will also need to be considered in terms of dose delivery from any associated device that is to be supplied as part of the product. Container-closure components will require adequate specifications covering description, identification, critical dimensional tolerances, and test methodology (including pharma-copeial and noncompendial methods). More data are likely to be required for liquid or semi-liquid products than for solid dosage forms. In the latter, product stability data and container-closure system specifications may suffice. 

The primary application of the VSP is to obtain data necessary to calculate the vent design (size and relief setting) for emergency venting of nonvolatile and reactive runaway systems. The calculated vent design is to limit the maximum pressures at the point of emergency venting to acceptable levels. A secondary application is to provide thermal stability data for reactive systems. 

Stability data should be generated on at least three primary batches, which should be manufactured to a minimum of pilot scale by the same synthetic route and manufacturing process as the production batches. The quality of the API placed on a formal stability program should be similar to the quality of the material to be made on a commercial production scale. The container closure system must be the same or simulate the packaging proposed for storage and distribution of marketed product. 

Stability data should be generated on at least three primary batches of the drug product, with the manufacturing process simulating the production batches, with... 

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. 

Developing stability data for an ANDA product generally requires fewer laboratory studies than those required with an NCE. The primary goal of an ANDA should be to mimic the stability profile of the innovator product, barring any intellectual property issues that might prevent the generic manufacturer from formulating a sim-... 

Where long term data are not amenable to statistical analysis, but relevant supporting data are provided, the proposed shelf life can be up to one-and-a-half times, but should not be more than 6 months beyond, the period covered by long term data. Relevant supporting data include satisfactory long term data from development batches that are (/) made with a closely related formulation to, ( /) manufactured on a smaller scale than, or (/7/) packaged in a container closure system similar to, that of the primary stability batches. 

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. 

Data on laboratory scale batches is not acceptable as primary stability information. Data on associated formulations or packaging may be submitted as supportive information. The first three production batches manufactured post approval, if not submitted in the original Registration Application, should be placed on accelerated and long term stability studies using the same stability protocols as in the approved drug application. 

If the complete stability data generated on the first three annual batches under the ICH long-term conditions using an approved alternate protocol (as defined above) support the previously approved expiration dating period under the non-ICH conditions, the alternate stability protocol can be adopted as the primary stability protocol through an annual report. 

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