Primary batches

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. 

Stability testing of the drug product after constitution or dilution, if applicable, should be conducted to provide information for the labeling on the preparation, storage condition, and in-use period of the constituted or diluted product. This testing should be performed on the constituted or diluted product through the proposed in-use period on primary batches as part of the formal stability... 

The long-term testing should cover a minimum of 12 months duration on at least three primary batches at the time of submission and should be continued for a period of time sufficient to cover the proposed shelf life. Additional data accumulated during the assessment period of the registration application should be submitted to the... 

Data from stability studies should be provided on at least three primary batches of the drug product. The primary batches should be of the same formulation and packaged in the same container closure system as proposed for marketing. The manufacturing process used for primary batches should simulate that to be applied to production batches and should provide product of the same quality and meeting the same specification as that intended for marketing. 

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. 

The same stability protocol used for the primary batches must be used for the stability commitment unless scientifically justified otherwise. In this case prior agreement with the regulatory agencies is recommended. 

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. 

The stability protocol used for long-term studies for the stability commitment should be the same as that for the primary batches, unless otherwise scientifically justified. 

For ANDAs, the primary batch or batches to support the application are usually manufactured in the production facility. If the primary stability batch or batches are not made at the intended commercial site, stability data should be generated on the drug product manufactured at that site, that is, site-specific batches, and the data should be included in the original submission to demonstrate that the product made at each site is equivalent. 

The main activities are similar for small molecules and macromolecules at this stage. The primary focus is in the areas of scale-up, generation of primary batches... 

Q1A(R2) also indicates that the commitment batches must be placed on stability with the same protocol as submission batches. Therefore, if there is signiticant change on the accelerated conditions of the primary batches and samples of intermediate conditions must be tested, then samples of intermediate condition of three production batches must also be tested. 

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