9 A general acceptance criterion of not more than the identification threshold

9 a general acceptance criterion of not more than the

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with relative retention of 0.9”). A general acceptance criterion of not more than ( ) the identification threshold (Attachment 1) for any unspecified degradation product and an acceptance criterion for total degradation products should also be included. For a given degradation product, its acceptance criterion should be established by taking into account its acceptance criterion in the drug substance (if applicable), its qualified level, its increase during stability studies, and the proposed shelf life and recommended storage conditions for the new drug product. Furthermore, each acceptance criterion should be set no higher than the qualified level of the given degradation product. Where there is no safety concern, degradation product acceptance criteria should be based on data generated from batches of the new drug product manufactured by the proposed commercial process, allowing sufficient latitude to deal with normal manufacturing and analytical variation and the stability characteristics of the new drug product. Although normal manufacturing variations are expected, significant variation in batch-to-batch degradation product levels can indicate that the manufacturing process of the new drug product is not adequately controlled and validated (see ICH Q6A guideline on specifications, decision tree #2, for establishing an acceptance criterion for a specified degradation product in a new drug product). In this guideline, the use of two decimal places for thresholds (See Attachment 1) does not necessarily indicate the precision of the acceptance criteria for specified degradation products and total degradation products. In summary, the new drug product specification should include, where applicable, the following list of degradation products: Each specified identified degradation product Each specified unidentified degradation product Any unspecified degradation product with an acceptance criterion of not more than ( ) the identification threshold Total degradation products. VI QUALIFICATION OF DEGRADATION PRODUCTS Qualification is the process of acquiring and evaluating data that establishes the biological safety of an individual degradation product or a given degradation profile at the level(s) specified. The applicant should provide a rationale for establishing degradation product acceptance criteria that includes safety considerations. The level of any degradation product present in a new drug product that has been adequately tested in safety and/or clinical studies
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© EMEA 2006 7 would be considered qualified. Therefore, it is useful to include any available information on the actual content of degradation products in the relevant batches at the time of use in safety and/or clinical studies. Degradation products that are also significant metabolites present in animal and/or human studies are generally considered qualified. Degradation products could be considered qualified at levels higher than those administered in safety studies based on a
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