Impurities identification threshold

Identification Threshold A limit above (>) which an impurity should be identified. 

Attempts at structural identification of the compound are expected for impurities above the identification threshold. The evaluation of biological safety is expected above the qualification threshold. 

However, analytical procedures should be developed for those potential impurities that are expected to be unusually potent, producing toxic or pharmacological effects at a level not more than the identification threshold. (From Refs. 55 and 56.)... 

A 0.1% threshold for identification and isolation of impurities from all new molecular entities is under consideration by the International Conference on Harmonization as an international regulatory standard [4,5]. However, where there is evidence to suggest the presence or formation of toxic impurities, identification should be attempted. An example of this is the 1500 reports of Eosinophilia-Mylagia Syndrome and more than 30 deaths associated with one impurity present in L-tryptophan which were present at the 0.0089% level [6]. 

Table 2 ICH Q3B(R) reporting and identification thresholds for impurities in drug product...

The studies conducted to characterize the structure of actual impurities present in the new drug substance at a level greater than 0.1% (depending on the daily dose, calculated using the response factor of the drug substance) should be described. Note that all specified impurities at a level greater than the identification threshold in batches manufactured by the proposed commercial process should be identified. 

A rationale for the inclusion or exclusion of impurities in a specification should be presented. The rationale should include a discussion of the impurity profiles observed in the safety and clinical development batches, together with a consideration of the impurity profile of batches manufactured by the proposed commercial process. Specified, identified impurities should be included along with specified, unidentified impurities estimated to be present at a level greater than the identification threshold given. For impurities known to be tmu-sually potent or that produce toxic or unexpected pharmacological effects, the quantification/detection limit of the analytical procedures should be commensurate with the level at which the impurities should be controlled. For unidentified impurities, the procedure used and assumptions made in establishing the level of the impurity should be clearly stated. Specified, unidentified impurities should be referred to by an appropriate qualitative analytical descriptive label (e.g., "unidentified A," "unidentified with relative retention of 0.9"). A general acceptance criterion of not more than the identification threshold for any unspecified impurity and an acceptance criterion for total impurities should be included. 

Table 1.1 Limits or thresholds for the reporting, identification, and qualification of impurities...

ICH Q3 A(R) [8] provides a clear guidance for the control of the organic impurities. Table 1.1 describes the hmits or thresholds for the reporting, identification, and qualification of the impurities based on the maximum daily dose of the drug substance administered per day. 

Table 8.1 ICH guidelines for reporting, identification, and qualification thresholds for impurities in drug substances and drug products [7, 8]...

In general, the detection and identification of impurities present in API and formulations play an integral role in the drug development process and methods need to be developed to adequately resolve these species and quantitate them. The International Conference on Harmonization (ICH) [3] has published a guidehnes on impurities in new drug substances and new drug products (see Table 8-1). The acceptable limit of the impurities in drug substances is dependent upon the maximum daily dose and the quahfication threshold however, lower thresholds are sometimes deemed necessary if the... 

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