Impurities reporting thresholds

The outcome of planning should include the generation of a method definition requirement document (MDRD) in which all stake holders agree, prior to method development, on the critical attributes of the method. Considerations such as what impurities/degradation products should be monitored, requisite reporting thresholds, the need for an MS-compatible method, if identical methods for DP and DS are required, etc., should be clearly decided and agreed upon by all stakeholders. 

Filtered and unfiltered samples are compared for the API and the impurities. Additionally, there should be no new impurities higher than the reporting threshold detected. 

The reporting threshold is a limit above which (>) an impurity needs to be reported. The reporting threshold is determined as described by the... 

ICH guidelines, and is generally 0.05% for DS and 0.10% for DP methods. Any impurity above this level should be reported. Especially for stability indicating methods, it may be valuable to apply a lower level as the reporting threshold to allow for a better trending process for degradation products at levels below 0.05% and 0.10% for DS and DP methods, respectively. 

Unspecified impurities are those that are typically found at levels below the reporting threshold. These are typically reported by the summation of all the impurity peaks. 

Reporting Threshold A limit above (>) which an impurity should be reported. (The limit of quantification should be less or equal to the reporting threshold.)... 

Higher thresholds may be proposed with justification and qualification if the target-reporting threshold cannot be achieved. For toxic impurities and degradation products, the proposed specification limit should be much lower than that recommended in the ICH guideline to ensure the safety of the product. 

FIGURE 4.6. (a) Influence of factors on each response based on the results of the Box-Behnken design. The separation of each peak is predicted as a function of the investigated factors. The closeness of a response that is targeted for each response is presented by a desirability valued. The horizontal dotted lines predict the expected resolution value, (b) Structure of R209130 and electropherograms of the compound spiked with 1.0% of the stereoisomeric impurities (line C) under optimized separation conditions. Lines A and B represent a blank solution and the reporting threshold of 0.1%, respectively. (Adapted with permission from Reference 28.)... 

The same type of methods may have different goals for a different sample. For an API sample, its impurities must be separated from API and each other, and the limit of quantification (LOQ) for the impurities must be lower than the reporting threshold recommended in ICH Q3A(R2) guideline (12). For SM or IM, its impurities must be separated from SM or IM and from each other, and LOQs are determined by the criticality of the impurities. For a dmg product, its impurities must be separated from its API, excipients, and each other, and LOQ must be lower than the reporting threshold recommended in ICH Q3B(R2) guideline (13). 

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. 

If compounds with very low odor thresholds and very small concentrations contribute to a material s odor their detection can be very challenging, especially when only applying routine emission measurements like GC—MS. Such compounds will easily be overlooked, for their detection GC—O can often be the only choice, but so far this method is seldom used in material analysis. Instead concentrations determined by emission measurements are compared with published odor thresholds to decide whether a compound might contribute to the odor or not. One problem is that published odor thresholds can differ quite a lot, even by several orders of magnitude (van Gemert, 2003). The value depends on the method and the panel but also on the purity of the compound used for threshold determination (if small impurities of a substance with a low odor threshold were present in a sample the odor threshold determined would have been too low ). Many factors influence odor threshold determination, therefore many published values are questionable and they are hard to rely on. Some authors (Knudsen et al., 1999 Wolkoff, 1999 Wolkoff et al., 2006) assume that many of the odor thresholds reported in the literature are actually much lower, because if they compare concentrations of compounds emitted and measured with odor thresholds published,... 

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

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