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Unlike earlier guidelines, ICH M7 specifically addresses the issue of mutagenic degradants. Similar to DS impurities, the guideline makes clear the primacy of ICH Q3B [8] and the identification thresholds for the product. It also makes clear again the need to focus on degradants likely to be present in the final DP. While clearly helpful, this nevertheless does not define how the risk posed by degradants should be evaluated. The guideline provides some advice defining degradants in terms of actual degradants and probable degradants. Actual degradants are those observed to form over prolonged storage at ambient temperature, i.e. ICH long‐term accelerated storage conditions. Probable degradants are defined in terms of those observed under accelerated conditions, e.g. 40°/75%. Reference is made within the guideline to the use of knowledge derived from stress studies. The evaluation of mutagenic degradants is examined in detail by Baertschi et al. [22]. The use of stress studies to identify major degradative pathways and their associated primary degradants is underpinned by the established relationship between degradants formed under stress conditions to those seen under ambient conditions. Baertschi [23] demonstrated that degradants formed under ambient conditions were a contained “sub‐set” of those observed to form under stressed conditions, this is illustrated in Figure 2.2, where the relationship between idealized and realistic degradation knowledge landscapes is considered.

Figure 2.2 Interrelationship between degradant classes.

Hypothetical degradants arise from in silico and in cerebro assessments; potential degradants are observed as major degradation products in stress testing and accelerated stability testing; actual degradation products are those that arise under ICH long‐term (real‐time) storage conditions.

Another important consideration in the assessment of degradants is what is an appropriate identification threshold within the context of a stress study. The identification threshold defined within ICH Q3B [7] for a DP with a dose of >10 mg – 2 g is set at 0.2% or 2 mg. This is relative to a typical maximal level of degradation of typically 2% total degradation in DP. In the context of a stress study where degradation levels may well exceed 10% total, an adjustment factor of five to the identification threshold would seem pragmatic, raising this to a value of 1.0%. Using such a structured approach will ensure that impurities identified during a stress study are the primary degradants and hence commensurate with the focus of the guideline on degradants likely to be present in the final DP.

Overall in terms of the impurity assessment the impurities for consideration are reflected in Figure 2.3.

Figure 2.3 Potential sources of mutagenic impurities.

This topic is examined in detail in Chapter 14.