insufficient duration, low animal numbers, and limited number of doses studied. Another important factor for consideration is tumor site and relevancy, for example forestomach tumors in rodents. Such tumors are often associated with local irritation/inflammation and are considered nonrelevant to humans, both from a physiological perspective (humans have no forestomach) and from an exposure perspective; the impurity at the low levels observed within a pharmaceutical product renders it extremely unlikely to result in such irritation.
As a result of the complexity described, a cross‐industry initiative was established that looked to develop an addendum table to the guideline. Included within this would be agreed limits for a range of common mutagenic/carcinogenic reagents. In addition to the actual agreed AIs, specific criteria were established to allow for the calculation of limits for other reagents in addition to those captured in the addendum. This ultimately culminated with the publication of the revised guideline in July 2017. The derivation of limits is described in detail in Chapter 7.
2.2.8.2 Acceptable Intakes for Class 2 and Class 3 Compounds
In the absence of specific carcinogenicity data, the ICH M7 guideline outlines AIs based on the TTC. Critically, for both products in clinical development and marketed products, limits are based on duration of exposure, i.e. a staged approach [26]. The recognition that limits should be based on duration of exposure irrespective of phase of development or marketing status is a major step forward as prior to finalization of the guideline the lifetime limit of 1.5 μg/day was routinely applied to marketed products, irrespective of their intended use and likely duration.
The calculation of less‐than‐lifetime (LTL) AIs is ultimately based on the principle of Haber's law, where concentration (C) × time (T) = a constant (k). The limits are described in Table 2.3.
Table 2.4 Acceptable intakes for an individual impurity.
Source: Reproduced from ICH M7.
| Duration of treatment | ≤1 month | >1–12 months | >1–10 years | >10 years to lifetime |
|---|---|---|---|---|
| Daily intake (μg/day) | 120 | 20 | 10 | 1.5 |
Within this section of the guideline is a specific section dedicated to clinical development. This proposes that for studies of <14 days in duration that limits only apply to those impurities for which there is actual in vitro safety data (Class 2), and that no specific controls are required over levels of impurities where there is only a structural alert (Class 3). While this is an interesting concept that would appear to provide flexibility, it remains to be seen whether or not this is utilized to a significant extent by applicants. In many cases it is unlikely that material will be restricted to use in clinical studies of <14 days duration, in which case in order to utilize material for longer duration studies, compliance with the limits outlined in Table 2.4 will be required for both Class 2 and Class 3 impurities.
In the context of marketed products, a particular challenge is defining duration. Again this is addressed through a specific note in the guideline, (Note 7), taking the form of a table where, based on specific therapeutic areas, the likely treatment durations are discussed. Useful advice is provided within the guideline itself where it is made clear that the duration of use should be defined based on typical use. This recognizes that, in some cases, a subset of the population of patients may extend treatment beyond the marketed products' anticipated duration of use. It states that in such instances the increase in risk is negligible.
It is important to note also the existence of a “quality cap.” Because limits for MIs are based on dose, this can create scenarios within low dose products where limits for an MI are very high in concentration terms, well beyond a level acceptable from a quality perspective. The guideline addresses this with the following statement:
The acceptable intakes derived from compound‐specific risk assessments (Section 7.2) can be adjusted for shorter duration of use in the same proportions as defined in the following sections (Section 7.3.1 and 7.3.2) or should be limited to not more than 0.5%, whichever is lower.
2.2.8.3 Multiple Impurities
One of the questions posed within the original ICH M7 concept paper relates to potential synergistic effect of multiple mutagenic impurities, especially where they are closely related. Based on the work of Bercu [29], the guideline concludes that such effects are unlikely at the low levels potentially present and hence permits the presence of up to three mutagenic impurities, to give a total AI as defined in Table 2.5.
Table 2.5 Acceptable total daily intakes for multiple impurities.
Source: Reproduced from ICH M7.
| Duration of treatment | ≤1 month | >1–12 months | >1–10 years | >10 years to lifetime |
|---|---|---|---|---|
| Total daily intake (μg/day) | 120 | 60 | 30 | 5 |
It is important to note that this total only applies to specified Class 2 and Class 3 impurities. In reality most synthetic routes will utilize multiple mutagenic reagents/intermediates; however, due to the innate reactivity of the reagents in question and the downstream process conditions, few actually pose a substantive risk in terms of potential carryover. This is discussed in detail in the control section.
2.2.8.4 Exceptions and Flexibility in Approaches
The final area covered in Section 7 of the guideline addresses various further scenarios where modified limits may apply. Areas include:
1 Where substantive exposure to the impurity may occur either exogenously or endogenously. Perhaps the clearest example of this is formaldehyde.
2 Exceptions to the use of the appropriate AI can be justified in cases of severe disease, reduced life expectancy, late onset but chronic disease, or with limited therapeutic alternatives. In practice this is likely to be applicable where effective control has not been possible, in such instances levels will likely be controlled to as low as reasonably practical (ALARP) and justified following subsequent consultation with regulatory authorities.
3 Where the mutagenic impurity, based on its structure, is considered to likely be a potent carcinogen (cohort of concern), i.e. aflatoxin‐like‐, N‐nitroso‐, and alkyl‐azoxy structures, the guideline states that if these compounds are found as impurities in pharmaceuticals, AIs would likely be significantly lower than the AIs defined in this guideline. This area has of course been brought sharply into focus by issues surrounding N‐nitrosamines, this being examined from both a quality and safety perspective in Chapters