from the registered starting material (RSM) onward. However, this should be put into the context of where in the synthesis the RSM is introduced (see ICH Q11 [20]). If the RSM is introduced four or five stages before the active pharmaceutical ingredient (API), then there is likely to be effective purging of any mutagenic impurities in the downstream chemistry, whereas for an RSM introduced in the penultimate stage, such an assessment is very important. This is reflected in Section 5.1. (Relationship between the risk assessment and testing of starting materials):
For starting materials that are introduced late in the synthesis of the drug substance (and where the synthetic route of the starting material is known) the final steps of the starting material synthesis should be evaluated for potential mutagenic impurities.
This may suggest that in the context of an existing product, where a starting material is introduced late in the synthesis and changes are subsequently made to the route/process of the material (i.e. preregistered stages), that in such instances a reevaluation would be necessary.
2.2.4.2 Post‐approval Changes to Drug Product Chemistry, Manufacturing, and Controls
In the context of changes to the DP, such as a modified formulation, the guideline makes clear that the focus is specifically on the DP and on any new or increased levels of a mutagenic degradant arising as a result of that change. Critically, it makes clear that changes to the formulated product do not trigger a reevaluation of the route of synthesis of the DS, unless there is a concomitant change.
2.2.4.3 Changes to the Clinical Use of Drug Products
This applies where there is a change in either dose or duration (increase) or a change in indication from a serious or life‐threatening condition to an indication for a less serious condition where the existing impurity acceptable intakes (AIs) may no longer be appropriate. An obvious example of the latter would be in instances where an anticancer treatment used in late stage disease for which limits have been based on ICH S9 [8] is then used for either a revised patient population, e.g. adjuvant therapy, or a new non‐oncology indication.
Another important point that relates to the innate conservatism of the TTC is the statement that changes to patient population in terms of age do not trigger the need for reassessment and revision of limits. Previously the draft FDA guideline [4] had indicated the need to modify limits for pediatric indications. This has been removed from the ICH M7 guideline.
In addition, the earlier FDA draft guideline had indicated that different limits may be applicable dependent on the planned route of delivery, i.e. oral, pulmonary, etc. Similarly, this has been removed from the ICH M7 guideline.
2.2.5 Other Considerations for Marketed Products
The section relates to where a new impurity is discovered and there is “a cause for concern.” Previously, EDQM stated that structural alert alone is insufficient to trigger a concern, there must be new safety data and this point is reiterated in ICH M7: “The existence of impurity structural alerts alone is considered insufficient to trigger follow‐up measures, unless it is a structure in the cohort of concern.”
New safety data may be generated for a number of reasons and via a variety of routes. One such example is REACH testing, where chemical registration requirements require a battery of safety tests that may include an assessment of mutagenicity.
What is REACH?
REACH is a European Union (EU) regulation concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals. It came into force on 1 June 2007 and replaced a number of European directives and regulations with a single system.
REACH has several aims:
To provide a high level of protection of human health and the environment from the use of chemicals.
To make the people who place chemicals on the market (manufacturers and importers) responsible for understanding and managing the risks associated with their use.
To allow the free movement of substances on the EU market.
To assess risk, safety testing may be performed.
There are concerns over how new safety data are managed in practice. As a result of REACH, a coupling reagent 1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide (EDAC) (see Figure 2.1) was shown to be Ames positive. This chemical was widely used and at the time the data were generated there was no clear guidance as to how should authorities be informed of this new finding. Also uncertain is the impact on marketing authorization, would such a finding lead to immediate suspension of the license for the product(s) impacted or would time be permitted to make the changes needed to ensure control to appropriate levels? In the case of EDAC, the issue was minor due to the instability of the coupling agent, meaning that it was readily purged and thus presented no concern in terms of levels in associated products. Nevertheless, given the wide utility of commodity reagents like EDAC, the impact could be significant, impacting multiple products globally.
Figure 2.1 EDAC.
What is not entirely clear is how to address the scenario whereby an impurity is detected that based on its' structure belongs to the cohort of concern. It is clear based on the example of N‐nitrosamines (see Chapter 10) that detection of such an impurity would be a trigger for investigation.
2.2.6 Drug Substance and Drug Product Impurity Assessment
This section (Section 5 of the guideline) is essentially the start point for the overall risk assessment process itself. Critically, in practical terms, this essentially advocates the same approach as previous guidelines. The emphasis remains focused on actual impurities and potential impurities likely to be present in the API/DP. Another important aspect of this section of the guideline is that it also looks to link the ICH M7 [1] to ICH Q3A [5]/Q3B [6] reporting and identification requirements. Actual impurities are defined as those observed in the DS above the ICH Q3A reporting thresholds. Identification of actual impurities is expected when the levels exceed the identification thresholds outlined by ICH Q3A [6]. This confirms the primacy of ICH Q3A in terms of identification thresholds.
In practical terms this means that there is no formal requirement to attempt to identify every possible impurity at a TTC‐like level. Such an attempt would be in reality, impractical. Instead, the guideline tacitly accepts the finite but low risk of a mutagenic impurity existing, unidentified, at level below the ICH Q3A identification threshold. This is considered to be an acceptably low risk provided a comprehensive risk assessment is made of the synthetic process, its related impurities, DP manufacturing process, and associated degradants.
2.2.6.1 Synthetic Impurities
Unlike earlier regional guidelines, ICH M7 clearly defines a start point in terms of the risk assessment, indicating that such an assessment may begin at the starting materials. As described above there is a caveat that relates to the proximity of the starting material to the final API. The guideline states that for starting materials that are introduced late in the synthesis of the DS (and where the synthetic route of the starting material is known), the final steps of the starting material synthesis should be evaluated for potential mutagenic impurities. One may consider – what is meant by final steps? Two steps or perhaps three? This is not defined. Despite this uncertainty, the guideline provided by ICH M7 is much clearer in terms of its starting point than previously and should make the process simpler as a consequence.
Another important aspect