It should also be noted that impurities considered to be highly potent form part of a cohort of concern and require control to limits lower than the TTC. This concept and its implications are illustrated by the example of N‐nitrosamines (Chapter 12).
Since the time that the TTC concept was first introduced through this draft guideline, the TTC has come under question principally because of its conservative nature [7]. A detailed evaluation reveals that the TTC derivation process is shaped by the use of the lowest statistically significant TD50s (which can produce a false‐carcinogen phenomenon) and by employing linear extrapolation for nonmutagenic carcinogens. Despite such concerns, no effective alternative methodology has been developed, and hence the TTC remains the effective baseline for control of MIs. The 2004 EMA draft guideline [6] and indeed more latter ICH M7 [1] itself explicitly recognize this conservatism. For this reason, the necessity of this specific threshold can be questioned. To understand the importance of the TTC concept, it is imperative to look at it in the context of the initial concept paper. Before the TTC concept was introduced, the primary objective was elimination of risk and only where this was proved impossible could limits be established. However, setting limits would, as already described, require extensive in vivo studies. Set in this context the concept of an agreed baseline limit, even if conservative, was valuable in establishing the basis of regulation.
One addition at this point was the widening of the scope of evaluation to include excipients. It is assumed this was to address concerns in relation to some excipients, e.g. modified cyclodextrins (concern over residues of alkylating agents used to modify the cyclodextrin). In many ways, excipients are very similar to existing products in that their safety has been well established through use over an extended period in multiple formulations. In addition, many are used in other areas including the food industry, and thus any exposure related to intake of pharmaceuticals is likely to be small compared to other sources. It is though important to note this presumption of suitable safety based on a history of use is only applicable to well‐established excipients. Novel excipients are expected to be assessed in a manner very similar to a new active substance.
At this point in time, there was a lack of any guidance relating to permissible doses during short‐term clinical trials. This led, in some instances, to an expectation to meet the 1.5 μg/day lifetime exposure limit, even for very short duration studies. This led to the development of a position paper, outlining a “staged” TTC concept for durationally adjusted control limits. This now well‐established concept is described below.
1.1.3 PhRMA (Mueller) White Paper
A Pharmaceutical Research and Manufacturers of America (PhRMA) expert group, led by Lutz Mueller, sought to establish acceptable limits for MIs linked to duration of exposure. This was referred to as a “staged TTC” approach and was based on the established principle that certain types of exposure risk can be defined in terms of cumulative dose [8]. Inherent to this principle is that the risk associated with an overall cumulative dose of a mutagen will be equivalent in terms of risk, irrespective of dose rate and duration. Thus, short‐term exposure limits could be based on linear extrapolation from accepted long‐term exposure limits.
The group published the outcome of their deliberations in January 2006. The key aspect of this paper, the proposed “staged TTC” limits, is displayed in tabular form in Table 1.1.
Table 1.1 Proposed allowable daily intakes (μg/day) for potential genotoxic impurity (PGIs) during clinical development, a staged TTC approach depending on duration of exposure.
| Duration of Exposure | |||||
|---|---|---|---|---|---|
| ≤1 month | >1–3 month | >3–6 month | >6–12 month | >12 month | |
| Allowable daily intake (μg/day) for different duration of exposure (as normally used in clinical development) | 120a or 0.5%b whichever is lower | 40a or 0.5%b whichever is lower | 20a or 0.5%b whichever is lower | 10a or 0.5%b whichever is lower | 1.5c b |
a Probability of not exceeding a 10−6 risk is 93%.
b Other limits (higher or lower) may be appropriate, and the approaches used to identify, qualify, and control ordinary impurities during development should be applied.
c Probability of not exceeding a 10−5 risk is 93%, which considers a 70‐year exposure.
It is important to note that included within this proposal is the application of a 1 in 1 000 000 risk factor when calculating limits for durations <12 months, as opposed to the 1 in 100 000 applied in relation to the standard TTC based on lifetime exposure. This precautionary approach was taken in recognition of the fact that during the clinical phase studies are often performed on healthy human volunteers and also that, even for patients at this stage, the therapeutic benefit has often yet to be established.
As well as the staged TTC principle, the paper also proposed a classification system for impurities, defining five classes:
Class 1: genotoxic carcinogens
Class 2: genotoxic – carcinogenicity unknown
Class 3: alerting structure – unrelated to parent
Class 4: alert related to parent, with associated known toxicological potential
Class 5: no alerts
This classification and effectively the limits defined within this paper have become the basis of the impurity management system used in ICH M7.
Based on this classification system, the paper defined a strategy for impurity assessment based on the use of structure activity relationships (SARs). SAR evaluation is used as the first stage to give a preliminary evaluation of risk. Thereafter, this can be augmented by the use of safety testing, specifically the Ames test, to determine whether or not the impurity is actually genotoxic. This is particularly true where the impurity is classified as Class 3. Alternatively, one can simply assume the compound in question to be genotoxic on the basis of the prediction and control in line with the appropriate TTC level.
Such a strategy, often augmented by a science‐based impurity purge assessment (incorporating factors such as reactivity of the impurity and downstream process conditions), has become the foundation of most, if not all, control strategies used within the industry (see Chapter 9 for a detailed evaluation of such strategies).
1.1.4 Finalized EMA Guideline on the Limits of Genotoxic Impurities – June 2006
The finalized version of the EMA guideline was issued on 28 June 2006 with an effective date of 1 January 2007 [9]. In terms of the final guideline, a number of key points were addressed, and it would be wrong not to recognize this or to ignore the significant progress made from the original position paper; however, it is equally important to note that concerns remained around several key areas. Outlined below are the key areas that had been addressed and also a reflection on the areas of concern.
The published guidance attempted to clarify how the concepts of the guidance