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Significant revisions were made to the original position paper before its rerelease as a draft guideline in June 2004 [6]. The revised guideline struck a carefully considered note. For example, the “as low as technically feasible” terminology used previously was replaced with the ALARP (as low as reasonably practical) principle, a small but in many ways significant shift in emphasis. ALARP does not expect, for example, exploration of unusual or extremely difficult technologies that could be required to be evaluated, irrespective of other impacts (e.g. synthetic efficiency) under “as low as technically feasible (ALATF).” For example, in the context of analysis, ALARP would typically be considered as the application of available standard techniques such as high performance liquid chromatography – mass spectrometry (HPLC‐MS), rather than as low as technically feasible that might refer to the need to attempt to apply “state of the art” or even revolutionary experimental approaches. Another important change was the removal of the requirement to introduce an alternative route/process should one “less at risk” be identified. The need to provide justification of the route selected remained.

The most significant change was the acceptance that the concept of elimination of risk in its entirety (zero risk) was often going to be unachievable and therefore an alternative to this principle was required. This led to the adoption of the concept of an acceptable risk level. This acceptable risk was defined as a level sufficiently low that even if the compound in question was ultimately shown to be carcinogenic it would pose a negligible risk to human health. This took the form of the TTC. This concept obviates the need to generate extensive in vivo data to establish specific limits, by adoption of a conservative generally applicable limit.

The most important aspect of the TTC concept is the derivation of a single numerical limit of 1.5 μg/day based on a lifetime (70 years) exposure resulting in a worst‐case excess cancer risk of 1 in 100 000. Within other areas (e.g. food) a 1 in 1 000 000 figure had been applied; this was revised by a factor of 10 in relation to pharmaceuticals to recognize the specific, desired, and otherwise unavailable benefit derived from pharmaceutical treatment. This concept allows an adequate basis of safety and control limits to be established in the absence of specific in vivo data on a particular impurity.

The guideline, having established this TTC limit, also stated that, under certain circumstances, higher limits could be established. Such circumstances included short‐term exposure, treatment of a life‐threatening condition for which no safer alternatives existed, where life expectancy was less than five years, or where the impurity was a known substance for which exposure from other sources (e.g. food) was significantly greater than that associated with exposure from pharmaceuticals. Notably, no fixed alternative limits were provided that could be applied in such instances, perhaps as there are a myriad of potential circumstances where such considerations could apply and thus it was considered that this topic was best left to the assessment of a specific product and a specific risk benefit analysis to agree acceptable limits. It is reasonable that product‐specific risk/benefit considerations are applied, and this in many ways supports not establishing fixed acceptable limits in the guideline. Many of these concepts were revisited in the development of ICH M7, this being discussed in depth in Chapter 2.

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.