from those sections are described below.
1.1.1.2 Toxicological Background
Within the position paper, genotoxic compounds were split into two categories:
1 1) Genotoxic compounds, for which sufficient evidence existed to support a thresholded mechanism.(A thresholded mechanism is one for which a clearly discernible limit exists below which no significant toxicological effect is observed. Several examples were given within the paper of mechanisms of genotoxicity for which a thresholded mechanism may exist, including, for example, topoisomerase inhibition, inhibition of DNA synthesis, and overload of defense mechanisms.)
2 2) Genotoxic compounds without sufficient evidence for a thresholded mechanism.The position paper stated that such thresholds either were unlikely to exist or would be difficult to prove for DNA‐reactive chemicals.
This categorization of impurities, on the basis of a mechanistic understanding of toxicological action, has remained in place in the finalized ICH M7 guideline, and the belief that DNA‐reactive compounds have no threshold remains widely held. However, as will be explored in a later chapter, there is significant evidence now challenging this for even the most potent of mutagenic carcinogens (Chapter 8).
1.1.1.3 Pharmaceutical (Quality) Assessment
The assumption that some “in vivo” genotoxins can damage DNA at any exposure level, and therefore that any level can represent a risk, led to a conservative stance being proposed in terms of quality assessment. It was stipulated that a justification must be provided in relation to the manufacturing process that clearly explained why, for that specific process, the presence of genotoxic impurities was “unavoidable.” The position paper also stated that, wherever possible, alternative routes that avoid genotoxic residues should be used and that an applicant was obliged to update the manufacturing process should a safer alternative process be available. If, after these steps had been taken, a risk remained, it was suggested residual levels should be reduced to the level that was “as low as technically feasible.” It is interesting to reflect on recent issues relating to contamination of sartans (most notably valsartan [4]) where similar language to that within this preliminary position paper has been used with calls for “nitrosamine free” sartans being requested by some authorities. This is perhaps not entirely unreasonable for the sartans, given that one route to a particular sartan can bring nitrosamine risk and another manufacturing process (or indeed another sartan) can be free from nitrosamine risk.
1.1.1.4 Toxicological Assessment
The guideline made it clear that only after the use of a genotoxic reagent had been justified and every effort had been made to reduce levels should a toxicological assessment be made. Different options were provided by which risk assessments could be carried out, these being through either:
1 1) Quantitative risk assessments – this being essentially based on the linear extrapolation of the dose–response curve from rodent cancer bioassays from a high dose to low dose region. In this case the low dose recommended being one associated with a 1 in 100 000 risk. (One excess cancer death per 100 000 people exposed to the agent concerned over a lifetime [70 years]).
2 2) Uncertainty factor approach –this approach, one that involves the determination of a no effect level (NOEL) from preclinical studies, along with the subsequent application of uncertainty factors would be appropriate where a threshold‐mediated mechanism has been established. Such an approach is consistent with that described within ICH Q3C – Residual Solvents [5].
The position paper in this initial form was a cause of significant concern to the industry. The main concern perhaps related to the safety testing requirements. For many reagents the only safety data available often relates to limited in vitro studies, e.g. an Ames test. Such data are unsuitable for establishing a NOEL or for performing a quantitative risk assessment. Thus, to generate data to support the determination of a NOEL or to carry out a quantitative risk assessment as prescribed in the concept paper would require the conduct of further significant in vivo studies. This could have resulted in a significant increase in animal studies, something considered potentially unacceptable both at the time and now as efforts are made to refine, reduce, and replace animal experimentation.
Thus, alternatives to this were immediately sought. An alternative approach, previously adopted within other spheres, such as the food arena, was the concept of a “virtually safe dose.” This had been developed to deal with low‐level contaminants within food. This concept itself was based on the principal of establishing a level at which any new impurity, even if it was subsequently shown to be carcinogenic, would not constitute a significant risk. This paved the way ultimately for the employment within subsequent versions of the guideline of the Threshold of Toxicological Concern (TTC) concept.
1.1.2 Guideline on the Limits of Genotoxic Impurities – Draft June 2004
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.