showing genotoxicity of an expected PGI
1.1.5.3 Avoidance and ALARP
It was confirmed by the SWP in a Q/A that if MIs associated with a product or substance had been shown to be controlled (i.e. that any MIs associated with the product were controlled to an appropriate safety‐based limit), then it was not necessary to conduct further work to further reduce the levels present. Thus, the driver to have ALARP principles drive further process development of an acceptably safe product was unnecessary.
1.1.5.4 ICH Identification Threshold and its Relation to MI Assessment
Another topic addressed within the EMEA Q&A document was the question as to how to relate the ICH identification threshold to unknown impurities and how this related to MI assessments. The answer provided by SWP was to confirm that the identification threshold outlined in ICH Q3a remained appropriate, because the overall quality of drug substance is supported by a well‐defined and reasoned risk assessment of the manufacturing process, which serves to identify significant potential major concerns. This focused risk assessment is employed to assure the quality of the drug substance and should mean that the level of risk associated with any unknown impurity present below the identification threshold has a low probability of being potentially mutagenic. As demonstrated by the discovery of N‐nitrosamines in sartans, this relies very heavily on a detailed knowledge of the chemistry employed; this is explored in detail in Chapter 12.
The EMEA guideline and subsequent Q&A document [10] of course are technically related only to Europe. Up to the end of 2008, the FDA's position remained somewhat unclear although it was clear from podium presentations that the FDA supported the underlying principles, e.g. the TTC of the EMEA guideline. In December 2008 the FDA finally published their draft guideline addressing the topic of genotoxic impurities [17].
1.1.6 FDA Draft Guideline
Drafted in December 2008 but never finalized, unsurprisingly there were significant similarities between this FDA draft guideline and the EMA guideline, certainly in terms of the key principles such as the TTC, the acceptance of a staged approach where study duration is limited, and the use of SAR evaluation.
There were though areas of concern the most significant perhaps was the suggestion of the need to introduce lower limits for different patient populations, specifically pediatric populations. Additional safety factors of 3 and 10 were mentioned and suggested for consideration. The need for this additional level of control for pediatric medicines was unclear when considered in the context of the extremely conservative assumptions that form the basis of the calculated TTC control.
Additionally, other subtler differences also existed, including differences in staged TTC values in relation to very short (less than 14 days) studies; the FDA favoring the extension of the 120 μg/day for the whole of this period.
Taken together the differences between the two guidelines would ultimately present anyone faced with having to comply with both with a challenge. It was the recognition of these challenges and others described in more detail below that led to establishment of an ICH process to deliver what became ICH M7. The development of ICH M7 is discussed in Chapter 2.
1.1.7 Other Relevant Guidance
As well as the main guidelines and supporting documents described, there are a short series of other documents that relate to this area that warrant comment.
It has certainly been interesting to follow publications on two related topics – the control of potential genotoxic (GT) impurities in herbal medicines and a paper considering the degree of risk associated with MIs in pharmaceutical excipients. Each of these is briefly examined below.
1.1.7.1 Excipients
The EMEA's CHMP was requested by the European Commission to provide an opinion on the risks associated with possible presence of carcinogens, mutagens, and substances toxic to health within excipients used as ingredients of medicinal products for human use. The CHMP published this opinion (in a joint paper from the QWP and SWP, published as EMEA/CHMP/SWP/146166/2007 on 18 October 2007) [13]. The conclusion of this evaluation was that the accumulated safety and pharmacovigilance data regarding well‐known, established, and standard excipients that meet EP requirements for quality served to provide a generally acceptable proof of acceptable safety and quality.
1.1.8 Herbals
A draft guideline was published by the EMEA's Committee of Herbal Medicine (EMEA/HMPC/107079/2007, dated 31 October 2007) [18] addressing how genotoxic impurity (GTI) management of herbal medicines should potentially be approached. This proposed a very simple approach – a herbal medicine and its source and manufacturing process should simply be evaluated in genotoxicity studies, and if the material is free of genotoxic response, then the impurity profile needs no further risk assessment. This is despite that for genotoxic tests like the Ames test to be effective in determining the true risk of an impurity being genotoxic there needs to be a particular level of exposure to the impurity in the test (250 μg/plate as a stated recommended threshold). An impurity below this threshold in the test cannot be deemed to be non‐genotoxic if the test comes back without adverse findings. Thus, the acceptance of such an approach as the basis of defining the safety for herbal medicine is different from EU/ICH M7 expectations for synthetically derived pharmaceuticals, where a deeper (and more stringent) evaluation of risk coming from particular impurities is possible and is mandated.
1.1.9 ICH S9
ICH S9 – Nonclinical evaluation for anticancer pharmaceuticals reached Step 4 in late 2009 [19]. This, as the title suggests, aims to provide guidance relating to the level of safety evaluation required to support the use of anticancer pharmaceuticals particularly in the context of the stage of disease. It suggests a reduced package of testing where treatment is associated with advanced disease, recognizing the inconsequential impact any toxicity‐related issues would have in terms of patient risk/benefit.
ICH S9 contains the specific statement:
It is recognised that impurities are not expected to have any therapeutic benefit, that impurity standards have been based on a negligible risk (e.g. an increase in lifetime risk of cancer of one in 105 or 106 for genotoxic impurities) and that such standards might not be appropriate for anticancer pharmaceuticals intended to treat advanced stage patients.
In 2018 ICH S9 was augmented by a Q&A document [20]. Within this specifically in relation to ICH M7 the following is tabulated (Table 1.4).
Table 1.4 Extracted text from ICH S9, Q&A document relating to MIs.
| 4.12 | Should impurities exceeding the established qualification limits in ICH Q3A/B be assessed in genotoxicity studies? When the API is genotoxic? When the API is non‐genotoxic? | API genotoxic? | Impurity exceeds 3A/B qualification threshold? | Proposed action |
| Yes | No | None | ||
|
Yes
|