Frequently Asked Questions
5. How does the ICH M7 guidance on genotoxic impurities assist in the evaluation of extractables and leachables?
The SCT (see Q6) and the AET (see Q7) were both defined by the PQRI guidance document 'Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products'. This guidance was specifically directed at orally inhaled and nasal drug products (OINDP), with the SCT for individual leachables defined as 0.15 µg per day. The PQRI set this extremely conservative level based on a number of contributing factors, but especially because
i) OINDPs are dosed directly to diseased tissue
ii) OINDPs are usually associated with chronic conditions, such as asthma, and so are taken by patients during their entire lives
Looking at these two factors, it is clear that the extremely conservative figure of 0.15 µg per day is unlikely to be relevant for other drug products, which either have different routes of delivery, or which are not used for chronic conditions. Examples could include parenterals, pre-filled syringes, autoinjectors, ophthalmics, topicals, etc.
The ICH M7 guidance 'Assessment and Control of DNA Reactive (mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk', provides a similar threshold based approach for assessing genotoxic impurities in drug substances and drug products. ICH M7 defines a Threshold of Toxilogical Concern (TTC) of 1.5 µg per day, for exposure to a genotoxic impurity for > 10 years to lifetime.
In addition, ICH M7 also provides thresholds for 'less than lifetime' (LTL) exposures, which are potentially more relevant for drug products used for acute conditions.
Drug product taken for ≤ 1 month; Acceptable daily intake = 120 µg per day
Drug product taken for > 1 - 12 months; Acceptable daily intake = 20 µg per day
Drug product taken for > 1 - 10 years; Acceptable daily intake = 10 µg per day
Drug product taken for > 10 years to lifetime; Acceptable daily intake = 1.5 µg per day
Using this approach, the ICH M7 guidance has been successfully applied to the assessment of extractables and leachables in non-OINDPs. Both the 1.5 µg per day lifetime exposure figure, and the LTL exposures have been used, and have been accepted by regulatory agencies around the world.
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