Regulatory Highlights pubs.acs.org/OPRD
Regulatory Highlights for February−August 2013
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NEW ICH GUIDELINE ON GENOTOXIC IMPURITIES The International Conference on Harmonization (ICH) has now published the long-awaited draft M7 guideline on the determination and the control of DNA reactive (mutagenic) impurities in medicinal products.1 This complements previous guidance on the same topic from the European Medicines Agency (EMA)23 and the US Food and Drug Administration (FDA),4 and will presumably replace those earlier guidelines once it has been finalised. While adopting essentially the same approach as the existing guidelines, it clarifies a number of issues which those documents left unresolved. The M7 guideline will apply to new drug products, including those in clinical development. It is not intended to be applied retrospectively to products already approved for marketing, although it may be appropriate to employ it when certain postapproval changes (e.g., to the route of synthesis) are proposed, or if there is some specific cause for concern. Actual and potential impurities that are likely to arise during the synthesis, workup, and storage of a new drug substance, or product, should be assessed for their genotoxic potential. Actual impurities include those observed in the drug substance, either on release or during stability testing, above the ICH Q3A reporting thresholds.5 Potential impurities could include starting materials, reagents and intermediates, identified impurities in starting materials and intermediates, and reasonably expected reaction byproducts or degradation products based on knowledge of the chemical reactions and conditions involved. It is acknowledged that during clinical development the reporting thresholds are likely to be higher than the Q3A guideline suggests. For hazard assessment, a framework originally developed by the Pharmaceutical Research and Manufacturers of America (PhRMA)6 is used, where each impurity is assigned to one of five classes: (1) known mutagenic carcinogens, (2) known mutagens with unknown carcinogenic potential, (3) impurities exhibiting an alerting structure, unrelated to drug substance structure, with no mutagenicity data, (4) impurities showing the same alert as the drug substance, which has been tested and is nonmutagenic, (5) impurities with no structural alerts, or with sufficient data to demonstrate lack of mutagenicity. A computational toxicology assessment should be performed using two complementary (Q)SAR methodologiesone expert rule-based and the other statistical-basedthat predict the outcome of a bacterial mutagenicity assay. The absence of structural alerts from this exercise is sufficient to conclude that the impurity is of no concern, and no further testing is required (Class 5). To follow up on a structural alert (Class 3), a bacterial mutagenicity assay can be applied. Here a negative assay would overrule any structure-based concern, and such impurities would be considered nonmutagenic. A positive bacterial mutagenicity result would warrant further hazard assessment and/or control measures (Class 2). Alternatively, adequate control measures in the case of a positive structural alert alone could be applied in place of bacterial mutagenicity testing. © XXXX American Chemical Society
For impurities belonging in Classes 1, 2, and 3 (Class 3 only if the presence of a structural alert is not followed up in a bacterial mutagenicity assay), acceptable intake levels (μg/day) should be derived. In common with previous guidelines, an intake of a mutagenic impurity of 1.5 μg per person per day is considered to be associated with a negligible risk (theoretical excess cancer risk of
