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Regul Toxicol Pharmacol. 2017 Mar;84:116-123. doi: 10.1016/j.yrtph.2016.12.011. Epub 2016 Dec 27.

Management of organic impurities in small molecule medicinal products: Deriving safe limits for use in early development.

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GlaxoSmithKline R&D, Park Road, Ware, Hertfordshire, SG12 0DP, United Kingdom. Electronic address:
Pfizer, Ramsgate Road Sandwich, Kent, CT13 9N, United Kingdom.
AstraZeneca, Silk Road Business Park, Macclesfield, Cheshire, SK10 2NX, United Kingdom.
GlaxoSmithKline R&D, Park Road, Ware, Hertfordshire, SG12 0DP, United Kingdom.
Janssen R&D, Turnhoutseweg 30, 2340 Beerse, Belgium.


Management of organic non-mutagenic impurities (NMIs) in medicinal products is regulated by the ICH Q3A, B and C guidelines that are applicable at late stages of clinical development (Phase III onwards) and as a consequence there is no guidance for the assessment and control of NMIs in early clinical trials. An analysis of several key in vivo toxicology databases supports the ICH Q3A defined concept that a lifetime dose to 1 mg/day of a NMI would not represent a safety concern to patients. In conjunction with routine (Q)SAR approaches, this 1 mg/day value could be used as a universal qualification threshold for a NMI during any stage of clinical development. This analysis also proposes that modification of this 1 mg/day dose using an established methodology (i.e. Modified Haber's Law) could support 5 mg/day or 0.7% (whichever is lower) as an acceptable limit for a NMI in a drug substance or product in early clinical studies (<6 months). Given the controlled nature of clinical development and the knowledge that most toxicities are dose and duration dependent, these proposed NMI limits provide assurance of patient safety throughout clinical development, without the requirement to commission dedicated in vivo toxicology impurity qualification studies.


1 mg/day; Haber's law; ICH M7; ICH Q3A; ICH Q3B; ICH Q3C; Impurity qualification; Impurity safety; Non-mutagenic impurities; TTC

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