Feb - Mar 2020

Control of Genotoxic and Elemental Impurities

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Acceptable Intake

Treatment duration needs to be considered for applying acceptable intake.

Treatment duration should be located in RLD label. Alternatively, refer to treatment durations based on clinical use scenarios (ICH M7, Note 7).

Following are acceptable intakes for an individual impurity. Acceptable intakes for multiple impurities are slightly different.

Treatment duration of ≤ 1 month: e.g., drugs used in emergency procedures (antidotes, anaesthesia, acute ischemic stroke), actinic keratosis, treatment of lice.

Treatment duration of > 1 – 12 months: e.g., anti-infective therapy with maximum up to 12 months treatment (HCV), parenteral nutrients, prophylactic flu drugs ( ~ 5 months), peptic ulcer, Assisted Reproductive Technology (ART), pre-term labour, preeclampsia, pre-surgical hysterectomy) treatment, fracture healing (these are acute use but with long half-lives).

Treatment duration of > 1 -10 years: e.g., stage of disease with short life expectancy (severe Alzheimer’s), non-genotoxic anticancer treatment being used in patient population with longer term survival (breast cancer, chronic myelogenous leukemia), drugs specifically labelled for less than 10 years of use, drugs administered intermittently to treat acute recurring symptoms (chronic Herpes, gout attacks, substance dependence such as smoking cessation), macular degeneration, HIV.  

Treatment duration of > 10 years to lifetime: e.g., chronic use indications with high likelihood for lifetime use across broader age range (hypertension, dyslipidemia, asthma, Alzheimer’s (except severe Alzheimer’s disease), hormone therapy (e.g., growth hormone, thyroid hormone, parathyroid hormone), lipodystrophy, schizophrenia, depression, psoriasis, atopic dermatitis, Chronic Obstructive Pulmonary Disease (COPD), cystic fibrosis, seasonal and perennial allergic rhinitis.

A TTC-based acceptable 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 <1 in 100,000 over a lifetime of exposure) and can, in general, be used for most pharmaceuticals as a default to derive an acceptable limit for control. This approach would usually be used for mutagenic impurities present in pharmaceuticals for long-term treatment (> 10 years) and where no carcinogenicity data are available (Classes 2 and 3).

ICH M7 Classification of Impurities

  • Class 1: Known mutagenic carcinogens.
  • Class 2: Known mutagens with unknown carcinogenic potential (bacterial mutagenicity positive*, no rodent carcinogenicity data).
  • *Or other relevant positive mutagenicity data indicative of DNA-reactivity-related induction of gene mutations (e.g., positive findings in in vivo gene mutation studies).
  • Class 3: Alerting structure, unrelated to the structure of the drug substance; no mutagenicity data.
  • Class 4: Alerting structure, same alert in drug substance or compounds related to the drug substance (e.g., process intermediates) which have been tested and are non-mutagenic.
  • Class 5: No structural alerts, or alerting structure with sufficient data to demonstrate lack of mutagenicity or carcinogenicity.