The Q&A here makes the distinction between limits that derive from TTC or compound/class specific AI and PDEs. The limits that derive from mutagenicity/carcinogenicity data fall under the assumption that cancer risk of known carcinogens increases as a function of cumulative dose; however, the toxicity of other end points that are used in order to calculate PDEs does not necessarily increase as a function of cumulative dose; therefore, LTL is not applicable to PDEs. Conversely, the answer to this question also refers to an option of assigning higher limits than a calculated PDE for short‐term dosing (30 days or less), as mentioned in the ICH Q3C and Q3D guidelines. This concept is further elaborated in Harvey et al. (https://doi.org/10.1016/j.yrtph.2016.12.011) where it is proposed to modify the AI of nonmutagenic impurities for clinical studies of less than six months duration, based on the Haber's Law (the same rule upon which the LTL concept is based on).
An interesting example for the use of LTL is the case of monofunctional alkyl chlorides that have a class‐specific AI of 10 times the default TTC (Note 5 in the ICH M7 guideline). For a monofunctional alkyl chloride in a DP that is administered for ≤1 month, the theoretical LTL AI can be calculated to be: 15 μg/day × 80 (the ratio between 120 and 1.5 μg/day) = 1200 μg/day. However, this limit now exceeds the 1 mg/day, and thus it may be necessary to perform a screen of genotoxicity studies to qualify such a level (see Question 1.3 above).
2.4.7.4 Question 7.4
This Q&A relates to the AI of HIV treatment that under Note 7 (Table 2.7) of the M7 guideline falls under the LTL category of a treatment duration of >1–10 years where the AI is defined as 10 μg/day. The HIV disease has now been moved from “treatment duration <10 years” to “lifetime” treatment. The Q&A provides further explanation to this change.
Table 2.7 Examples of clinical use scenarios with different treatment durations for applying AIs.
| Scenarioa | Acceptable intake (μg/day) |
| Treatment duration of ≤1 month: e.g. drugs used in emergency procedures (antidotes, anesthesia, acute ischemic stroke), actinic keratosis, and treatment of lice | 120 |
| 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), preterm labor, preeclampsia, presurgical (hysterectomy) treatment, and fracture healing (these are acute use but with long half‐lives) | 20 |
| Treatment duration of >1–10 years: e.g. stage of disease with short life expectancy (severe Alzheimer’s), nongenotoxic anticancer treatment being used in a patient population with longer term survival (breast cancer, CML), drugs specifically labeled for less than 10 years of use, drugs administered intermittently to treat acute recurring symptomsb (chronic Herpes, gout attacks, substance dependence such as smoking cessation), macular degeneration, and HIVc | 10 |
| 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 AD), hormone therapy (e.g. GH, TH, PTH), lipodystrophy, schizophrenia, depression, psoriasis, atopic dermatitis, COPD, cystic fibrosis, and seasonal and perennial allergic rhinitis | 1.5 |
a This table shows general examples; each example should be examined on a case‐by‐case basis. For example, 10 μg/day may be acceptable in cases where the life expectancy of the patient may be limited, e.g. severe Alzheimer’s disease, even though the drug use could exceed 10‐year duration.
b Intermittent use over a period >10 years but based on calculated cumulative dose it falls under the >1–10 year category.
c HIV is considered a chronic indication but resistance develops to the drugs after 5–10 years and the therapy is changed to other HIV drugs.
| Question | Answer |
|---|---|
| Why was HIV disease moved to the “Treatment duration of >10 years to lifetime” in the clinical use scenarios table? How should this change be implemented? | The treatment duration category was changed because of advances in the clinical treatment of HIV disease. To avoid disruption of supply of HIV drugs already on the market, this change would not be applied to currently marketed products. For example, when a new DS supplier is proposed, the AI would remain at 10 μg/day in cases where the DS produced by this supplier, using the same route of synthesis, is a component of an existing DP marketed in the specific region (see ICH M7 Section 4.1). For regulatory submissions 18 months after the date that the M7 Q&A reached Step 4, the 1.5 μg/day or other appropriate AI would be applied in the following situations: New DSs and new DPs during their clinical development and subsequent applications for marketing.Changes to the DS synthesis resulting in new or increased acceptance criteria for existing impurities.Changes in the formulation, composition, or manufacturing process resulting in new degradation products or increased acceptance criteria for existing degradation products.Introduction of a new source of the DS through a drug master file (DMF) from a supplier who has not had a previously accepted DMF in the relevant region.Changes made to a specific synthetic step as described in ICH M7 Section 4.1.A newly discovered Class 1 or Class 2 impurity, a structure in the cohort of concern, or new relevant impurity hazard data, as described in ICH M7 Section 4.4 |
2.4.7.5 Question 7.5
This Q&A relates to the need of assigning limits to individual impurities when three or more Class 2 and Class 3 impurities are present.
| Question | Answer |
|---|---|
| Does “Table 2.2: Acceptable Intakes for an Individual Impurity” apply when three or more Class 2 or Class 3 impurities are specified in the DS specification? | Yes. In this scenario, a limit for each “Individual Impurity” should be listed in the DS specification as per limits provided in Table 2.2 (for example >10 years to lifetime not more than (NMT) 1.5 μg/day). Additionally, a limit for “Total Mutagenic Impurities” should be listed in the DS specification as per limits provided in Table 2.7 (for example >10 years to lifetime NMT 5 μg/day). As stated in the guidance, compound‐specific or class‐related acceptable limits (Class 1) and degradation products that form in the DP are excluded from total mutagenic impurity limits. |
This Q&A clarifies that in the case where there are three or more Class