Revision of the ICH Guideline Q3C: New toxicological Data for Methyl Isobutyl Ketone and Triethylamine

Recommendation

23-25 April 2024
Barcelona, Spain

Global Registration and Life Cycle Management for APIs

The ICH guideline Q3C "Impurities: Guideline for residual solvents" contains specifications for several organic solvents that are used in the synthesis of active pharmaceutical ingredients, intermediate products or raw materials. Due to their, in some cases, high toxic potential, appropriate limit values in the final products must be checked and observed, specifying the remaining solvent content.

ICH Q3C divides solvents into 4 classes:

• Class 1: Solvents to be avoided. These substances are highly toxic, in some cases genotoxic or harmful to the environment and should not be used. If their use is unavoidable, the stated limit values must be observed. 
• Class 2: Solvents to be limited. These solvents are toxic in certain concentrations but can be tolerated below their maximum permitted daily doses (PDE values). 
• Class 3: Solvents with low toxic potential. The intake of these solvents is uncritical in quantities of up to 50 mg per day without any significant health risk. However there are no long-term toxicology studies for most of these solvents. 
• Class 4: Solvents for which no adequate toxicological data was found. According to ICH Q3C manufacturers of active ingredients and excipients still must give a reason for the remaining content of these substances in the final product (important for the authorisation dossier).

In the course of scientific advances, this guideline was revised on several occasions due to the reclassification of solvents or a change in their PDE values as a result of new toxicological data. The currently valid ICH Q3C version is the ICH Q3C(R5).

In June this year the ICH published a further revision as a "Draft Consensus Guideline" ICH Q3C(R6)" (Step 2 document). The document contains the following changes:

• Reassessment of methyl isobutyl ketone (MIBK): In more recent studies, a higher toxic potential was determined compared to the data from older studies. As a result, MIBK was reclassified from class 3 to class 2. 
• Addition of triethylamine to the guideline: This solvent is frequently used due to its favourable solubility properties, which allows it to catalyse certain chemical reactions. Based on the latest toxicological data, it is classified under class 3.

ICH Q3C(R6) was released for comment on 4 August 2015 on the "Scientific Guidelines" site of the EMA as a Step 2b document (end of consultation period: 3. November 2015).