ICH Q3C (R6) Residual solvents

This document recommends acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. It recommends use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents. Read together with the annexes on PDF iconspecifications for class 1 and class 2 residual solvents in active substances and residues of solvents used in the manufacture of finished products .

Prior to 2017, the ICH Q3C Guideline Summary Table 2 listed ethylene glycol (EG) as a Class 2 residual solvent with a PDE of 6.2 mg/day. In 2017, ICH was notified by an external party of a discrepancy between Summary Table 2 of the guideline and the monograph for EG listed in Appendix 5. The PDE indicated in the monograph was 3.1 mg/day. This issue was presented to the Q3C EWG for discussion and given the lack of any additional information or awareness of a supporting rationale for the value listed in Summary Table 2, the EWG considered the discrepancy to be a transcription error in the Summary Table 2. The EWG then recommended that Summary Table 2 of the guideline be revised to reflect the PDE indicated in the Appendix 5 monograph (3.1 mg/day). This error correction was finalized in 2018 and published as ICH Q3C(R7).

In 2019, ICH received a request to suspend the error correction for EG. Based on archival documents and a review of the literature, it appears that the EG PDE of 6.2 mg/day was accepted at Step 4 of the Q3C guideline in 1997 following reassessment of the toxicity data. However, while Summary Table 2 was revised to reflect the updated PDE, the Appendix 5 monograph was not. This information was evaluated by the EWG and the group concluded that the original PDE value listed in Summary Table 2 (6.2 mg/day; 620 ppm) was appropriate and recommended reinstituting the PDE value for EG. Therefore, Summary Table 2 has been corrected to reflect a PDE of 6.2 mg/day and 620 ppm in the latest (and currently valid) version of the guideline, published here as ICH Q3C(R6).

Keywords: Organic solvent, impurity, limits, class, reporting levels, permitted daily exposure (PDE), toxicological

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