CEI-MS-12 — worked example

§6Worked example

§6.1Worked example — converting a permitted daily exposure into a concentration limit

1. Dichloromethane is an ICH class 2 solvent with a permitted daily exposure of 6.0 mg per day.
2. For a compound with a maximum daily dose of 10 mg, the concentration limit is the permitted daily exposure divided by the daily dose: 6.0 mg ÷ 0.010 g = 600 mg/g, that is 600 000 ppm. The limit is not restrictive at this dose.
3. For a compound with a maximum daily dose of 2 g, the limit becomes 6.0 mg ÷ 2 g = 3.0 mg/g = 3 000 ppm, which is the ICH default option-1 limit for dichloromethane and is restrictive.
4. The instructive point is that residual-solvent limits scale inversely with dose, so a limit that is irrelevant for a milligram-dosed peptide becomes controlling for a gram-dosed excipient. A report stating a solvent concentration without the dose against which the limit was calculated has not established compliance, exactly as with the endotoxin calculation in CEI-MS-05.

§6.2Illustrative mass balance

References cited on this page

References are numbered in order of first citation in this document. Each superscript in the text links to its entry below.

1. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. ICH Q3C(R9) Impurities: Guideline for Residual Solvents. ICH Harmonised Guideline 2024;Step 4 version. identifier not held by the Institute
2. United States Pharmacopeial Convention. General Chapter ⟨1225⟩ Validation of Compendial Procedures. United States Pharmacopeia — National Formulary (USP–NF) 2024;USP 2024 Issue 1. identifier not held by the Institute

Identifiers are reproduced only where the Institute holds them. Where a digital object identifier or PubMed identifier is not shown, the Institute has recorded the journal and year and has not constructed an identifier.