💊 Residual solvents — GC
In short
Identification and control of residual solvents in active substances, excipients and medicinal products by gas chromatography with headspace sampling according to the general chapter of the European Pharmacopoeia. The test is performed according to European Pharmacopoeia 2.4.24, ICH Q3C(R9); Class 1 (to be avoided): benzene 2 ppm, carbon tetrachloride 4 ppm, 1,2-dichloroethane 5 ppm, 1,1-dichloroethene 8 ppm, 1,1,1-trichloroethane 1500 ppm. The procedure comprises 5 steps; it is used for: Active substances, excipients and medicinal products whose manufacture or purification uses or produces solvents (ICH Q3C, section 2), Control of the limits for Class 1 and Class 2 solvents (ICH Q3C, Tables 1 and 2), Substances with only Class 3 solvents — a validated non-specific method such as loss on drying (ICH Q3C, 3.4).
At a glance
- Standard: European Pharmacopoeia 2.4.24, ICH Q3C(R9)
- Category: Pharma
- Procedure steps: 5
- Class 1 (to be avoided): benzene 2 ppm, carbon tetrachloride 4 ppm, 1,2-dichloroethane 5 ppm, 1,1-dichloroethene 8 ppm, 1,1,1-trichloroethane 1500 ppm
- Class 2 (to be limited) — examples, Option 1: acetonitrile 410, chloroform 60, dichloromethane 600, hexane 290, methanol 3000, toluene 890 ppm
- Class 3 (low toxic potential): e.g. acetone, ethanol, ethyl acetate, tert-butyl methyl ether, dimethyl sulfoxide — up to 50 mg per day (5000 ppm, 0.5 % under Option 1) without justification
Overview
STATUS (as of 03.11.2026). General chapter Ph. Eur. 2.4.24 “Identification and control of residual solvents” applies in the wording of the 12th edition of the European Pharmacopoeia (version 12.3, in force from 1.07.2026). A draft of the completely revised chapter was published in Pharmeuropa 37.4 (30.09.2025, comments until 31.12.2025): a clear distinction between targeted and non-targeted analysis, a separate system suitability solution prepared from a subset of Class 2 solvents, and new Class 2 chromatograms covering cyclopentyl methyl ether and tert-butyl alcohol. According to an EDQM notice, the European Pharmacopoeia Commission adopted the new text at its 185th session (23–24.06.2026); it is published in Issue 13.3 (October 2026) and applies from 1.07.2027. The solvent limits are given in guideline ICH Q3C(R9) (Step 4 version of 24.01.2024).
CLASSES AND LIMITS (ICH Q3C(R9), sections 3 and 4). Class 1 — solvents to be avoided (known and strongly suspected human carcinogens and environmental hazards): benzene 2 ppm, carbon tetrachloride 4 ppm, 1,2-dichloroethane 5 ppm, 1,1-dichloroethene 8 ppm, 1,1,1-trichloroethane 1500 ppm (environmental hazard). Class 2 — solvents to be limited (non-genotoxic animal carcinogens, possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity, and solvents suspected of other significant but reversible toxicities); limits according to Option 1, calculated from the permitted daily exposure (PDE) for a product mass of 10 g per day, e.g. acetonitrile 410 ppm, chloroform 60 ppm, dichloromethane 600 ppm, hexane 290 ppm, methanol 3000 ppm, toluene 890 ppm. Option 2 allows the sum of a solvent from all components of the product to be assessed against the PDE with the known maximum daily dose. Class 3 — solvents with low toxic potential (PDE of 50 mg per day or more), e.g. acetone, ethanol, ethyl acetate, tert-butyl methyl ether, dimethyl sulfoxide; amounts of up to 50 mg per day (5000 ppm, i.e. 0.5 % under Option 1) are considered acceptable without justification.
SCOPE AND ANALYSIS (ICH Q3C(R9), sections 2 and 3.4). Only solvents used or produced in the manufacture or purification of active substances, excipients or the medicinal product need to be tested; the content in the product can also be calculated by the cumulative method from the levels in the ingredients. Residual solvents are typically determined by chromatographic techniques such as gas chromatography; where feasible, harmonised pharmacopoeial procedures are used. If only Class 3 solvents are present, a validated non-specific method may be used, such as loss on drying (result below 0.5 %), taking into account in the validation the impact of solvent volatility. According to an application note describing a method compliant with USP <467> and Ph. Eur. 2.4.24, Class 1 and Class 2 solvents are determined by gas chromatography with static headspace sampling and flame ionisation detection; for Class 3 the technique is flexible, although it is often included in the same analysis. In the revised text of the chapter, the procedure comprises identification and confirmation of the solvents (steps 1 and 2) and the determination of identified or specified solvents in a limit test (step 3).
WHAT WE DO NOT GIVE HERE. Columns, chromatographic conditions and headspace parameters, preparation of reference and test solutions, system suitability criteria and the detailed changes of Issue 13.3 — according to the text of chapter 2.4.24, which we did not have.
Method principle
Volatile residual solvents are determined by gas chromatography with headspace sampling and a flame ionisation detector. The solvents present in the substance are identified and confirmed, and the identified or specified ones are determined in a limit test. The results are assessed against the limits of guideline ICH Q3C for Classes 1, 2 and 3; if only Class 3 solvents are present, a validated non-specific method such as loss on drying may be used.
Applications
- Active substances, excipients and medicinal products whose manufacture or purification uses or produces solvents (ICH Q3C, section 2)
- Control of the limits for Class 1 and Class 2 solvents (ICH Q3C, Tables 1 and 2)
- Substances with only Class 3 solvents — a validated non-specific method such as loss on drying (ICH Q3C, 3.4)
- Assessment of a medicinal product by the cumulative method from the levels in the ingredients or by testing the product (ICH Q3C, section 2)
Key parameters
| Parameter | Value |
|---|---|
| Class 1 (to be avoided) | benzene 2 ppm, carbon tetrachloride 4 ppm, 1,2-dichloroethane 5 ppm, 1,1-dichloroethene 8 ppm, 1,1,1-trichloroethane 1500 ppm |
| Class 2 (to be limited) — examples, Option 1 | acetonitrile 410, chloroform 60, dichloromethane 600, hexane 290, methanol 3000, toluene 890 ppm |
| Class 3 (low toxic potential) | e.g. acetone, ethanol, ethyl acetate, tert-butyl methyl ether, dimethyl sulfoxide — up to 50 mg per day (5000 ppm, 0.5 % under Option 1) without justification |
| Option 1 | limit in ppm = 1000 × PDE / dose, assuming a daily dose of 10 g |
| Technique | gas chromatography with headspace sampling and flame ionisation detection (Classes 1 and 2) |
Standard
- Standard number
- European Pharmacopoeia 2.4.24, ICH Q3C(R9)
- Title (PL)
- Identyfikacja i kontrola rozpuszczalników resztkowych
- Title (EN)
- Identification and control of residual solvents
Step-by-step procedure
-
Solvents to be controlled
Establish the solvents used or produced in the manufacture and purification of the substance and product — only these need to be tested (ICH Q3C, section 2).
-
Identification
Perform gas chromatography with headspace sampling and a flame ionisation detector and identify the Class 1 and Class 2 solvents present in the substance (application note of a method compliant with Ph. Eur. 2.4.24).
-
Confirmation and limit test
Confirm the identity of the detected solvents and determine the identified or specified solvents in a limit test — this is how the revised text of the chapter organises steps 1–3 (Pharmeuropa 37.4).
-
Class 3
If only Class 3 solvents are present, you may use a validated non-specific method such as loss on drying, taking solvent volatility into account (ICH Q3C, 3.4).
-
Evaluation of results
Compare the results with the limits: Class 1 — Table 1, Class 2 — Table 2 (Option 1 or 2), Class 3 — up to 50 mg per day, i.e. 5000 ppm under Option 1, without justification (ICH Q3C, sections 3.3 and 4).
Required equipment and apparatus
| Equipment | Example | Indicative price |
|---|---|---|
| Gas chromatograph with flame ionisation detector | separation and detection of Class 1 and Class 2 solvents (application note of a method compliant with USP <467> and Ph. Eur. 2.4.24) | — |
| Headspace sampler (static headspace) | introduction of the vapour above the sample solution into the chromatograph (as above) | — |
Reagents, media and consumables
| Reagent | CAS | Details |
|---|---|---|
| Solvent reference standards | — | Class 1 and Class 2 solvents for identification, confirmation and the limit test; in the revised text of the chapter also a separate system suitability solution prepared from a subset of Class 2 solvents (Pharmeuropa 37.4) |
Health and safety (OHS)
- Class 1 solvents (e.g. benzene) are, according to ICH Q3C, known or strongly suspected human carcinogens and environmental hazards (section 3.1)
- The available sources contain no health and safety requirements for this procedure — rules for working with solvent reference standards are set by the laboratory
Frequently asked questions
Which standard describes this test?
The test is performed according to European Pharmacopoeia 2.4.24, ICH Q3C(R9) — “Identification and control of residual solvents”.
How does this method work?
Volatile residual solvents are determined by gas chromatography with headspace sampling and a flame ionisation detector. The solvents present in the substance are identified and confirmed, and the identified or specified ones are determined in a limit test.
What is the measuring range and accuracy?
Class 1 (to be avoided): benzene 2 ppm, carbon tetrachloride 4 ppm, 1,2-dichloroethane 5 ppm, 1,1-dichloroethene 8 ppm, 1,1,1-trichloroethane 1500 ppm; Class 2 (to be limited) — examples, Option 1: acetonitrile 410, chloroform 60, dichloromethane 600, hexane 290, methanol 3000, toluene 890 ppm; Class 3 (low toxic potential): e.g. acetone, ethanol, ethyl acetate, tert-butyl methyl ether, dimethyl sulfoxide — up to 50 mg per day (5000 ppm, 0.5 % under Option 1) without justification; Option 1: limit in ppm = 1000 × PDE / dose, assuming a daily dose of 10 g.
How long does the test take?
The procedure comprises 5 steps. The standard does not give a duration for every stage — the laboratory's own procedure decides.
What equipment is required?
Gas chromatograph with flame ionisation detector, Headspace sampler (static headspace).
Where is this test used?
Active substances, excipients and medicinal products whose manufacture or purification uses or produces solvents (ICH Q3C, section 2); Control of the limits for Class 1 and Class 2 solvents (ICH Q3C, Tables 1 and 2); Substances with only Class 3 solvents — a validated non-specific method such as loss on drying (ICH Q3C, 3.4); Assessment of a medicinal product by the cumulative method from the levels in the ingredients or by testing the product (ICH Q3C, section 2).
What safety precautions apply?
Class 1 solvents (e.g. benzene) are, according to ICH Q3C, known or strongly suspected human carcinogens and environmental hazards (section 3.1); The available sources contain no health and safety requirements for this procedure — rules for working with solvent reference standards are set by the laboratory.
Which laboratory can perform this test?
The test is performed by laboratories accredited to ISO/IEC 17025. On LabCoda you can find them by the standard number Ph.Eur. 2.4.24.