ICH Q3C (R8): Impurities: guideline for residual solvents in medicinal products

The ICH Q3C guideline describes permitted limits of residual solvents in active ingredients, excipients or medicinal products with regard to patient safety. Residual solvents are defined as volatile organic chemicals that are used in the manufacture of active ingredients and excipients or in the preparation of medicinal products or are formed during the manufacturing process and remain in the final product in traces.

In addition to yield, the choice of solvent can affect properties such as purity and crystal form of the final product, so the solvent may have a critical impact on the quality of the product.

Solvent residues have no therapeutic benefit, so they should be removed as much as possible. Based on their toxicological evaluation, solvents are divided into three classes. Class I solvents are highly toxic and should be avoided for the manufacture of active ingredients, excipients, and pharmaceuticals. If the use of class I solvents is indispensable in the context of manufacturing, the limits described must be observed. Otherwise, their use must be strongly justified as part of a risk-benefit assessment.

Class II solvents include chemicals with less severe toxicity, which should be used to a limited extent to protect patients from potential side effects.

Ideally, class III solvents should be used as they are considered to have low toxic potential.

Scope of the guideline

Active ingredients, excipients and medicinal products must be tested for solvent residues if solvents are used in the manufacturing process or may be generated during the process. Although manufacturers choose to test the final products, a cumulative method can be used to calculate the residual solvent content based on the values of the starting materials. If the calculated value is equal to or less than the recommended limit, the final product does not need to be tested for residual solvents. If the calculated value is above, testing is required to determine if the relevant solvent content could be reduced to an acceptable level during the manufacturing process.

The guideline applies to all dosage forms and routes of administration. Higher levels of solvents may be acceptable in certain cases, provided, for example, that the application is short-term (≤ 30 days) or topical. These values must be evaluated on a case-by-case basis.

Analytical methods

Usually, residual solvents are determined by headspace gas chromatography. Here, on the one hand, harmonized methods are available from the respective pharmacopoeias (see Ph. Eur. 2.4.24 and USP <467>).  On the other hand, manufacturers are free to use other validated methods. If only class III solvents are to be determined, a less specific method, e.g., determination of the loss on drying, may be chosen instead of the elaborate chromatographic method.

Amendment to the 8th revision of ICH Q3C

The 8th revision of the guideline became effective November 20, 2021, and includes the addition of Permitted Daily Exposure (PDE) values for 2-methyltetrahydrofuran (2-MTHF, 50 mg/day, ≤ 5000 ppm), cyclopentyl methyl ether (CPME, (15 mg/day, ≤ 1500 ppm), and tert-butyl alcohol (TBA, 35 mg/day, ≤ 3500 ppm). CPME and TBA are classified as class 2 residual solvents. 2 MTHF is a class 3 residual solvent that herewith now no longer requires a manufacturer-specific justification for its use.

2-MTHF is increasingly used as  solvent in organometallic and biphasic reactions instead of tetrahydrofuran (THF, PDE_THF= 7.2 mg/day). CPME is used in pharmaceutical chemical development as an alternative to its more common analogues, such as THF and tert-butyl methyl ether (t-BME, PDE_t-BME = 50 mg/day). TBA is used as an alcohol denaturing agent, a dehydrating agent, and a solvent, among other uses.

The adaptations were included in European Pharmacopoeia Supplement 10.7. (see Chapter 5.4. Residual Solvents).

Implementation of the Guideline

For most of the listed residual solvents, the described pharmacopoeial methods can be applied by means of HS-GS. As far as Class I and II residual solvents are concerned, only a short verification is required prior to the first application. This verifies the suitability of the method for the respective substance or residual solvent and at the same time demonstrates the feasibility in the test laboratory. Adaptations according to chromatography chapters Ph.Eur. 2.2.46 and USP <621> or the verification chapter USP <1467> are permitted and do not require further validation of the method. In the case of Class III residual solvents, a product-specific validation of the method becomes necessary. However, since these are mostly limit tests, the scope of validation is relatively small.

We would be pleased to support you with questions concerning residual solvents in pharmaceutical substances and products.

Sources: ICH Q3C (R8)