Residual Solvents

What Is Residual Solvents?

Residual solvents analysis determines organic solvents used during manufacture that remain in the product. ICH Q3C classifies solvents into three classes: Class 1 to be avoided, Class 2 restricted, Class 3 low toxicity. Measurement is by headspace gas chromatography.

Purpose of Residual Solvents

The purpose is to show residual solvent levels are below the ICH Q3C limits. Solvents provide no therapeutic benefit; they are expected to be reduced to the lowest level possible.

Which Products Is Residual Solvents Applied To?

Active pharmaceutical ingredients
Finished dosage forms
Excipients
Herbal extracts
Coating materials

In Which Sectors Is Residual Solvents Used?

PharmaceuticalsBiotechnologyChemistry

Standards Related to Residual Solvents

ICH Q3C(R8) (residual solvents guideline)
Ph. Eur. 2.4.24 (identification and control of residual solvents)
Ph. Eur. 5.4 (residual solvents general chapter)
USP <467> (residual solvents)

Residual Solvents Conditions

Classification: ICH Q3C Class 1, 2 and 3; a different approach for each class
Method: Headspace GC-FID or GC-MS
Analytical scope: Determined based on knowledge of the solvents used in the manufacturing route
Limits: PDE and concentration limits for Class 2 are defined in ICH Q3C

Equipment for Residual Solvents

GC-FID with headspace sampler
GC-MS
Analytical balance
Headspace vials and crimping system

Sample Requirements for Residual Solvents

Sufficient specimen quantity
The list of solvents used in the manufacturing route must be provided
Batch number and maximum daily dose must be provided
The specimen must be sent in an airtight container; solvents are volatile

Duration of Residual Solvents

Headspace GC analysis is relatively quick, and results are usually available within a few working days.

Residual Solvents Procedure

1The solvents used in the manufacturing route are identified.
2A suitable headspace GC method is set up.
3Standard solutions are prepared.
4The specimen is weighed into a headspace vial and dissolved.
5Injection is made from the gas phase after heating.
6Solvent concentrations are calculated and compared against the limits.

Residual Solvents Acceptance Criteria

ICH Q3C sets very low limits for Class 1 solvents and calls for their use to be avoided; for Class 2 it gives permitted daily exposure and concentration limits; for Class 3 a general level is considered acceptable. Applicable values are confirmed from the guideline's current edition.

Evaluation of Results

Targeted analysis only finds the solvents being tested for: a solvent not known to be used in the manufacturing route, if left off the list, will not appear in the report. The analytical scope must therefore be built from knowledge of the manufacturing route; a supplier change can introduce new solvents.

Residual Solvents Report

Specimen identification, batch and manufacturing route information
List of solvents analysed and their classes
Method and conditions applied
Result and limit of quantification for each solvent
ICH Q3C limits compared against

Accreditation

EUROLAB holds internationally recognised accreditation obtained from accreditation bodies party to the IAF and ILAC multilateral recognition arrangements, under ISO/IEC 17025 for laboratory testing, ISO/IEC 17020 for inspection and surveillance, and ISO/IEC 17021-1 and ISO/IEC 17065 for system and product certification. This chain ensures the reports and certificates issued are accepted worldwide.

Whether this test can be offered within accredited scope depends on your product and the standard applied; since accreditation is method-based, the scope is confirmed in writing at the quotation stage.

Scope and authorisations

Related Regulations

2001/83/EC Directive on Medicinal Products for Human Use
GMP Guide (EudraLex Volume 4)

Pharmaceutical Analysis — What Does This Testing Field Cover?

The section below describes the field that the Residual Solvents test belongs to; the conditions and acceptance criteria of this particular test are given in the sections above. The scope specific to your product is confirmed in writing at the quotation stage.

Pharmaceutical analysis determines the identity, purity, quantity and behaviour of an active substance and of the finished product. What sets this family apart is that the methods are largely defined in PHARMACOPOEIAS: the European Pharmacopoeia (Ph. Eur.) and the United States Pharmacopeia (USP) give both the method and the acceptance framework together.

The binding nature of the pharmacopoeial method shapes how the field works. In other sectors a laboratory can choose a suitable method, whereas here the method in the monograph governs; if an alternative method is to be used, its equivalence must be demonstrated. This is what makes results comparable worldwide.

Analyses are carried out in several groups. Identity and assay (HPLC, UV, titration) show what the product is and how much active substance it contains. The impurity profile and residual solvents look for unwanted compounds arising from the manufacturing process. Elemental impurities address metals originating from catalysts and equipment. Dissolution and disintegration behaviour is the most important in vitro indicator of how the drug will be released in the body.

The DISSOLUTION TEST is one of the most critical measurements in the field. It is not enough for a tablet to contain the right amount of active substance; that substance must dissolve at a suitable rate. The dissolution profile is used to assess the effect of formulation changes on bioavailability and holds a central place in generic drug licensing.

METHOD VALIDATION is a mandatory step in this family. If a pharmacopoeial method is used, it is verified that the method works properly under that laboratory's conditions. If an in-house method has been developed, it is validated against parameters such as linearity, precision, accuracy, specificity, limits of detection and quantification, and robustness. A result produced with an unvalidated method cannot be used in a licence dossier.

Stability studies determine shelf life and are the longest-running work in the field. The product is held under defined temperature and humidity conditions, analysed at set intervals, and the results become the basis of the shelf life and storage condition claims. Accelerated conditions give preliminary information but real-time data is what counts.

The microbiological side is a separate body of work: microbial enumeration, testing for specified microorganisms, sterility testing for sterile products and the bacterial endotoxin test. For sterile products, packaging integrity and sterilisation validation also come into play.

Data integrity has moved to the centre of inspections in recent years. It is not enough for the result to be correct; the raw data must be traceable, unalterable and auditable. Validation of electronic record systems has therefore become an inseparable part of analysis.

Method groups in this field

Identity and assay
HPLC, UPLC, UV-Vis spectrophotometry, titration, identity confirmation by FTIR.
Impurities and residues
Related impurities, degradation products, residual solvents (GC headspace), nitrosamine screening.
Elemental impurities
Determination of elemental impurities by ICP-MS and ICP-OES and the associated risk assessment.
Physicochemical
Dissolution and disintegration, hardness, friability, uniformity of dosage units, water content (Karl Fischer), particle size.
Microbiological
Microbial enumeration, specified microorganisms, sterility, bacterial endotoxin, preservative efficacy.
Stability
Real-time and accelerated stability studies; photostability and in-use stability.

Commonly confused in this field

The pharmacopoeial method is binding; an alternative method may be used only by demonstrating its equivalence.
A result produced without method validation cannot be used in a licence dossier.
Accelerated stability does not replace real-time data; shelf life is supported by real-time results.
The dissolution profile is sensitive to apparatus type, agitation rate and medium; the conditions must be complete in the report.
A shortcoming in data integrity produces a non-conformity in an inspection even when the result is correct.
A change of formulation or supplier requires analytical comparison and, where necessary, a new stability study.

Which decisions these results support

The licence dossier and batch release
Determining shelf life and storage conditions
Method transfer and method validation
Incoming raw material acceptance control from suppliers
Assessing the effect of a formulation change on bioequivalence

Related Tests

Frequently Asked Questions About Residual Solvents

Isn't analysis needed for Class 3 solvents?

Class 3 solvents have low toxicity and have a general acceptable level; if staying below this level can be shown, general tests such as loss on drying may be accepted instead of specific analysis. The approach must be justified in the marketing authorisation dossier.