Residual Solvents

Why test for residual solvents? It is important to test for residual solvents because manufacturing techniques may not completely remove these organic volatile chemicals. Solvents are used in the manufacturing process for a variety of reasons such as better yield or improving the purity or solubility of a drug. Solvents can be important elements in the manufacturing process, however, can also present a risk to the patient. Since they can be a risk to the patient and they have no therapeutic benefit, residual solvents need to be tested and controlled.

Safety data based on potential risk to human health has been established for residual solvents and different risk classes have been established by both the USP and ICH Q3C (R8). As listed in the USP and ICH Q3C the classes are:

Class 1 Solvents: Solvents to be avoided and should not be used in manufacturing drug substances, excipients and drug products. These are known human carcinogens and also present risks to the environment. If these substances are used, they need to be identified and quantitated.
Class 2 Solvents: These solvents should be limited in the manufacture of drug substances, excipients, and drug products. Class 2 solvents are non-genotoxic animal carcinogens and can be a causative agents’ for neurotoxicity or teratogenicity. If present in concentrations greater than those listed in USP and ICH Q3C, these solvents need to be identified and controlled.
Class 3 Solvents: Available data indicate that these solvents are less toxic in acute short-term studies and show that they are negative for genotoxicity. These solvents tend to have higher limits than Class 1 or 2.

Primera can work with you and your team to determine if your drug substance, excipients, or drug product have any residual solvents that result from manufacture, packaging or drug storage. We are experienced in running USP Chapter <467> procedures or we can develop and validate methods specifically for you by Head-Space Gas Chromatography (HS-GC) or Gas Chromatography – Mass Spectrometry (GC-MS).

Our team of experts will work with you to determine the best option for you. All work is conducted with adherence to cGMP practices and therefore will meet all regulatory requirements for your submission.

Maintaining state-of-the-art instrumentation to detect, identify and quantitate residual solvents is critical to our clients. Primera’s instruments for residual solvents analysis include:

Agilent 7890 and 6890 GCs with FID, TCD and NPD Detectors

Agilent 5977B and 5973 Mass Detectors
Agilent 7697 and 1888 Headspace Samplers

Primera’s typical approach to USP <467> is:

Screen Class 1 and Class 2 residual solvents via Procedure A per USP<467>
Confirmation of Class 1 and 2 solvents detected by Procedure A via Procedure B or C (quantitation) per USP<467>
Class III Residual Solvents by Procedure C or 0.5% Loss on Drying per USP<467> Chapter

Residual Solvents

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