Residual Solvents – Basics, Classification and Assessment

Solvent – A substance, majorly liquid capable of dissolving or diluting other substances to form a solution.  Generally, several solvents are used in the manufacturing of drug substance, excipients and drug products as a routine practice. The solvents are used to enhance the solubility, yield and to determine several critical factors needed for the final product, considered as a critical element in the manufacturing process.

The solvents are organic and volatile in nature that are evaporated during the processing steps. However, these solvents cannot be completely removed as a whole by practical manufacturing techniques from the desired product. The residues or traces of solvents remain in the final products hence termed as “residual solvents”.

The residual solvents don’t possess any therapeutic benefit so, they should be removed or controlled to a specific level in the final product the extent possible to meet product specifications, good manufacturing practices, or other quality-based requirements.

Based on the learning it should be noted that the residual solvents are to be controlled and monitored for human exposure. World Health Organization (WHO) proposed a limit for exposure of toxic chemicals by “Acceptable Daily Intake (ADI)”. Specific to drugs, a new measure “Permitted Daily Exposure (PDE)” is defined to represent the pharmaceutically acceptable intake” for toxic materials. 

All the solvents to be used in the manufacturing of pharmaceutical products must be evaluated and justified for the limits based on the PDE.

It is recommended to limit to acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. Drug products should contain no higher levels of residual solvents than can be supported by safety data.

It is only necessary to test for solvents that are used or produced in the manufacture or purification of drug substances, excipients, or drug product. Drug product should also be tested if a solvent is used during its manufacture. The “permitted daily exposure” (PDE) is a pharmaceutically acceptable intake of residual solvents.

Classification of Residual Solvents:

Acceptable Limits of Residual Solvents:

Class 1 Solvents

Class solvents should not be used in the manufacturing of drug substances, excipients, and drug products. These types of solvents are not recommended because of their unacceptable toxicity or their deleterious environmental effects.

Class 2 Solvents

Class 2 solvents should be limited in pharmaceutical products because of their inherent toxicity.

Class 3 Solvents

Class 3 solvents may be less toxic and of lower risk to human health. These solvents are not to have any human health hazard at levels normally accepted in pharmaceuticals.

Other Solvents

The other solvents may also be of interest to manufacturers of excipients, drug substances, or drug products. However, no adequate toxicological data on which to base a PDE was found. Manufacturers should supply justification for residual levels of these solvents in pharmaceutical products.

Acceptable Limits:

“Likely to be present” refers to the solvent used in the final manufacturing step and to solvents that are used in earlier manufacturing steps and not removed consistently by a validated process.

Class 3:

• If only Class 3 solvents are present, a non-specific method such as loss on drying is sufficient.
• It is considered that amounts of these residual solvents of 50 mg per day or less (corresponding to 5000 ppm or 0.5% under Option-1) would be acceptable without justification.
• Higher amounts may also be acceptable provided they are realistic in relation to manufacturing capability and good manufacturing practice.

Class 2:

• Two options are available to assign limits for Class 2 solvents.
• The concentration limits in ppm stated in Table 2 can be used. They were calculated using below equation considering a product mass of 10 g administered daily.

Option-1: Concentration (ppm) = (1000 ug/mg x PDE (mg per day)) / dose (g per day)

The Option-1 to be applied if the daily dose is not known or fixed.

If all excipients and drug substances in a formulation meet the limits given in Option-1, then these components may be used in any proportion. No further calculation is necessary if the daily dose does not exceed 10 g.

The Products that are administered in doses greater than 10g per day should be considered using Option-2.

Option-2 may be applied by adding the amounts of a residual solvent present in each of the components of the drug product. The sum of the amounts of solvent per day should be less than that given by the PDE.

When residual solvents are different classes are used in the manufacturing, ideally, they should be controlled as described below.

In the event of manufacturing if:

• Class 3 solvents are used; they should be controlled with a loss on drying < 0.5%.
• Class 2 solvents are used; they should be controlled below the Option-1 limit.
• Class 2 and Class 3 solvents are used; they should be controlled below the Option-1 limit and < 0.5% respectively.
• If solvents of Class 2 or Class 3 are present at greater than their Option-1 limits or 0.5%, respectively, they should be identified and quantified.
• Class 1 solvents are used; they should be identified and quantified.