Organic impurities

Fill in the maximum daily dose of the API, in mg/day, and click on Go!.

Fill in the maximum daily dose of the API, in mg/day, and click on Go!.

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Residual solvents

Option 1: select the solvents and click on Go!.

Option 2 (API): Select the solvents (Class 2 or Class 3), fill in the maximum daily dose of the API, in mg/day, and click on Go!. This limit is only valid if the API is the only component of the formulation of which the solvent is a contaminant.

Option 2 (drug product): select the solvents (Class 2 or Class 3), fill in the maximum daily dose of the drug product, in mg/day, and click on Go!. This limit is valid for the drug product, as well as for the components of the formulation (API and excipients).

When the maximum daily dose exceeds 10g, Option 2 must be used.

When Option 2 is used and the limit is higher than Option 1 (i.e., Option 2 with a maximum daily dose lower than 10g), it should be demonstrated that the concentration of the residual solvent has been reduced to the practical minimum.

Mutagenic impurities

Select the class of the mutagenic impurity and fill in the maximum daily dose of the API, in mg/day. If applicable, change to duration of treatment to less than lifetime (three initial options). Then, click on Go!.

TD50 is only required for Class 1 impurities and it should be expressed in mg/(kg.day). The assessment of the toxicological studies by which the TD50 is derived is outside of the scope of this document.

The limit for Class 2 impurities is also valid for Class 3 impurities, should the applicant/API manufacturer choose not to conduct the mutagenicity assay.

When there are more than two Class 2 or Class 3 impurities, refer to Section 7.4 of ICH M7.

In the case of intermittent dosing, the duration of treatment should be based on the number of dosing days, not on the actual duration of treatment.

For mutagenic impurities with compound-specific acceptable intakes (ICH M7, Appendix 3) or N-nitrosamines (provisional limits), select the impurities, fill in the maximum daily dose of the API and click on Go!.

Elemental impurities

Option 1: select the elemental impurities and click on Go!.

Option 2a: select the elemental impurities, fill in the maximum daily dose of the drug product, in mg/day, and click on Go!.

Option 2b (API): select the elemental impurities, fill in the maximum daily dose of the API, in mg/day, and click on Go!. The Option 2b limit generated by this spreadsheet is only valid if the API is the only component of the formulation of which the elemental impurity is a potential contaminant.

Option 3: select the elemental impurities, fill in the maximum daily dose of the drug product, in mg/day, and click on Go!.

When the maximum daily dose exceeds 10g, Options 2a, 2b or 3 must be used.

Solubility (BCS)

Fill in the highest therapeutic dose, in mg, and the lowest solubility in physiological pH, in mg/mL. Then, click on Go!.

The test should be conducted at 37ºC and it should comprise the pH range of 1.2 to 6.8. Typically, pHs 1.2, 4.5 and 6.8 are tested.

ANVISA currently uses the highest therapeutic dose for BCS classification, not the largest dosage strength.