3.2.S.2.3 - Control of Materials
Raw materials:
A list of raw materials used in the manufacturing process should be provided.
- All materials used in the manufacturing process are classified as raw materials, including starting materials, reagents, solvents, catalysts, substrates, auxiliary materials and recovered materials.
The specification and analytical methods for all raw materials should be provided, as well as batch analysis, when relevant.
- The quality of raw materials should be appropriate for their intended use.
- The specification of recovered solvents and recovered materials should be justified.
- If the specification of a recovered material contains wider acceptance criteria than those of the fresh grade, the DIFA holder should demonstrate that the quality of the API manufactured with the recovered material is equivalent to that of the API manufactured with the fresh grade.
Starting materials:
For starting materials, the following information should be provided:
- Name and chemical structure;
- Specification;
- Analytical methods;;
- name and address of manufacturers;
- Synthetic route for each manufacturer, including reagents, solvents and catalysts;
- Batch analysis; and
- Justification for selection of the starting material.
- The specification of the starting materials should be justified and should include, as applicable, tests for specified and unspecified impurities, total impurities, solvents, catalysts, elemental impurities and mutagenic impurities.
- For semisynthetic APIs whose starting material is obtained by fermentation or derived from a substance obtained by fermentation, the justification for selection of the starting material should include a discussion on the carry-over of impurities arising from the fermentation process (ex. DNA, proteins) into the API.
- For semi-synthetic APIs whose starting material is isolated from a botanical material or derived from a substance isolated from a botanical material, the justification for selection of the starting material should include a discussion on the carry-over of impurities arising from cultivation (ex. pesticides, heavy metals, aflatoxins) and the extraction process into the API.
- When there is more than one manufacturer of a starting material, a discussion regarding the specification of the starting material with respect to the differences in the manufacturing processs of different sources should be provided.
- A technically inadequate justification of the starting material will lead to a redefinition request.