This general information chapter is intended to provide common terminology for impurities and degradation products that may be present in compendial drug substances and drug products. Impurities or degradation products in drug substances can arise during the manufacturing process or during storage of the drug substance. The degradation products in drug products can arise from drug substances or reaction products of the drug substance with the environment, with an excipient, or an immediate container–closure system. Biological and biotechnological products, fermentation products and semisynthetic products derived therefrom, and radiopharmaceutical products are not covered in this chapter.

Communications about impurities and degradation products in compendial articles may be improved by including in this Pharmacopeia the definitions of terms and the contexts in which these terms are used. (See Definitions below.) There has been much activity and discussion in recent years about the definition of terms. Certain industry-wide concerns about terminology and context deserve widespread publication and ready retrievability and are included here. See section 5.60, Impurities and Foreign Substances in section 5, Monograph Components under General Notices and Requirements, as well as the general chapter Ordinary Impurities 466. Some other general chapters added over the years have also addressed topics of purity or impurity as these have come into focus or as analytical methodology has become available. Analytical aspects are enlarged upon in the chapter Validation of Compendial Procedures 1225.

Purity or impurity measurements for drug products present a challenge to Pharmacopeial standards-setting. Where degradation of a drug product over time is at issue, the same analytical methods that are stability-indicating are also purity-indicating. Resolution of the active ingredient(s) from the excipients necessary to the preparation presents the same qualitative problem. Thus, many monographs for Pharmacopeial preparations feature chromatographic assays. Where more significant impurities are known, some monographs set forth specific limit tests. In general, however, this Pharmacopeia does not repeat impurity tests in subsequent preparations where these appear in the monographs of drug substances and where these impurities are not expected to increase. It is presumed that adequate retention specimens are in storage for the exact batch of drug substances used in any specific lot of a drug product. Whenever analysis of an official article raises a question of the official attributes of any of the drug substances used, subsequent analysis of retention specimens is in order.

The specification for a drug product should include a list of degradation products expected to occur during manufacture of the commercial product and under recommended storage conditions. Stability studies, knowledge of degradation pathways, product development studies, and laboratory studies should be used to characterize the degradation profile. The selection of degradation products in the drug product specification should be based on the degradation products found in batches manufactured by the proposed commercial process.

This rationale should include a discussion of the degradation profiles observed in the safety and clinical development batches and in stability studies, together with a consideration of the degradation profile of batches manufactured by the proposed commercial process. For degradation products known to be unusually potent or to produce toxic or unexpected pharmacological effects, the quantitation/detection limit of the analytical procedures should be commensurate with the level at which the degradation products should be controlled.

For drug products the concept for setting degradation product limits is based on sound scientific judgment as applied to available data on the safety and stability of the drug product, data that may include the degradation pathways of the drug substance, the manufacturing process, known excipient interactions, any safety assessment studies, stability studies conducted under the recommended storage conditions, and ancillary studies that may provide additional information on the stability profile of the drug product. Impurities that are not degradation products (e.g., process impurities from the drug substance) are often not controlled in the drug product, as they are typically controlled in the drug substance and these impurities are not expected to increase over time. Additional guidance for setting limits can be found in various ICH and FDA guidance documents, as well as in the USP monograph submission guidelines.

Documented evidence that the analytical procedure used to evaluate impurities or degradation products is validated and suitable for the detection and quantification of impurities or degradation products should be established.

Drug products should contain levels of residual solvents no higher than can be supported by safety data (see Residual Solvents 467).