This general information chapter covers impurities or degradation products in drug substances and degradation products in 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 an excipient or an immediate container–closure system. Biological, biotechnological, and radiopharmaceutical products are not covered in this chapter.

Concepts about purity change with time and are inseparable from developments in analytical chemistry. If a material previously considered to be pure can be resolved into more than one component, that material can be redefined into new terms of purity and impurity. Inorganic, organic, biochemical, isomeric, or polymeric components can all be considered impurities. Microbiological species or strains are sometimes described in similar terms of resolving into more than one component.

Communications about impurities or 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 term definition. Certain industry-wide concerns about terminology and context deserve widespread publication and ready retrievability and are included here. See Foreign Substances and Impurities in the section Tests and Assays 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.

Monographs for drug substances usually cite one of three types of purity tests: (1) a chromatographic purity test coupled with a nonspecific assay; (2) a chromatographic purity-indicating method that serves as the assay; or (3) a specific test and limit for a known impurity, an approach that usually requires a Reference Standard for that impurity. Modern separation methods clearly play a dominant role in scientific research today because these methods simultaneously separate and measure components and fulfill the analytical ideal of making measurements only on purified specimens. Nevertheless, the more classical methods based on titrimetry, colorimetry, spectrophotometry, single or multiple partitions, or changes in physical constants (or any other tests or assays) lose none of their previous validities. The purity profile of a specimen that is constructed from the results of experiments using a number of analytical methods is the ultimate goal.

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.

Pharmaceutical manufacturers interact with regulatory agencies in developing new drug substances and new drug products, and cooperate with the compendia in writing official monographs for the compendial articles the manufacturers produce. Establishment of impurity limits in drug substances and drug products should proceed on a rational basis so that everyone involved in the development and approval phases can carry on their work in a predictable manner. Although drug development in the United States is the primary focus of this section of the chapter, the subject also has broad applicability across national boundaries.

Manufacturers share with regulatory agencies and with the compendia the goal of making available to the public high-quality products that are both safe and efficacious. This goal continues to be achieved through rational approaches to the complex process of drug development. Tests used at all stages of drug development and marketing should not be interpreted individually but as a whole. Controls on raw materials and on manufacturing as well as those on drug substances, along with toxicological and clinical studies performed, ensure the safety and efficacy of drug products. It is more rational to identify impurities or degradation products and to set limits based on the factors detailed here, relying on the scientific judgments of manufacturers, the compendia, and regulators to arrive at sets of acceptable limits for identified and unidentified impurities or degradation products.

Limits are set for impurity levels or degradation products as one of the steps in ensuring the identity, strength, quality, and chemical purity of drug substances or drug products. The ultimate goal is to produce a final drug product of high quality that is safe and efficacious and remains so throughout its shelf life. The setting of limits for impurities or degradation products in drug substances is a complex process that considers a number of factors:

Concepts for setting impurity or degradation product limits in drug substances are based on chemistry and safety concerns. As such, limits for organic and inorganic impurities and residual solvents should be established for drug substances. The basic tenet for setting limits is that levels of impurities or degradation products in a drug substance must be controlled to ensure its safety and quality throughout its development to use in a drug product.

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, which 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. A rationale should be provided for exclusion of those impurities that are not degradation products (e.g., process impurities from drug substance and impurities arising from excipients).

For drug substances and drug products, limits are appropriately set no higher than the level that can be justified (e.g., safety data, literature references, etc.) and no lower than the level achievable by the manufacturing process and analytical capability. Where there is no safety concern, limits should be based on (a) data generated on actual batches of the drug substance or drug product, allowing sufficient latitude to deal with normal process and analytical variation, and (b) stability characteristics.

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.

The setting of limits on impurities or degradation products is an evolutionary process, beginning in the United States before an investigational new drug (IND) is filed and continuing until well after the approval of a new drug application (NDA). Therefore, it is appropriate to address different stages in drug development as separate issues. There are three points in the drug development process where the setting of limits may be significantly different: (1) at the initial IND application, (2) at the filing of the NDA, and (3) after NDA approval. The filing of an abbreviated new drug application (ANDA) is another activity in which limits are set on impurities or degradation products. Since the approach may vary from that of filing an NDA, it is addressed as a separate issue. The underlying assumption is that the analytical methods used to evaluate impurities or degradation products are suitable for their intended purpose at each stage in the development.

Limits are set on total impurities, and an upper limit may be set on any single impurity. The limit for total impurities should maintain, if possible, a nominal composition material balance.
Impurity profiles are documented. These are profiles of the lots of drug substances used in clinical studies and in toxicological studies that establish the safety of drug substances. The lots used in these studies should be typical products of the manufacturing process in use at that time.
Limits for residual solvents are based on the known toxicology of the solvents and on the manufacturing capabilities and dosing regimens.
General inorganic impurities are monitored by appropriate tests such as a heavy metals limit test and/or a test for residue on ignition. Traditional compendial limits are applied unless otherwise indicated. Specific residual metals that appear during manufacturing should be monitored by appropriate analytical techniques, and limits should be set based on the toxicological properties of these metals.
Appropriate limits are set for impurities known to be toxic.
If appropriate, enantiomeric purity is controlled.

Although water is not classified as an impurity, limits for water content may be needed to ensure the stability or ease of processing a drug substance.

Consistency of the impurity profile of a drug substance has been established.
IND limits for total and individual impurities (identified and unidentified) are reviewed and adjusted based on manufacturing experience and toxicological data.
Impurities present in significant amounts are identified and individual limits are set. However, it is not always possible to identify or prepare authentic substances for impurities. The labile nature of some impurities precludes this possibility. Limits may be set on these substances based on comparison of lots produced and used in toxicological and clinical studies.
The impurity profiles of the lots designated for marketing should not be significantly higher than those of the lot(s) used for toxicological and clinical studies.
The composition material balance should be used, if possible, to evaluate the adequacy of the controls.
Limits for residual solvents are based on the known toxicology of the solvents and on the manufacturing capabilities and dosing regimens.
Limits are set for inorganic impurities by appropriate tests such as a heavy metals limit test and/or by a test for residue on ignition. Traditional compendial limits are applied unless otherwise indicated. Based on toxicological properties, limits may be set for specific residual metals that appear during manufacturing.
Additional guidance for setting limits can be found in various ICH and FDA guidance documents.

After approval and marketing of a pharmaceutical product, significant changes may be made in manufacturing the drug substance. There may be technological, ecological, economic, or safety reasons for these changes. If they occur, the Pharmacopeial and NDA impurity and degradation product limits and rationale should be reviewed; the limits should be revised when indicated to ensure similar or improved quality of the drug substance or drug product.

The drug substance for a pharmaceutical product eligible for ANDA status is frequently an official article and should be well characterized analytically. Drug substances are typically available from multiple sources, and each source may have a different manufacturing process. Therefore, it is essential that the dosage form manufacturer evaluate each supplier's drug substance impurity or degradation profiles. Limits can then be set based on the more detailed concepts described for NDA filing, including review of compendial monographs for appropriateness.