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 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 Industrial Concepts below.) See Foreign Substances and Impurities, in the section Tests and Assays, under General Notices and Requirements, as well as the recently adopted 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 Methods 1225.

Monographs on bulk pharmaceutical chemicals 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 on finished preparations present a challenge to Pharmacopeial standard setting. Where degradation of a preparation 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 bulk pharmaceutical chemicals and where these impurities are not expected to increase. It is presumed that adequate retention specimens are in storage for the exact batch of bulk chemicals used in any specific lot of a preparation. Whenever analysis of an official preparation raises a question of the official attributes of any of the bulks used, subsequent analysis of retention specimens is in order.

Foreign Substances

Residual Solvents

Toxic Impurities

Concomitant Components

Signal Impurities

Ordinary Impurities

Related Substances

Process Contaminants

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 should proceed on a rational basis so that everyone involved in the development and approval phases can carry on their work in a predictable fashion. 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 has been suggested that impurities should be identified when they exceed some set amount, e.g., 0.1, 0.3, or 0.5%. It is more rational to identify impurities 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.

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

(1) the toxicology of a drug substance containing typical levels of impurities and/or the toxicology of impurities relative to a drug substance;

(2) the route of administration, e.g., oral, topical, parenteral, or intrathecal;

(3) the daily dose, i.e., frequency and amount (micrograms or grams) administered of a drug substance;

(4) the target population (age and disease state), e.g., neonates, children, or senior citizens;

(5) the pharmacology of an impurity, when appropriate;

(6) the source of a drug substance, e.g., synthetic, natural product, or biotechnology;

(7) the duration of therapy, i.e., administration over a long period (treatment of chronic conditions) versus administration intended for a short duration (treatment of acute conditions); and

(8) the capability of a manufacturer to produce high-quality material at a reasonable cost to consumers.

Concepts for setting impurity limits in bulk drug substances are the concerns of the regulatory and compendial agencies as well as the pharmaceutical industry. The basic tenet for setting limits is that levels of impurities in a drug substance must be controlled to ensure its safety and quality throughout its development into and use as a drug product. The concepts are derived from issues and experiences with drug substances from traditional sources and technologies. Issues arising from biotechnologically produced drug substances, e.g., recombinant DNA and hybridomas, are still being defined and so are not necessarily covered by these concepts. However, the concepts can serve as a general foundation to address specific issues arising from biotechnology.

The setting of limits on impurities in drug substances 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. 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 in a drug substance are suitable for their intended purpose at each stage in the development.

An impurity is any component of a drug substance (excluding water) that is not the chemical entity defined as the drug substance. The impurity profile of a drug substance is a description of the impurities present in a typical lot of a drug substance produced by a given manufacturing process. The description includes the identity or some qualitative analytical designation (if unidentified), the range of each impurity observed, and the classification of each identified impurity.

Following are two more terms that enlarge upon those given under Definitions.

At the initial IND filing, the chemical nature of a bulk substance has generally been defined. The manufacturing process normally is in an early stage of development, and materials may be produced on a laboratory scale. Usually few batches have been made and, therefore, little historical data are available. The reference materials of a drug substance may be relatively impure. Limits for the purity of a drug substance are set to indicate drug quality. The setting of limits on related substances and process contaminants can be characterized as follows.

(1) 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.

(2) 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.

(3) Limits for residual solvents are based on the known toxicology of the solvents and on the manufacturing capabilities and dosing regimens.

(4) General inorganic contaminants 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 metal contaminants that appear during manufacturing should be monitored by appropriate analytical techniques, and limits should be set based on the toxicological properties of these metals.

(5) Appropriate limits are set for impurities known to be toxic.

(6) 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.

During the IND phases of drug development, the manufacturing process for a drug substance may undergo a number of revisions. Generally, the scale will have changed from laboratory size and will approach or reach full production batch size. A number of batches will normally have been produced, and a historical data base of the results of testing for impurities will exist. When significant changes in a manufacturing process are made, the impurity profile should be reviewed to determine if the toxicological studies are still supportive.

At the NDA stage a reference standard of defined purity is available, analytical methods have been validated, impurity and degradation profiles are known, and enantiomeric purity has been evaluated. The setting of limits on related substances and process contaminants can be characterized as follows.

(1) Consistency of the impurity profile of a drug substance has been established.

(2) IND limits for total and individual impurities (identified and unidentified) are reviewed and adjusted based on manufacturing experience and toxicological data.

(3) Impurities present in significant amounts are identified and individual limits are set. However, it is not always possible to identify and/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.

(4) The impurity profiles of the lots designated for marketing should not be significantly different from those of the lot(s) used for toxicological and clinical studies.

(5) The composition material balance should be used, if possible, to evaluate the adequacy of the controls.

(6) Limits for residual solvents are based on the known toxicology of the solvents and on the manufacturing capabilities and dosing regimens.

(7) Limits are set for inorganic contaminants 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 metal contaminants that appear during manufacturing.

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

The drug substance for a pharmaceutical product eligible for ANDA status normally is 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 profiles. Limits can then be set based on the more detailed concepts described for NDA filing, including review of compendial monographs for appropriateness.