The US Food and Drug Administration defines a reference-standard material as a "highly purified compound that is well characterized" (1). The US Pharmacopeia (USP) defines reference-standard materials as "highly characterized specimens of drug substances, excipients, reportable impurities, degradation products, compendial reagents, and performance calibrators" (2). Scientists performing analytical testing use reference standards to determine quantitative (e.g., assay and impurity) as well as qualitative (e.g., identification tests) data, performance standards, and calibrators (e.g., melting point standards). The quality and purity of reference standards, therefore, are critical for reaching scientifically valid results.
Reference standards can be segregated into two groups: chemical and nuclidic (1). Chemical purity must be determined for both groups; nuclidic reference standards, however, also need to be evaluated for radionuclidic and radiochemical purity. This article addresss chemical reference standards only.
Types of reference-standard materialsReference-standard materials can be broadly categorized as such:
The level of characterization depends on the intended use of the reference standard. For example, a reference standard used to determine potency requires full characterization and qualification. A reference standard used as a resolution component or identification requires less discerning analyses.
Sources of reference-standard materials
Reference standards can be compendial or noncompendial and are typically obtained from the following sources.
Reference-standard materials that are synthesized by the user or supplied by a contract manufacturer or secondary company must be characterized (3). Both the reference standards and drug substance may be synthesized initially using the same process. The reference standard should be of the highest purity possible; the drug substance may require further purification to become a reference standard (additional purification steps used for a drug substance should be fully described and included in any regulatory filing).