Reference-Standard Material Qualification

The author reviews the types of reference-standard materials used in drug-product manufacturing, discusses current regulatory requirements, and outlines a reference-standard qualification program.
Apr 01, 2009

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 materials

Reference-standard materials can be broadly categorized as such:
  • Assays—used to determine potency for active pharmaceutical ingredients (APIs) and salts
  • Degradation products—used to identify and possibly to quantitate degradation products
  • Process impurities—used to identify and possibly quantitate process-related compounds
  • Resolution—used to determine assay performance or impurity method
  • Metabolites—used to identify and possibly to quantitate substances generated through a metabolic process.

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.

Compendial (primary):

  • Pharmacopeias such as the United States Pharmacopeia (USP), European Pharmacopoeia (EP), or Japanese Pharmacopoeia (JP)
  • Nationally recognized standard institutions such as the National Institute for Standards and Testing (NIST).

Noncompendial (secondary):

  • The user (custom manufactures or synthesizes the reference standard)
  • Contract manufacturer
  • Companies such as chemical suppliers.

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).