Reference Substances / Qualification

Analytical testing is a critical part in every step of drug development and manufacturing. The qualitative and quantitative results generated from validated analytical testing provide first-hand information to control and ensure the quality and safety of raw materials, intermediates, and finished products. Like many other CMC (chemical, manufacturing and control) activities, analytical testing is also frequently outsourced. Many factors are attributed to this rapid market growth, including continuous outsourcing from pharmaceutical companies, growing pipelines for biological candidates, and increasing demand for more analytical details on drugs and process development by regulatory agencies. In response to the changing market dynamics, service providers are striving to provide analytical testing with quality, accuracy, and robustness all within tight timelines. As the contract research organizations (CROs) have become more integrated, small analytical labs need to establish their niche to succeed. Global contract anlytical Laboratories provide QC laboratory analysis, method development, validation and expert advice for both finished products and raw materials for pharmaceutical and biopharmaceutical companies. The US Food and Drug Administration defines a reference-standard material as a "highly purified compound that is well characterized" . 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". 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. Chemical purity must be determined for both groups; nuclidic reference standards, however, also need to be evaluated for radionuclidic and radiochemical purity. 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 and 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.