January 1, 1970 (Vol. , No. )
Edith Chang, Ph.D. USP
Tina Morris, Ph.D.
Reference standards can help provide solutions that support discovery, regulatory compliance, and process efficiency.
Compared to small molecule drugs, biologics have more complex structures and often cannot be fully characterized. Thus, quality determination of and quality control for biologic drugs often require the application of multiple analytical approaches including physicochemical methods, assays that measure for potency, or some combination thereof. Highly-characterized reference standards—biologic materials—that specifically address quality-related testing needs of the biopharmaceutical community could help here. These include standards for individual product assays; procedural standards for method development, qualification, and validation; standards for ancillary and process materials; and more.
Reference standards can be utilized in different ways by manufacturers and can help supply solutions that support discovery, regulatory compliance, and process efficiency.
- Reference standards can be used to assign a potency value to a biologic drug. For example, some reference standards of known potency include various analogs of insulin, and peptides such as desmopressin acetate and vasopressin, as well as glycosaminoglycans like the heparins.
- Confirmation of a drug substance’s identity is critical for determining quality. An array of reference standards are available that can be used in identification tests for biologic drug substances.
- For system suitability tests, well-characterized biologic reference standards are important for determining that a quality control assay is working appropriately. Reference standards like goserelin system suitability mixture, gonadorelin acetate-related compound A, and high-molecular weight insulin are specifically used to test for system suitability.
- For some enzymes, it is important to determine that the substrate being used is working as it should. For example, a reference standard for trypsin crystallized may be used by a manufacturer to determine substrate quality.
- Some biological reference standards are used to test for the presence of specific impurities. To measure dermatan sulfate and other galactosamine-containing impurities in heparin sodium, glucosamine hydrochloride and galactosamine hydrochloride reference standards can be used. Being able to test against well-characterized reference standards for galactosamine-containing impurities can help to ensure that their presence in a heparin product is below the acceptable limit.
- Certain species of a biologic substance can have differing molecular weights. Using a set of specific dextran reference standards of a known molecular weight, a manufacturer can calibrate for the appropriate dextran product being tested. A similar approach is used to determine molecular weight distribution and weight-average molecular weight of enoxaparin sodium, a commonly-used low-molecular weight heparin for anticoagulant therapy.
Edith Chang, Ph.D., is reference standards scientist IV, and Tina Morris, Ph.D., is vp of biologics & biotechnology, USP-NF, United States Pharmacopeial Convention (USP).