USP Product-Class Standards for Biologics

While the current pharmaceutical marketplace is still dominated by drugs that are small, chemically synthesized entities, biologics and biotechnology-derived articles continue to gain importance and marketshare. The US Pharmacopeial Convention (USP) has been setting standards for biologics and biotechnology-derived articles of all classes, from highly purified small peptides, such as insulin and glucagon (which are both multimanufacturer products), to highly complex biological mixtures, like pancreatin or heparin. The flexible monograph mechanism allows the accommodation of multisource materials as well as the application of different, yet equivalent, procedural approaches to the determination of established quality attributes for a given molecule. USP has been developing, and continues to develop, monographs for products where biosimilars already exist in other markets (e.g., erythropoietin and filgrastim [monograph proposal in Pharmacopeial Forum 36(5)]). The expected increase in biologics manufactured by multiple manufacturers in the US market underscores the importance of public standards that aid in product-characterization and comparability assessment.

Tina Morris, PhD

Scientifically sound and broadly applicable public procedures form the basis for the consistent evaluation of any biologic. USP General Chapters for biologics provide procedures and acceptance criteria that are representative of current scientific industry practice and assure that key attribute measurements are performed in a consistent and appropriate manner. This pertains to the assessment of primary structure (e.g., Harmonized Chapter Peptide Mapping <1055>), post-translational modifications (i.e., Glycoprotein and Glycan Analysis – General Considerations <1084>) and, importantly, also to the correct determination of strength or potency via biological assays in connection with established World Health Organization's International Standards (IS). Beyond that, USP establishes and maintains key standards that speak to the limitation of harmful impurities (Bacterial Endotoxins Test <85>) as well as the quality control of important process and ancillary materials used in biologic-drug manufacturing (Protein A Quality Attributes <130>).

Biological products can be divided into molecular classes based on their structure and function (e.g. peptide hormones, enzymes, glycosaminoglycans, immunoglobulins, and others). For many of these molecule classes, established platform approaches exist in terms of manufacturing, regulatory expectations (often reflected in FDA guidance to industry), and consequently, analytical characterization and quality control. Approaching characterization and comparability by product class as much as possible affords important advantages. For instance, this approach provides the opportunity to establish and define acceptable assay approaches in crucial areas, such as potency determination, detection of common process impurities, or characterization of known, class-specific post-translational modifications. These approaches, in turn, are linked to general and public (compendial) procedures that are not reliant on a single manufacturer's experience. The procedures also clearly establish the baseline for what is "good enough"for the measurement of a given quality attribute. Further, a class approach helps define and establish critical quality attributes that are common to a class of molecules rather than to an individual product, and can help focus and delineate scientific discussions around product identity and uniqueness.

USP is establishing an expert panel to create Quality Attributes of Therapeutic Monoclonal Antibodies <129> to apply these principles to this important class of molecules. In the area of low molecular weight heparins (LMWH), the existing USP panel is already working on Anti-Factor IIa and Anti-Factor Xa Assays for Low Molecular Weight Heparins <208> and Low Molecular Weight Heparin Molecular Weight Determinations <209>, which are class-specific procedural General Chapters that will establish consistency in how LMWH products are analyzed in terms of potency and molecular-weight distribution, two critical product attributes. Class standards fully support individual active pharmaceutical ingredient and product monographs for individual medicines, aid comparability, and facilitate the establishment of appropriate acceptance criteria. Class standards form an important new component in USP's standards portfolio designed to support current and future needs of biopharmaceutical quality control, but most importantly in support of our mission to protect public health.

Tina Morris, PhD, is vice-president of biologics and biotechnology at the US Phamacopeial Convention, tsm@usp.org.