title: Product quality considerations for mammalian cell culture process development and manufacturing.
abstract: The manufacturing of a biologic drug from mammalian cells results in not a single substance, but an array of product isoforms, also known as variants. These isoforms arise due to intracellular or extracellular events as a result of biological or chemical modification. The most common examples related to biomanufacturing include amino acid modifications (glycosylation, isomerization, oxidation, adduct formation, pyroglutamate formation, phosphorylation, sulfation, amidation), amino acid sequence variants (genetic mutations, amino acid misincorporation, N- and C-terminal heterogeneity, clipping), and higher-order structure modifications (misfolding, aggregation, disulfide pairing). Process-related impurities (HCP, DNA, media components, viral particles) are also important quality attributes related to product safety. The observed ranges associated with each quality attribute define the product quality profile. A biologic drug must have a correct and consistent quality profile throughout clinical development and scale-up to commercial production to ensure product safety and efficacy. In general, the upstream process (cell culture) defines the quality of product-related substances, whereas the downstream process (purification) defines the residual level of process- and product-related impurities. The purpose of this chapter is to review the impact of the cell culture process on product quality. Emphasis is placed on studies with industrial significance and where the direct mechanism of product quality impact was determined. Where possible, recommendations for maintaining consistent or improved quality are provided.
authors.affiliation: Baxter Healthcare, 9450 Winnetka Ave N, Brooklyn Park, MN, 55445, USA, michael_gramer@baxter.com.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gramer
mesh_terms: D000465:Algorithms; D061249:Batch Cell Culture Techniques / Q000295:instrumentation / Q000592:standards*; D001688:Biological Products / Q000378:metabolism / Q000592:standards*; D002469:Cell Separation / Q000295:instrumentation / Q000592:standards; D015195:Drug Design; D004345:Drug Industry / Q000592:standards*; D004867:Equipment Design / Q000592:standards*; D019544:Equipment Failure Analysis / Q000592:standards*; D038622:Internationality; D011786:Quality Control
chemical_list: D001688:Biological Products