Cells and cell-derived reagents form the basis of an operationally challenging class of test methods used in execution of product potency testing (stability and lot release), assessments of pharmacokinetic/pharmacodynamic (PK/PD) profiles, detection of antidrug antibodies (ADAs) or neutralizing antibodies (NAB), and characterization and comparability testing of biopharmaceutical products. Frequently, cell-based assays provide the only measurement of the tertiary/quaternary structure of each batch of product at the time of lot release and during stability testing to assist in determining product shelf-life. Cultured cells themselves are often used to generate monoclonal antibodies (MAbs), enzymes, or substrates for use as critical reagents in other types of tests, including ligand binding and enzymatic assays. In all these applications, the cells serve as highly critical, highly complex “reagents” that require distinct characterization and control measures to ensure operational consistency over time.
Cells are sensitive to innumerable chemical and physical elements that can alter expression of their cellular proteome and change growth characteristics or responsiveness to ligands/biopharmaceuticals. Establishment and characterization of homogeneous, stable cell banks are necessary to ensure that starting cellular material for each assay is as consistent as possible. Appropriately established and stored master and working cell banks (MCBs and WCBs) provide a continuous supply of viable cells to generate accurate, reliable results within specified test methods or provide the cell-derived reagents used in those methods.
Although the strategy for preparing cell banks is clearly defined by regulators for cells used to produce biotechnology products, it is less clear what strategies should be applied to cells that are used solely as part of analytical or bioanalytical test methods. An early FDA points-to-consider (PTC) guidance on characterization of cell lines for producing biologicals (1) outlined many MCB and WCB characterization requirements that were later adopted into ICH Q5D for production cell lines (2). But it is still common to find the phrase PTC testing used in relation to the list of tests applied to nonproduction cell banks even though that guidance was not intended to apply to such banks.
In the absence of clarifying information about the significant differences in intended use between production cell lines and those used for analytical/bioanalytical methods, some laboratories choose to apply the entirety of the PTC guidance to both. Conversely, others fail to establish cell banks at all for analytical use, severely jeopardizing the desired state of assay control. The US Pharmacopeia recently published a suite of chapters — <1032> Development (3), <1033> Validation (4), and <1034> Assay Analysis (5) — providing guidance on good manufacturing practice (GMP) potency bioassays. Several paragraphs in USP <1032> provide a general outline for MCB and WCB preparation; however, specific details are not provided to assist laboratories with the less obvious but still critical aspects of creating, characterizing, and storing MCBs and WCBs.
Recommendations presented herein support and significantly elaborate on principles noted in USP <1032> for establishment and characterization of mammalian and bacterial cell banks used to support analytical/bioanalytical testing. These approaches may also be extrapolated (when applicable) to include cells used for reagent production, for growing viruses used in test methods, and so on. These strategies represent our combined opinions on best practices in establishment, characterization, and maintenance of controlled and consistent cell sources using a risk-based and product-phase–appropriate approach. Each sponsor should determine which recommendations to adopt and when each will be performed based on the level of risk acceptable in developing and validating methods that use cells or cell-derived reagents.
References
(1) CBER. Points to Consider in the Characterization of Cell Lines Used to Produce Biological Products. US Food and Drug Administration: Rockville, MD, 1993; www.fda.gov/downloads/biologicsbloodvaccines/safetyavailability/ucm162863.pdf.
(2) ICH Q5D: Derivation and Characterization of Cell Substrates Used for Production of Biotechnological/Biological Products. US. Fed. Reg. 63(182) 1998: 50244–50249
(3) USP <1032> Development and Design of Biological Assays. Pharmacop. Forum 36(4) 2010: 956.
(4) USP <1033> Validation of Biological Assays. Pharmacop. Forum 36(4) 2010: 986.
(5) USP <1034> Analysis of Biological Assays. Pharmacop. Forum 36(4) 2010: 1005.
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