1. INTRODUCTION
Biological assays (also called bioassays) are an integral part of the quality assessment required for the manufacturing and release of biological products. Biological products include biotherapeutics, vaccines, and cell and gene therapies. Bioassays commonly used for potency estimation can be distinguished from chemical tests by their reliance on a biological substrate (e.g., animals, living cells, functional complexes of target receptors, and immunological reagents). Because of multiple operational and biological factors arising from this reliance on biology and biochemical reactions, bioassays typically exhibit a greater variability than chemically based tests do. They produce measures of functional activity or potency relative to a standard, and rely on a fundamental assumption that the test and standard contain the same active constituents.
Bioassays are one of several methods with procedures and acceptance criteria that control critical quality attributes of a biological product. As described in the International Council for Harmonisation guideline ICH Q6B Specifications—Test Procedures and Acceptance Criteria for Biotechnological/Biological Products, section 2.1.2, bioassay methods may measure an animal’s biological response to the product, a biochemical or physiological response at the cellular level, enzymatic reaction rates, or biological responses induced by immunological interactions such as ligand- and receptor-binding. Over time, the scope of bioassay approaches is likely to expand. Therefore, this USP general chapter emphasizes validation approaches that provide flexibility to adapt to new bioassay technologies, new biological products, or both.
Good manufacturing practice requires that test methods used for assessing compliance of pharmaceutical products with quality requirements should meet appropriate standards for accuracy and reliability. Assay validation is the process of demonstrating and documenting that the performance characteristics of the method underlying a procedure meet the requirements for the intended application and that the assay is thereby suitable for its intended use. Validation of Compendial Procedures 〈1225〉 describes the assay validation parameters that should be evaluated for separation methods supporting small-molecule pharmaceuticals. Although the evaluation of these validation parameters is straightforward for these methods, their interpretation and applicability for bioassays and biological products is unclear. This chapter addresses bioassay validation from the point of view of the measurement of potency rather than mass or other physicochemical properties, with the purpose of aligning bioassay performance characteristics with uses of bioassays in practice.
Assessment of bioassay performance is a life cycle process (see Analytical Procedure Life Cycle 〈1220〉 and Biological Assay Chapters—Overview and Glossary 〈1030〉). Bioassay validation (called procedure performance qualification in these USP chapters) is a stage in the life cycle when bioassay method design and development has been completed and the SOP has been fully documented. Bioassay validation is guided by a validation protocol describing the goals (validation parameters and acceptance criteria), design (sample selection and replication strategy), and analysis of data from the validation study.
Parameters that will be addressed in this chapter are relative accuracy, IP (includes repeatability), linearity, and range, using what has become known as a dilutional linearity study. Definitions of these parameters are given in 3. Bioassay Validation Parameters. Other parameters, which are discussed in 〈1225〉 and ICH Q2(R2)—Guideline on Validation of Analytical Procedures, such as LOD and LOQ, are not considered in this chapter because they are mostly irrelevant to the uses of bioassay. These may be useful, however, in the validation of ancillary assays such as those used to score responders or measure response in an in vivo bioassay.
Repeatability has been omitted from the list of validation parameters because this is a component of IP, and there is no use in the bioassay that informs an acceptance criterion on this parameter. In addition, this is frequently built into the bioassay SOP as an acceptance criterion for replicate variability. Within-run replicates should nevertheless be included in the validation design to assess alternative release procedure formats (combinations of within-run and between-run replicates) and to facilitate design of other procedures.
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