Managing the Analytical Lifecycle for Biotechnology Products

Biotechnology pipelines have demonstrated significant growth over the past decade, with many therapeutic candidates evolving in a single class of protein molecules: the monoclonal antibodies (MAbs). To develop such therapeutic candidates, a scalable drug development process must leverage in-house and industry-wide knowledge so biotechnology companies can address the economic and medical needs of 21st-century medicine. Biotherapeutics development is complex, resource intensive, and time consuming, taking some 10 years of effort to go from target validation to commercialization. This reality, coupled with rapid technological advances and evolving regulatory expectations, limits the ability of biotechnology companies to progress rapidly with their pipeline candidates. Also, the biopharmaceutical industry is heavily regulated, but most regulations are targeted at commercial products, with a significant gap in available guidance for earlier stages of product development. This two-part article discusses the analytical activities associated with the progression of biotherapeutic candidates from the early stages of clinical development through their appearance as licensed drugs on the market. The analytical program for a given biotherapeutic has a lifecycle analogous to that of a manufacturing process used to prepare material for clinical and commercial use. Here we examine the stages it goes through, and Part Two will provide more detail on method qualification, validation, and remediation. The lifecycle of analytical methods for biotechnology products can be divided into two distinct phases: a developmental phase (activities that span initial method development through use in a clinical program) and a validated phase (late-stage activities for methods used in commercial settings). Activities associated with the former are extensively described in scientific publications, whereas the validation phase is described in regulatory guidance documents such as those contained in the US Code of Federal Regulations (CFR), US Pharmacopeia (USP), and International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). An ICH guidance document covers validation activities for product registration, so the guidance is specifically applicable to commercial products (1). Although no specific guidance on method validation is available for earlier stages of product development, industry practices have evolved to provide assurance of acceptable method performance in such earlier stages. The generally accepted term for precommercial activities is method qualification, but the scope of that qualification, its timing with respect to the stages of product development, and its relationship to validation activities has not been consistently delineated or practiced. To organize qualification practices and requirements into a single logical construct, the spectrum of analytical activities can be thought of in a lifecycle model using the following fundamental principles: • The analytical lifecycle can be divided into well-defined segments that relate to each specific stage of product development. Organizing the analytical lifecycle this way provides a basis for consistency and scalability because it applies to multiple methods for multiple development candidates and commercial products. • Method validation is considered the pivotal point in this lifecycle because it justifies use of a method in commercial settings. In addition, this activity defines the point at which ownership of methods transfers from an analytical development group to a quality group. These activities are typically initiated after a sponsor has committed to The authors describe a chain of events that can lead from method development to quality by design.