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Plasma protein binding (PPB) is an important parameter for a drug's efficacy and safety that needs to be investigated during each drug-development program. Even though regulatory guidance exists to study the extent of PPB before initiating clinical studies, there are no detailed instructions on how to perform and validate such studies. To explore how PPB studies involving bioanalysis are currently executed in the industry, the European Bioanalysis Forum (EBF) has conducted three surveys among their member companies: PPB studies in drug discovery (Part I); in vitro PPB studies in drug development (Part II); and in vivo PPB studies in drug development. This paper reflects the outcome of the three surveys, which, together with the team discussions, formed the basis of the EBF recommendation. The EBF recommends a tiered approach to the design of PPB studies and the bioanalysis of PPB samples: 'PPB screening' experiments in (early) drug discovery versus qualified/validated procedures in drug development.

Following intensive discussions, review, alignment of procedures and multiple surveys among their member companies, the European Bioanalysis Forum (EBF) is providing a recommendation on how to integrate incurred sample reproducibility (ISR) in the bioanalytical process. The recommendation aims to provide guidance throughout the lifecycle of a validated method, including the application of the method in study support. In its recommendation, the EBF considers both the internal discussions with EBF member companies, as well as the input provided in international meetings where ISR was discussed. The ultimate goal of the EBF recommendation is to ensure that bioanalytical methods can provide accurate and reproducible concentration data for pharmacokinetic and/or toxicokinetic evaluation, without any compromise, while safeguarding the optimal use of laboratory resources.

The relationship between the exposure to drug metabolites and overall drug safety has become an integral part of the drug-development process. In-depth discussions in the scientific community, as well as recent guidelines on Drug Safety Testing of Metabolites from the US FDA (often referred to as the MIST guidance and ICH M3(R2) from the International Conference on Harmonization (ICH), has brought clarity to the regulatory requirements of the sponsor company in providing documentation on circulating levels of qualifying metabolites. However, less attention has been given to the challenges now faced by the bioanalytical community in supporting these new guidance policies. In this paper, the European Bioanalysis Forum (EBF) is providing a recommendation on which quality standards to apply when assessing the (relative) abundance or absolute concentrations of metabolites. This paper is the result of both an intensive consultation within the EBF (through internal surveys amongst EBF member companies and discussions) and consultation of the broader bioanalytical community (through discussions at international conferences). These recommendations will provide an increased understanding of how to apply a tiered approach to metabolite quantification as part of the bioanalytical strategy. As such, it aims to provide support to the bioanalytical community on the appropriate level of validation required at each stage of the drug-development process.