The 5th Workshop on Recent Issues in Bioanalysis (WRIB) was organized by the Calibration and Validation Group as a 2-day full immersion workshop for pharmaceutical companies, CROs and regulatory agencies to discuss, review, share perspectives, provide potential solutions and agree upon a consistent approach to recent issues in the bioanalysis of both small and large molecules. High quality, better compliance to regulations and scientific excellence are the foundation of this workshop. As in the previous editions of this significant event, recommendations were made and a consensus was reached among panelists and attendees, including industry leaders and regulatory experts representing the global bioanalytical community, on many 'hot' topics in bioanalysis. This 2011 White Paper is based on the conclusions from this workshop, and aims to provide a practical reference guide on those topics.

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.

ABSTRACT. The A2 harmonization team, a part of the Global Bioanalysis Consortium (GBC), focused on defining possible tiers of chromatographic-based bioanalytical method performance. The need for developing bioanalytical methods suitable for the intended use is not a new proposal and is already referenced in regulatory guidance language. However, the practical implementation of approaches that differ from the well-established full validation requirements has proven challenging. Advances in technologies, the need to progress drug development more efficiently, and emerging new drug compound classes support the use of categorized tiers of bioanalytical methods. This paper incorporated the input from an international team of experienced bioanalysts to surmise the advantages and the challenges of tiered approaches and to provide recommendations on paths forward.

The A8 Global Harmonization Team focused on the documentation needed to support both small and large molecule bioanalysis. Current regulatory requirements were compiled and compared. The scope of the team's discussions included the validation report, the bioanalytical report, study plans, raw data, and bioanalytical summaries for the common technical document (CTD). A common high-level table of contents for method validation and sample analysis reports is proposed. Suggestions have been made as to how the CTD can be standardized to improve usability and review. Additional comments have been made on reports of failure investigations, study plans, and raw data documentation. The recommendation is that no prescriptive guidelines are required in these areas but should be led by good scientific practices subject to particular circumstances.