The challenges for implementing Good Clinical Practices in the bioanalytical laboratory: a discussion paper from the European Bioanalysis Forum.

This manuscript reports back from the discussion in the European Bioanalysis Forum community on the challenges observed when implementing Good Clinical Practices in the bioanalytical laboratory. It is not intended to challenge any regulatory requirements but to open a discussion on where the bioanalytical community sees ambiguities on implementing Good Clinical Practices or areas where expectations are either felt not being owned by Bioanalysis or where Good Clinical Practices requirements are at risk of getting contaminated with requirements originating from Good Laboratory Practices. In addition to this, the discussions focused on three additional main challenges: the informed consent withdrawal, expedited reporting of unexpected results and the risk-based approach to quality management, The European Bioanalysis Forum community is continuing discussions, but already this manuscript should help to appreciate the challenges and to try and resolve them, involving all stakeholders.

Recommendations and feedback from the European Bioanalysis Forum Workshop: 1 year into ICH M10 - keeping our finger on the pulse.

The ICH M10 guideline on bioanalytical method validation and sample analysis is being adopted since 2023. However, and inevitably, some paragraphs or requirements remain ambiguous and are open for different interpretations. In support of a harmonized interpretation by the industry and health authorities, the European Bioanalysis Forum organized a workshop on 14 November 2023 in Barcelona, Spain, to discuss unclear and/or ambiguous paragraphs which were identified by the European Bioanalysis Forum community and delegates of the workshop prior to the workshop. This manuscript reports back from the workshop with recommendations and aims at continuing an open scientific discussion within the industry and with regulators in support of a science-driven guideline for the bioanalytical community and in line with the ICH mission - that is, achieve greater harmonization worldwide to ensure that safe, effective and high-quality medicines are developed and registered in the most resource-efficient manner.

Mechanistic modeling of a human IgG4 monoclonal antibody (tralokinumab) Fab-arm exchange with endogenous IgG4 in healthy volunteers.

Therapeutic IgG4 antibodies engage in Fab-arm exchange with endogenous human immunoglobulin G4 (IgG4 ) to form monovalent hybrid molecules. A mechanistic population model was developed to quantitatively characterize the dynamic Fab-arm exchange of tralokinumab, a human IgG4  monoclonal antibody currently being developed for the treatment of atopic dermatitis, with endogenous IgG4 in healthy volunteers. The estimated pharmacokinetic parameters for IgG4 were similar to those of immunoglobulin G1 or immunoglobulin G2 in humans. However, the mechanistically modeled clearance of half molecules is 21-fold higher, likely due to the loss of avidity for the neonatal Fc receptor. Half molecules of tralokinumab randomly associate with those of endogenous IgG4 to form monovalent hybrid molecules, which became the dominant form of tralokinumab within 1 day postdose in healthy volunteers. As the potency of monovalent tralokinumab is comparable with that of bivalent tralokinumab, the IgG4 Fab-arm exchange with endogenous IgG4 is not expected to affect the potency of neutralization of interleukin-13 in vivo.