2016 White Paper on Recent Issues in Bioanalysis: Focus on Biomarker Assay Validation (BAV): (Part 2 – Hybrid LBA/LCMS and Input from Regulatory Agencies)

Abstract

The 2016 10th Workshop on Recent Issues in Bioanalysis (10 WRIB) took place in Orlando, Florida with participation of close to 700 professionals from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations, and regulatory agencies worldwide. WRIB was once again a 5-day, weeklong event - A Full Immersion Week of Bioanalysis including Biomarkers and Immunogenicity. As usual, it is specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small and large molecules involving LCMS, hybrid LBA/LCMS, and LBA approaches, with the focus on biomarkers and immunogenicity. This 2016 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. This White Paper is published in 3 parts due to length. This part (Part 2) discusses the recommendations for Hybrid LBA/LCMS and regulatory inputs from major global health authorities. Parts 1 (small molecule bioanalysis using LCMS) and Part 3 (large molecule bioanalysis using LBA, biomarkers and immunogenicity) have been published in the Bioanalysis journal, issues 22 and 23, respectively.

The Decennial Index of The White Papers in Bioanalysis: ‘A Decade of Recommendations (2007–2016)’

“…If biotransformations of biotherapeutics are present in quantities of more than 10% of the starting material, it was recommended to follow the MIST guidance regarding quantification recommendations. For quantities below 10%, the minor modified biotherapeutic is likely to have less impact on the overall activity, depending on how important the b iotransformation is to the biotherapeutic [15].…”

“…LCMS assays using IA enrichment should consider critical reagent sourcing, resupply strategies and long-term management [13]. Selectivity should be tested in both pooled control and predose patient matrices; the effects of specific ligands, such as soluble targets, at expected physiological concentrations upon drug quantitation in spiked QCs should be examined; as well as the impact of added ADAs of known high titers [15]. Recovery and digestion efficiency should be examined during method validation.…”

“…It is also generally less prone to matrix interference due to high specificity offered by the detection step. Scientists ideally should consider developing LBA and hybrid methods in parallel with a clear stopping point to deciding which one to proceed with based on available results [15].…”

“…Parallelism experiments should be performed during validation and potentially also with (pooled) incurred samples. The issue of reagent management for hybrid LBA/ LCMS assays requires c onsiderations similar to LBA reagents including reagent stability, suitability and lot-to-lot comparability [15].…”

Automation of LBA-LC-MS/MS assays

“…Despite the obvious needs, LC-MS/ MS is still viewed today as being cutting-edge technology for supporting clinical PK of large molecules. Today, the biopharma industry is quickly evolving to a point where LC-MS/MS technology is being viewed as a standard tool in the armamentarium for regulated bioanalysis of biotherapeutics [1,2]. The FDA has certainly been engaged in discussions regarding this evolution in bioanalytical technology.…”