Main Workshop DAY 1 - Tuesday April 2, 2019, 7am to 6:45pm

"LCMS, HRMS & Hybrid DAY"

(You can click on each blue topic title below to see details, or simply scroll down to see details)

Day 1A: LCMS, HRMS & Hybrid - Innovation in Method Development and Novel Solutions

Innovation in Small Molecules Mass Spec

LCMS & HRMS Advancements for Small Molecules

Latest Updates on Hybrid Methods

2019 White Paper on LCMS, HRMS & Hybrid

  • Consensus and Conclusions on LCMS, HRMS & Hybrid - Innovation in Method Development and Novel Solutions for 2019 White Paper in Bioanalysis will be presented

 

Day 1B: ICH M10 BMV Draft Guideline - Chromatography Assays

Harmonized Topics among US FDA, EU EMA, Health Canada, Japan MHLW regulations

  • Topics will be announced once ICH Draft Guideline is Published

Unresolved Issues and On-going Industry/Regulators’ Discussions

  • Topics will be announced once ICH Draft Guideline is Published

Panel Discussion on ICH M10 BMV Draft Guideline Chromatography Assays

  • Industry Recommendations to ICH M10 Major Participating Regulatory Agencies

    • Dr. Brian Booth (US FDA / EWG Regulatory Chair)
    • Dr. Jan Welink (EU EMA / EWG Member)
    • Dr. Akiko Ishii (Japan MHLW / EWG Rapporteur)
    • Dr. Yoshiro Saito (Japan MHLW / EWG Member)
    • Dr. Anna Edmison (Health Canada / EWG Member)
    • Ms Thais Correa Rocha (Brazil ANVISA / EWG Member)

 

 

Day 1A Details:
LCMS, HRMS & Hybrid - Innovation in Method Development and Novel Solutions

Innovation in Small Molecules Mass Specs

  • Topic 1
    "Return of the Small Molecules: Episode I" - Evolution, Novel Development Strategies and Recent Advancements in Targeted Protein Degradation Small Molecules (PROTAC)
    • Innovative new Small Molecules drugs
      • How novel biological discoveries can expand the use of small molecules
      • Abandoning old traditional small molecules over-used targets for new innovative ones “thinking out of the box”
    • Traditional small molecules advantages vs biotherapeutics
      • Ability to easily reach tissues and intracellular targets
      • Good biodistribution and cell permeability
      • Oral bioavailability of small molecules
      • Simpler PK and no immunogenicity issues
      • Easy to synthesize, formulate and deliver
    • Early developments of PROTACT-like Small Molecules
      • Proteolysis-Targeting Chimeras (PROTAC) & Specific and Nongenetic IAP-dependent Protein Erasers (SNIPER)
      • Discovery Bioanalysis approaches to PROTAC developments
      • Bioanalytical challenges for PROTAC advantages for not to bind to the active site of a protein
        • Dealing with efficacy based on from transient binding
    • Using bifunctional tethered Small Molecule ligands for Targeted Protein Degradation
      • Impact on cells proteins destruction mechanism and potential application for oncology and neurodegenerative disorders
      • Effects on ubiquitin mechanism for maintaining protein homeostasis and transfer of ubiquitin to target protein for destruction
  •  

  • Topic 2
    Discovery of Selective RNA-Binding Small Molecules by Affinity-Selection Mass Spectrometry "Return of the Small Molecules: Episode I" - Evolution, Novel Development Strategies and Recent Advancements in RNA-targeting Small Molecules (Ribocil)
    • Innovation in Small Molecules by developing innovative strategies
    • Early developments of Ribocil-like Small Molecules
      • RNA-targeting small molecules for inhibit of RNA activities
      • Small molecules ability to bind to RNA functional secondary and tertiary structures such as unique binding sites or pockets
      • Selection of Small Molecule able to interact with RNA
    • Targeting the Riboswitches
      • Non-coding RNA structures located in messenger RNAs
      • Novel and unexplored class of drug targets
      • Change of conformation and impact on regulation of gene expression
    • Case Studies on characterization of Selective RNA-Binding Small Molecules by Affinity Selection Mass Spectrometry (ASMS)
      • Ribocil a highly selective chemical modulator of bacterial riboflavin riboswitches
      • Current development status of Non-coding RNAs as small molecule drug targets using ASMS
      • Applications of ASMS in the assessment of the binding of candidate molecules to receptors
        • Power of coupling LCMS with ultrafiltration, gel permeation, or size-exclusion chromatography
        • Selective detection of small molecule–non-coding RNA interactions
  •  

  • Topic 3
    Current Applications and on-going developments of Acoustic Dispensing - Mass Spectrometry (AD-MS) in Small Molecule Bioanalysis: Is this the Bioanalytical Platform of the Future?
    • Learning the recent developments of Acoustic Dispensing - Mass Spectrometry
      • A brand-new technique that offers unique & innovative advantages vs other direct analysis approaches already on the market
      • Acoustic-liquid handler
        • Piezoelectric transducer for acoustic sampling
        • Production of nL-scale droplets
        • ADE transfer technology
      • Open Pore Probe (OPP) sampling interface
      • 384-well microplate format
    • Bioanalytical applications of the next generation of ultra-high throughput platform for Drug Discovery & Development
    • Applications in pharmacokinetics and metabolism studies
      • Avoiding cleanup steps before MS analysis by direct plasma sample analysis
      • Case studies on direct analysis of plasma samples
        • Quantitative bioanalysis with cycle time of less than 1 sec/sample
        • Fit for purpose Bioanalytical Method Validation and discussion on key parameters evaluated
      • Overall Performance evaluation for handling direct human PK analysis without any sample preparation
  •  

  • Topic 4
    Patients Centric Microsampling, Impact on Bioanalytical Method Development and Additional BMV Steps: Real world experience in the clinical setting, what are the challenges the industry is facing?
    • Point-of-care home sampling approaches & patient centric technologies
      • What have we learnt from the pitfalls of microsampling
      • What type of bioanalytical assays should be made available to clinicians in the real-world setting?
      • Is the microsample representative?
    • How the bioanalytical scientist can help with trials at home & patient centric sampling
      • Teaching the patient to take the bioanalytical sample
        • Bioanalytical reflections on how this can work
      • How can bioanalytical scientist make sure patients know how important the sampling is to accurately measure analytes of interest
    • Overcoming bioanalytical challenges for home & patient centric sampling
      • Sample analysis for non-conventional microsampling formats
      • Additional validation steps
      • Sample transfer
      • Sample storage
    • New microsampling techniques and impact on method development
      • Emerging sampling technologies beyond VAMS and their application in Bioanalysis
    • Case studies on real world experience using VAMS in the clinical setting

 

LCMS & HRMS Advancements for Small Molecules

  • Topic 5
    Novel Ultrasensitive Microflow-LCMS Assays: Are we finally ready to Replace Accelerator Mass Spectrometry (AMS) for Microdosing Studies?
    • Are we ready to replace traditional AMS with Novel Microflow-LCMS Assays for microdosing?
      • Case studies with validated Microflow-LCMS Assays at pg/mL level LLOQ
      • How Microflow-LCMS techniques are able to provide sensitivity gains to enable new approaches or make formerly difficult approaches more routine
      • Method development challenges in using Microflow-LCMS for microdosing absolute bioavailability study
        • On-going progress using stable isotope labeled drugs
        • Strategies to avoid the isotopic interferences
      • Advantages of Novel Microflow-LCMS assays vs AMS-based assays
        • Significant cost and time saving
        • Better data quality by avoiding the use of radioactive drug
        • Exclusion of potential metabolite interference
    • Latest progresses in Microflow-LCMS for small molecule applications
      • Is it robust enough for routine sample analysis?
      • Unbiased method development tips and drawbacks
        • Pitfalls in using microfluids devices in bioanalysis
        • Microflow with trapping and without trapping approaches
      • Actual industry data confirming an increase in S/N between 10 to 100 times with Microflow LC vs. conventional approaches
        • Increase in ionization efficiency, reduction of source contamination and solvent consumption
  •  

  • Topic 6
    Complex Small Molecules Formulations: New Bioanalytical Challenges & Solutions to Overcome Issues with Drug Delivered by Nanomedicine Approaches
    • New developments in drug delivery and direct impact on Bioanalysis
      • How drug delivery sciences evolved from 2015 & 2016 White Paper in Bioanalysis Part 1 Recommendations
      • Lesson learnt from the application of the Recommendations
        • Updated perspective based on newly acquired experience on the bioanalytical considerations and project requirements to understand different elements of free/total
      • Learning updated approaches in for small molecules encapsulated drugs & nanoparticle drugs
        • Different solutions currently using SPE rather than liquid/liquid extraction approach
    • Nanomedicine draft FDA Guidance Bioanalysis section
      • Need to measure total, free, encapsulated drug when delivered by a nanomedicine approach
      • How to measure the free when it is so small relative to total
      • Formulation/chemistry is designed to be leaky or breakdown
      • Current Method submitted to Regulatory Agencies for the quantitation of Nanoparticle-Released Drug Concentrations
    • New case study data on actual validation that illustrates what is possible and what is not in this new field
      • Major focus on Stabilization as key feature to control complex delivery systems
        • Dealing with “compromises” about what it is not easy to do
    • What’s really innovative in Drug Delivery systems?
      • Bioanalysis of Dendrimer Delivered Drugs
      • Case studies for discussion on brand-new data for dendrimer delivered drugs
        • Challenges of stabilization of dendrimer
        • Release of drug
        • How to quality control stability & drug release
        • Validation approaches
    • Similarities between the bioanalytical challenges of LNP and Dendrimer Delivered Drugs
      • Free/total, stability, vehicle effect and distribution
  •  

  • Topic 7
    Advanced Applications of HRMS for the Quantification of Novel Transporter & CYP Small Molecule Biomarkers: A fast evolving field in Bioanalysis
    • Building on the 2018 White Paper in Bioanalysis Part 1 recommendations
      • Brand-new case studies from this fast-evolving field
        • Clinical study results to confirm suitability of Novel Transporter & CYP Small Molecule Biomarkers as a potential substitute for drug–drug interaction (DDI) study
        • Parallel studies conducted to demonstrate that endogenous biomarkers give the same DDI risk projections as dosing probe drugs
    • HRMS method development & BAV for CYP and transporter DDI evaluations
      • Need for robust and reliable assays to support the quantitation of small molecules biomarkers in plasma
        • Fit for purpose BAV for Novel Transporter & CYP Small Molecule Biomarkers
      • Triple quadrupole limitations vs power of HRMS to assess these potential biomarkers
      • Novel HRMS assays and applications in drug development to ensure DDI-related liabilities to establish safety and efficacy of NCE
      • Identification and solution of main challenges encountered with Novel Transporter & CYP Small Molecule Biomarkers
    • Overcoming endogenous interferences and sensitivity issues
      • Evaluation of parallelism, matrix effect and IS consistency in determining whether special extraction conditions
      • Achieving equivalent recovery from both authentic and surrogate matrix
    • Current interaction with Regulatory Agencies

 

Latest Updates on Hybrid Methods

  • Topic 8
    High Sensitivity Protein Biomarkers Quantification by Hybrid LBA/LCMS: Reaching Cytokines at low pg/mL and Advancements in Tissue Biomarker
    • Latest developments in protein biomarker quantification by hybrid LBA/LCMS
      • Improvements from 2017 White paper in Bioanalysis Part 2 recommendations
      • What’s new from the 2017 discussion and recommendations?
      • Improved best practices and new case studies to ensure high sensitivity in tissue assay development
      • Homogenization and extraction
      • Blood contamination in the tissue
      • Limitation of protein precipitation step and pellet digestion to reach high sensitivity
      • Hybrid LBA/LCMS using nanoflow/nanospray approaches for sensitivity improvements
      • Advantages of using antipeptide IA enrichment
      • Harsh denaturing tissue
    • New data in IA enrichment to maximize LCMS sensitivity & selectivity
      • Optimization of digestion time efficiency and bead density
      • Development of a high affinity immunocapture method
        • Target affinity capture reagent
        • Antibody capture reagent
    • Optimizing chromatography to improve sensitivity and remove co-eluting interferences
    • Use of additional sample cleanup using solid phase extraction (SPE) to increase sensitivity
  •  

  • Topic 9
    Absolute Accuracy for Biomarker Assays by Hybrid LBA/LCMS: Can Absolute Quantification (AQUA) technique be a suitable approach in Bioanalysis? Can AQUA Technique be Accepted by Regulators for Biomarkers Endpoints in Clinical Trials?
    • Regulatory Statement:
      • "Accuracy is one of the utmost fundamental requirements for validation of any assay including fit-for-purpose biomarker assays"
    • How the industry can work together to overcome the lack of absolute accuracy for Biomarkers LCMS and Hybrid LBA/LCMS assays not having an appropriate or exact reference standard
      • Can the use of Absolute Quantification (AQUA) technique help reach Absolute Accuracy?
      • Establishing analytic acceptance criteria for quantitative assays for Biomarkers by applications of AQUA in Regulated Bioanalysis
      • Addressing biomarker Hybrid LBA/LCMS assays accuracy issues
    • Current discussions on Absolute Accuracy in Biomarkers Hybrid LBA/LCMS assays
      • Struggles to establish a meaningful approach for validating biomarkers method accuracy
      • Understanding AQUA limitations as targeted quantitative technique for proteins and their modification states
        • Criteria for surrogate peptides synthesis with incorporated stable isotopes as internal standards to mimic native peptides formed by digestion
        • Ability to handle post-translational modifications by synthetic peptides containing covalent modifications
    • Case studies of AQUA application in biomarkers endpoints in clinical trials
      • Application of AQUA internal standard peptides to precisely and quantitatively measure the absolute levels of protein biomarkers
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