Program and Topics
The year of the NEW Guidances in Bioanalysis - Comments and Questions are collected before the meeting to prepare this interactive discussion with the Regulators
Advanced Method Development and Troubleshooting in Bioanalysis
- Oligonucleotides: Bioanalytical challenges & solutions
- Dr. John Grundy, Vice President, PK & Clinical Pharmacology, Isis Pharmaceuticals, USA
- Dr. Laixin Wang, Method Development Group Leader, Tandem Labs, USA
- Growing interest in therapeutic oligonucleotides (>230 therapeutic programs; >90 already in the clinic)
- LBA vs. LC-MS/MS: Is it possible to achieve LBA sensitivity but with LC-MS/MS selectivity?
- Method development strategies and Structural considerations to obtain the maximum sensitivity in LC-MS/MS
- Considerations and experience: Innovative approaches to this unique bioanalytical challenge (MS detection; chromatography, sample extraction, validation and samples analysis)
- Hemolysis issues during Method Development and Sample Analysis
- Dr. Fabio Garofolo, VP Bioanalytical Services, Algorithme Pharma, Canada
- Recent findings on Impact of hemolysis on drug stability
- Hemolysis impact
- Hemolyzed Samples and impact on IS variation
- Differential impact of hemolysis on parent drug and metabolites
- Dried Blood Spots (DBS): "Can science overcome the regulatory challenge?"
- Dr. Eric Yang, Vice President, Worldwide Bioanalysis and Systems Management, DMPK, GlaxoSmithKline, USA
- Focus on refining this technique increasing our understanding since FDA is not yet ready to accept this methodology without more evidence from the industry
- Discussion around what would constitute sufficient evidence for regulatory agencies to accept this technology in regulated bioanalysis
- What are the regulatory issues currently under discussion?
- What are the scientific issues currently under discussion/evaluation?
- Impact of the hematocrit
- Effect on dilutions
- Internal standard techniques to add it earlier
- Considerations on stability
- Does DBS have a real future for analysis of biologics? (degeneration due to drying/desiccation/ dehydration; interaction between cellulose cards with proteins; stability issues)
- Method transfers: Key troubleshooting tips
- Dr. Mark Arnold, Group Director, Bristol-Myers Squibb, USA
- What to consider during method development to consider a method easy "transferable"
- Harmonization for Assay Transfer
- Selectivity evaluation for methods used to analyze global multi-center studies: use blank matrices from different countries
- Present regulations and guidelines state that a partial validation is needed for method transfer. However, it is not clearly stated how and when to conduct it and how much extensive a partial validation should be: "what needs to be re-validated".
- Full vs. Partial validation
- Endogenous drugs: present challenges - presented & discussed at the interactive pre-workshop course
- Common approaches for the reliable estimation of endogenous drugs
- Why is standard addition not widely used since it is an excellent way to measure endogenous compounds?
- Acylglucuronides: Method Development Strategies - presented & discussed at the interactive pre-workshop course
- Is there a good way to measure acylglucuronides?
- Is there a way to overcome the use of incurred samples for metabolite testing during method development when the reference standards are not available?
- Improving Selectivity and Sensitivity in Bioanalytical Method Development - presented & discussed at the interactive pre-workshop course
- Clean up/Extraction strategies
- Focus on phospholipids & lipemic plasma
- Chromatographic strategies & Ionization strategies
- Reference Standard Material (RSM) and impact in Bioanalysis - presented & discussed at the interactive pre-workshop course
- Quality of RSM and certificate of analysis (CoA)
- Metabolite RSM with significant levels of parent drug or isomers
- Stable labeled Internal Standard RSM with significant level of parent drug (D0)
LBA & LM: Recent Issues related to Large Molecules (LM) and Ligand Binding Assay (LBA) bioanalysis
- Dr. Binodh DeSilva (Session Chair), Executive Director Bioanalytical Sciences-Biologics, Bristol-Myers Squibb, USA
- Dr. Russell Weiner (Session Chair), Executive Director - Clinical Development Lab, Merck Research Laboratories, USA (TBC)
- Biosimilars: Bioanalytical Challenges
- Dr. Joseph C. Marini, Associate Director, Janssen R&D, USA
- Importance of post-translation modifications for Biosimilar regulations
- Recommendations and requirements for the design of bioanalytical testing used in comparability studies for Biosimilar drug development
- Immunogenicity and neutralization assay development and validation for Biosimilars
- LBA new technologies and platforms: pros and cons
- Dr. Sherri Dudal, Senior Investigator, PK/PD Bioanalytics, Novartis Pharma AG, Switzerland
- Advances in developing LBAs on the Gyros platform
- Potential applications (e.g. LBA methods, affinity measurements)
- Pros and cons of the microfluidic systems
- Beyond MSD platform for developing LM Biomarker Assays
- Antibody-Drug Conjugates: The bioanalytical strategies and challenges
- Dr. Surinder Kaur, Senior Scientist/Group Leader, Bioanalytical Sciences, Genentech, USA
- Novel methods for characterizing ADC molecular changes in vitro and in vivo in serum/plasma
- Bioanalytical strategies for ADCs using ligand binding and mass spectrometric methods for pharmacokinetics assessment
- The importance of characterizing bioanalytical methods with appropriate DARs based on analyte data in vivo
- Overview of immunogenicity strategy for ADCs
- Technology advances in overcoming drug tolerance in Immunogenicity assays
- Dr. Dominique Gouty, Senior Director Immunochemistry, Intertek, USA
- Selection of the appropriate immunogenicity platform
- Advance Technologies allowing the detection of Anti Drug Antibodies in presence of high level of drug
- Recommendations and requirements for the development and validation of those assays
- Biomarkers Assays for Large Molecules: Challenges
- Dr. Lauren Stevenson, Senior Scientist at Biogen Idec, USA
- Case Studies on Using Biomarkers or Diagnostic Kits
- Biomarker Assay Validation Using Surrogate Matrix and Surrogate Analyte Approaches
- Strategies in the calibration curve/QCs preparation for endogenous drugs (matrix to use for the curve and for the QCs, placement of QCs in the dynamic range etc)
- Advanced and Focused Roundtable on Scientific Updates from Large Molecules Harmonization Teams for a Unified Bioanalytical Guidance
- Dr. Binodh DeSilva, Executive Director Bioanalytical Sciences-Biologics, Bristol-Myers Squibb, USA
- Face-to-face GBC L1-L6 HTs
- Large Molecule Specific Run Acceptance - L1
- Large Molecule Specific Assay Operation - L2
- Assay Formats- L3
- Reagents and Their Stability - L4
- Automation Practices in Large Molecule Bioanalysis - L5
- Anti-Drug Antibody (ADA) Interference of PK Assessments - L6
- LBA Free/Total: recent data and industry standards - presented & discussed at the interactive pre-workshop course
- Impact of reversible binding: bound, non-bound or partially bound
- Difficulties in measuring a specific form and LBA
- LBA platform and impact on binding equilibrium
- LBA new Technologies Available: pros and cons - presented & discussed at the interactive pre-workshop course
- ELISA; MSD; Gyros; RIA; Biacore; AlphaLISA; Luminex; Cell-based assays, others
- Antibody Interference in LBA: what to consider
- Multiplexing: pros and cons of multiplexing; advantages in performing multiple measurements
- LBA Stability Issues - presented & discussed at the interactive pre-workshop course
- Biologics, critical reagents and ADAs stability
- Impact on activity or binding or activity
- Impact on F/T, bench top and LT stability
Innovations in Bioanalysis: From Drug Discovery to Drug Development
- Large Molecules (LM) bioanalysis by LC-MS/MS: A practical and focused overview on advancement in this fast developing field
- Dr. Gabriella Szekely-Klepser (Session Chair), Sr. Director Bioanalytical Sciences & Scientific Operations, Allergan, USA
- Dr. Mohammed Jemal, Senior Research Fellow, Bristol-Myers Squibb, USA
- Dr. Jean Lee, Scientific Director, PKDM, Amgen, USA
- Dr. Magnus Knutsson, Director, Bioanalysis LC-MS/MS, Ferring Pharmaceuticals, Denmark
- Where are we? Are the new methods sensitive and rugged enough for being validated and used in regulated bioanalysis?
- Latest Progresses & Developments in:
- Immuno capturing techniques vs. size exclusion
- Digestion optimization: Trypsin digestion advantages of the in-silico approach
- Strategies for choosing the signature peptide
- Getting more sensitivity: Tricks in clean up and chromatography. Focus on peptides! Can derivatization increase sensitivity in peptide analysis?
- Internal standard strategies: when to use it, labeled protein vs. labeled signature peptide
- When to used LC-MS/MS instead of LBA in quantification of biologics
- PROS: no needs for high affinity reagent; uniform approach; large linear range; use of IS; higher selective; well accepted by Agencies
- CONS: impact of biotransformation in signature peptide; lack of sensitivity; free vs. total
- Is LBA vs. LC-MS/MS or LBA & LC-MS/MS?
- Importance of using immobilized ligand and immunoaffinity columns as preparative/enriching technique for LC-MS/MS quantitative analysis of biologics
- LC-MS as an important orthogonal method to LBA to provide structural elucidation of antibody drug conjugates and fusion protein
- Use of mass spectrometry to confirm immunoassay results
- LC-MS ability to determine therapeutic proteins structural changes that change their biological activity
- HRMS in Regulated Bioanalysis? Advantages of Qual/Quant High Resolution/Accurate Mass in Regulated Bioanalysis
- Dr. Kevin Bateman, Distinguished Senior Investigator, Merck, USA
- Qual/Quan using HRMS instrument is very well established in drug discovery, is accurate mass & high resolution really used in regulated bioanalysis?
- Technological advances in HRMS and appealing possibilities for quantification of drugs in regulated bioanalysis
- Triple quadrupole MRM vs. HRMS Accurate mass Full spectrum MS and MS/MS data: selectivity, sensitivity and linearity, signal-to-noise, acquisition speed & mass accuracy & spectral quality
- Microdosing: Bioanalytical challenges - presented & discussed at the interactive pre-workshop course
- "1/100th or less than the pharmacological dose" and the need for extremely sensitive bioanalytical methods to fully define the pharmacokinetic profile
- Methods commonly used: LC-MS/MS and Accelerator Mass Spectrometry (AMS)
- Microdosing: in drug discovery and in the drug development process
- Overviews of the concepts and examination on how & when microdosing can be most effectively applied to the DD and DD process: case studies
- Metabolites in Safety Testing (MIST) and Bioanalysis - presented & discussed at the interactive pre-workshop course
- Challenges faced by the bioanalytical community in supporting these guidance policies
- Tiered approach to metabolite quantification: Bioanalytical strategy, appropriate level of validation and fit-for-purpose approach
- Definition of a major human metabolite; preclinical safety coverage for important human metabolites; validated method vs. qualified method when synthetic standards are not available
Regulatory Findings from Audits/Inspections
- Recent Experience with Regulatory Agency Inspections: Industry & Regulators' Perspective
- Dr. Sam Haidar, Chief GLP and Bioequivalence Investigations Branch, Division of Scientific Investigation, Office of Compliance, US FDA
- Dr. Olivier Le Blaye, Inspector France AFSSAPS
- Mr. Joao Tavares Neto, Coordinator of Bioequivalence from General Office of Drugs, Brazil ANVISA
- Dr. CT Viswanathan, CT. Viswanathan & Associates, Inc. USA
- Dr. Eric Woolf, Senior Director, Merck, USA
- Dr. Roger Hayes, VP, GM of Laboratory Sciences, MPI Research, USA
- Dr. Mario Rocci, President, ICON, USA
- Getting 483s is always seen as "negative". Should we begin to look at 483s in a different way? Aren't 483s a learning experience from which we should all learn?
- FDA "Current thinking" through the 483 process: novel findings that introduce new expectations
- What are the most common 483s/findings for large molecule and LBA?
- Sharing findings as a unique opportunity to discuss science and address misunderstandings
- Beyond ISR Criteria
- Current ISR regulatory requirements and root cause for their development
- Effective implementation of ISR monitoring for clinical studies
- Case studies where questionable ISR results were "masked" by an ineffective ISR implementation
- Implications/ramifications from Recent FDA Untitled Letter
- Approach to perform "pre-conditioning” of the instruments before sample analysis
- How to prevent “pre-enter” time/initial from bioanalytical employees?
- Do we need to put in place a strict/bullet-proof system to check if our employees are in the building and cross check with time/initials reported in the bioanalytical forms?
- Is this a new FDA expectation?
- Open Discussions with Pharmas and Regulatory Agencies on Recent 483s/ Findings/Observations discussed at 2011 GCC Closed Forums & recommendations for LC-MS/MS and Ligand Binding Assays
- Calibrant and QC preparation
- Stability to be re-performed at lower concentration even if the previous stabilities were within range
- Reference standard material (RSM) shipment
- Validation QCs from at least 2 preparation
- Fresh STDs vs. Stored Bulk STDs and Independent Stock vs. Combined Stock for Matrix STD and QC Preparation
- LC-MS/MS System conditioning
- Validation reporting
- Observations on Carryover
- Other recent 483s
- Co-administered Drugs Stability & GCC Survey: An open forum to discuss the data gathered by the Global CRO Council (GCC) on co-administered and co-formulated drugs with industry leaders and regulators
- Dr. Eric Woolf, Senior Director, Merck, USA
- Dr. Stephen Lowes, Senior Vice President Scientific, Advion BioServices, USA
- Dr. Surendra Bansal, Research Director Bioanalytical R&D, Non-Clinical Safety, Hoffmann-La Roche, USA
- Dr. Brian Booth, Deputy Director, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US FDA
- Discussion on the results of the GCC survey & GCC Recommendations on Co-administered drugs stabilities
- Industry and Regulators' perspective
- Does the presence of co-administered drugs really affect mutual stability of the drugs? This question have been impacting the industry for a long time and this session will first get a scientific insight on the need to assess this parameter before discussing how.
- How to assess stability in fixed dosage combination products? At which concentrations should this be tested to reflect the fixed dosage?
- Should Long term stabilities include samples reflecting the concentration in study samples? How to address that for LBA samples are often very concentrated and diluted prior to analysis but stability is performed at QC levels?
- Stabilities performed with incurred samples for co-administered drugs
- Due to the complexity of performing co-administered and co-formulated drugs stability with spiked QC, could the use of incurred samples fix the problem? If this is a possible way forward, how and when to perform it? How to calculate the "time zero"?
- Observations on Internal Standard (IS): "Industry standards after one year of implementation"
- Dr. Mario Rocci, President, ICON, USA
- Discussion on recent Recommendations from White papers on this topic: feedback from the industry and regulators
- Are we still getting 483s/observation on IS criteria and IS variation?
- Acceptance criteria for the variation of IS for standard/QC vs. samples
- Do you need a stable labeled IS for each analyte/metabolite?
- Investigations - presented & discussed at the interactive pre-workshop course
- What to do when you investigate data but not assignable cause?
- How extensive should it be an investigation before it is determined that there is "no assigned cause"
- How to handle anomalous values and anomalous values "within acceptance criteria"
- Stability Issues in Bioanalysis - presented & discussed at the interactive pre-workshop course
- Definition of "fresh"
- Whole blood stability evaluation: industry standards
- Recent recommendations: pros & cons
- Stability at the blood collection stage & Freshly spiked vs. freshly extracted
Panel Discussion for "2012 White Paper for Bioanalysis"
Preliminary Topics:
- Reference standards play a critical role in bioanalysis. How to improve the quality of reference standard material (RSM) and stable labeled internal standards isotopic purity?
- How to harmonize electronic common technical documents (eCTDS) for regulatory submissions? What are the Global standards for electronic submission format? Is automated bioanalytical report writing a realistic goal for global submission?
- Large molecule bioanalysis by LC-MS/MS. What acceptant criteria to follow? LBA or LC-MS/MS? And why?
- Assay specificity: How does co-administered drug or DDI compound influence the selectivity of the assay?
- Incurred Sample Stability (ISS): differences between ISR and ISS. Should we consider performing ISS analysis? Should ISS become a Regulatory Requirement? When do you need to test ISS? Which experiments should be included in ISS?
- Preliminary Recommendations from the 6 GBC Large Molecule (LBA) Harmonization Teams (L1-L6)
- DBS
- Best way for storage, drying time and blood age?
- Best way to use internal standards with DBS?
- Best approach for DBS dilution?
- Should calibrants and QCs have the same hematocrit of the study samples?
- Hemolysis and lipemic sample testing in LBA. What are the general approaches
- How do you qualify the hemolysis and lipemic levels
- When do you do these experiments, preclinical or late stage clinical programs
- What is the relevance of assessing these attributes when in-study sample integritydata are not taken into during the PK analysis
- Use of total error in the calculations in LBA assays
- Use of dilutional QCs in the sample analysis runs (in-study)
- Use of automation in the LBA analysis
- Platforms of general use
- Data flows and processes
- Biomarkers analysis - when do you stick to the GLPs
- Specificity testing in the method development and not doing it in the validation if the method has not changed
- Parallelism - What is the general approach in LBAs
- How to best phrase "required" vs. "best practice"?
- General processes of sample treatment after arrival in the lab, e.g, thawing conditions (room temp, refrigerator, ice bath); refreezing process ( -80freezer, -20freezer, sub aliquot before refreezing) ; mixing sample to assure uniformity after thawing (rocking; vortex; snap bottom of tube; other)
- For a well developed method, do you run singlicate analysis in LBAs
What happened in Bioanalysis in 2011:
Like every year, the 6th WRIB will provide an exhaustive overview of the 2011 Hot Topics and Recent Issues in Bioanalysis
- Follow up on "unresolved" 2011 White Paper in Bioanalysis discussion topics - Bioanalysis (2011)3(18)
- Need-to-Know from 2011 Major Bioanalytical Conferences: NBC (May), ASMS (June), Land O' Lakes (July), APA (Sept.), CPSA (Oct.), AAPS (Oct.), EBF (Nov.)
- Up-to-date scientific approaches, global industry standards, new regulations and white papers consensus will be discussed in the pre-workshop specifically designed courses (for more info check courses' syllabus)
