ONE-DAY COURSE, Sunday only 19 Introduction to GLP Regulations and Bioanalytical Method Validation by LC-MS/MS Instructor

Perry G. Wang LC-MS Technical Expert Course Description and Rational: “GUIDANCE FOR INDUSTRY/Bioanalytical Method Validation” represents the Food and Drug Administration's current thinking on this topic and was first published in May 2001. Since then, almost all regulated bioanalytical methods have been validated based on the guidance even though it does not create or confer any rights for or on any person and does not operate to bind FDA or the public. In September 2013, FDA published a draft guidance, which provides general recommendations for bioanalytical method validation using advanced technologies. The content of the original guidance issued in 2001 was revised to reflect advances in science and technology related to validating bioanalytical methods. This one-day short course will focus on GLP regulations and the bioanalytical method validation for drugs and metabolites in biological matrices using LC-MS/MS. It will help audiences to comply with FDA‟s regulations for drug discovery and development in the pharmaceutical industry and CROs. The short course will also reflect the contents of the updated guidance and recently published white papers with regard to bioanalytical method validation using LC-MS/MS. International harmonization of bioanalytical method validation guidance will be discussed. Intended Audience: This one-day short course will benefit the analytical chemists, lab supervisors, QA/QC managers, regulators, GLP auditors and CRO consultants who work in the GLP-regulated labs and the pharmaceutical industry. This course will also benefit all levels of management as a refresher course to stay current with the GLP regulations. Detailed Outline: 1. Brief History of Food & Drug Laws and FDA’s Role  Pure Food and Drug Act  The Elixir Tragedy and Food, Drug, and Cosmetic Act (FDC)  Kefauver-Harris drug amendments  History of the FDA and its role 2. Introduction to GXPs  Good Manufacturing Practice (GMP)  Good Laboratory Practice (GLP)  Good Clinical Practice (GCP)  Laws, regulations, and guidance 3. Good Laboratory Practice (GLP)  History of GLP regulations  GLP driven by harm to the public – IBT incident  Specifications of GLP-type work  The key requirements for GLP-type work  GLP requirements for personnel  GLP requirements for study director and QAU  AQU responsibilities  Facility and equipment requirements  Reagents and reference standards

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Raw data and electronic records Reports and documentation Conducting a GLP study Archiving

4. GLP Inspection & Enforcement  Routine and ‘For cause’ inspections  What the FDA can do after inspection  GLP enforcement  When is an FDA Form 483 issued?  What is the significance of FDA Form-483?  Warning letters  The FDA can take enforcement action without issuing a Warning Letter 5. Guidance for Industry & Validation  2001 version and 2013 draft version  Regulations vs. Guidance  Effect of guidance  To validate a method is mandatory  The fundamental parameters of a validation  Full, partial, and cross validation 6. Bioanalytical Method Validation by LC-MS/MS  Study set-up and background information  Reference standards  Internal standard requirements and selection for LC-MS/MS  Method development  When and how to conduct full validation, partial validation and cross validation  Validation plan/protocol  LC-MS/MS qualification: installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ)  Calibration curve fitting and QC samples – accuracy and precision requirements  Weighing factor selection  Sensitivity  Selectivity  Evaluate standard linearity and precision and accuracy of QCs and LLOQ  Batch acceptance criteria  LLOQ and ULOQ acceptance criteria  How to determine low QC  Dilution evaluation  Matrix effects evaluation – ion suppression and enhancement  Matrix factors  Recovery study  Stability requirements o Stock solution stability o Working stock solution stability o Post-preparative stability: autosampler stability and extraction stability o Long-term storage stability o Freeze/thaw stability  Chromatographic re-integration  Carry over and contamination  Incurred sample reanalysis  Project logistics - pre-clinical studies vs clinical studies  Validation document and archive  What does the FDA expect to validate a bioanalytical method using LC-MS/MS? 7. Sample Analysis Using the Validated Method  For non-clinical studies  For clinical regulated studies  Perform a pre-study assay evaluation (PSAE) run  Review and approve PSAE data before analysis of regulated samples begins  Selects chromatograms for regulatory submission prior to sample analysis

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Design an analytical run Arrange samples - by subject or by period Use the same set of integration parameters to integrate all chromatograms in a run Evaluation of LLOQ, ULOQ and QCs How to approve or reject results Deviations and remedial actions Re-assay selection for clinical studies How to report bioanalytical results

8. Case Study and White Paper Discussion  Validation bottleneck and challenges  How to measure and minimize matrix effects  How to harmonize the various global bioanalytical guidance documents o How to deal with urine samples o How to improve the throughput

ONE-DAY COURSE, Sunday only 20 Ion Mobility Mass Spectrometry: An Introduction to Instrumentation, Applications, and Data Analysis Instructors

Brian H. Clowers Washington State University

Erin Baker PNNL

John A. McLean Vanderbilt University

Realization of the value-added by combining ion mobility spectrometry (IMS) and mass spectrometry (MS) has generated significant interest in its use in range of fields including omics pursuits, threat detection, and fundamental studies of gas-phase ion chemistry. This course provides students with a basic understanding of the most common instrumental configurations, experimental sequence, best practices, and the theory underlying the different types of ion mobility systems employed both in academic and commercial settings. An overview of hyphenated IMS-MS instrumentation with multiple practical applications and experimental designs will be presented including comparative discussions on advantages and disadvantages between different stand-alone and hyphenated techniques. This course will provide a comprehensive look at ion mobility spectrometry and its use in modern analytical chemistry. While ion mobility systems are largely compatible with all mass spectrometry systems each IM-MS combination possesses a range of unique advantages and applications. These instrumental considerations and specific experimental sequences will be covered in this course. Graduates of the course will have gained a detailed understanding of IMS and an overview of its practical applications for both stand-alone and MS-coupled operation. Learning Objectives:  Gain and understanding of the instrumental configurations most commonly found between ion mobility and mass spectrometry  Build a foundation to interpret experimental results from the range of hybrid instrumentation available  Develop a conceptual theoretical framework of the processes underlying the ion mobility experiment  Understand the capabilities, limitations, and application areas for the most common configurations of ion mobility and mass spectrometers. Course Outline: Introduction to Ion Mobility Mass Spectrometry Historical Perspective and Origins Theory and Fundamentals of Ion Mobility Spectrometry Introduction to Kinetic Theory and Momentum Transfer Origins of Ion-Neutral Cross Sections Drift Tube Ion Mobility Spectrometry Modern Instrumentation Experimental Sequence and Variable Control Applications Traveling Wave Ion Mobility Spectrometry Instrumental Configuration Experimental Sequence and Variables Data Interpretation Applications Field Asymmetric Waveform Ion Mobility Instrumental Configurations Experimental Variables and Data Collection Data Interpretation

Applications Outlook and Future Directions Omics Technologies IMS Informatics Role in Probing Gas-Phase Ion Chemistry and Structure Hybrid Instrumentation Prerequisite: Working knowledge of mass spectrometry.