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Short Course

Course Information
Course Title: (CANCELED) Introduction to GLP Regulations and Bioanalytical Method Validation by LC-MS/MS
Categories: 1 - Quality/Regulatory/Compliance
2 - Validation
Instructor(s): Perry Wang Course Number: 2
Affiliation: USFDA
Course Date: 03/04/2017 - Saturday Course Length: 1 Day Course
Start Time: 08:30 AM End Time: 05:00 PM
Fee: $575 ($775 after 2/18/17) Textbook Fee:

Course Description
“GUIDANCE FOR INDUSTRY / Bioanalytical Method Validation” represents the Food and Drug Administration's current thinking on this topic and was 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 In September 2013, FDA published a draft guidance, which provides general recommendations for bioanalytical method validation using advanced technologies including LC-MS/MS. The content of the original guidance issued in 2001 was revised to reflect advances in science and technology related to validating bioanalytical methods. This two-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.

Target Audience
This one-day short course will benefit chemists who use LC-MS/MS in GLP-regulated labs, lab supervisors, QA managers and personnel, GLP auditors and CRO consultants, who need a fundamental understanding of GLP regulations and guidance. This course is also useful to all levels of management as a refresher to stay current with the GLP regulations.

Course 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
 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 Plan

 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. HPLC Fundamentals

 HPLC types
 Chromatographic mechanism classified by the nature of stationary phases
 Plate theory and rate theory
 Chromatographic resolution and its estimation
 Recent development of HPLC

7. MS Fundamentals

 Units of mass
 Normal, average, monoisotopic, and exact mass
 Mass defect
 MS resolution in mass accuracy
 The role of MS resolution
 Ionization modes and selection
 Matrix effects – weakness of MS
 Causes and solutions of matrix effect

8. 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
 Selection of MS ionization and modes
 MS tune
 MS transition selection
 MS parameter optimization
 LC conditions (mode, column, and mobile phase)
 Sample preparation (protein precipitation, liquid-liquid extraction, and solid phase extraction)
 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
 Stock solution stability
 Working stock solution stability
 Post-preparative stability: autosampler stability and extraction stability
 Long-term storage stability
 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?

9. Sample Analysis

 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
 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

10. 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
 How to deal with urine samples
 How to improve the throughput

Course Instructor's Biography
Dr. Perry G. Wang is a research chemist in the Office of Regulatory Science, CFSAN, The US Food and Drug Administration (US FDA). Prior to joining the FDA, Dr. Wang worked in the pharmaceutical and medical-device industries. He received his Ph.D. degree at Oregon State University. His expertise in the pharmaceutical field focuses on high throughput drug analysis and validation by LC-MS/MS. His current research at the FDA includes developing analytical methods for chemical constituents and contaminants in cosmetics and personal care products by GC-MS/MS and LC-MS/MS. Dr. Wang has been invited to teach following short courses for the Pittsburgh Conference (PittCon), the ACS Annual Meetings, The HPLC Annual Meeting, Eastern Analytical Symposium (EAS), and Calibration and Validation Group (Canada) since 2008:  High-Throughput Method Development for Drug Analysis by LC-MS/MS  LC-MS Method Development for Small Molecule Pharmaceuticals  Introduction to GLP Regulations and Bioanalytical Method Validation by LC-MS/MS In addition to over 20 peer-reviewed publications, Dr. Wang has edited and/or co-edited five monographs: 1. High-Throughput Analysis in the Pharmaceutical Industry, CRC Press, ISBN: 978-1-4200-5953-3, 2008 2. Monolithic Chromatography and Its Modern Applications, ILM Publication, ISBN: 978-1-906799-03-8, 2010 3. Hydrophilic Interaction Liquid Chromatography and Advanced Applications, RC Press, ISBN: 978-1-4398-0753-8, 2011 4. Counterfeit Medicines, ILM Publications, ISBN: 978-1-906799-08-3, 2012 5. High Throughput Analysis for Food Safety, John Wiley & Sons Inc. ISBN-10: 1118396308), 2014