scott reuschel tandem labs - regulated bioanlysis for the pharmaceutical industry
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Regulated Bioanalysis for the Pharmaceutical Industry
Scott A. Reuschel, M.S.F.STandem Labs – Salt Lake City, UT
A Labcorp Company
Utah Life Science SummitUtah Life Science SummitState of the Industry - Growth and Success State of the Industry - Growth and Success
through Outsourcing/Partneringthrough Outsourcing/Partnering
• Our 33rd year of operation• 1981 Northwest Toxicology established in SLC, UT (clinical toxicology) • 1985 Certified drugs-of-abuse testing lab (NIDA, DoD, SAMSHA) – GC/MS• 1994 Established bioanalytical division, SLC, UT – GLP bioanalytical, GC/MS, LC/MS• 1998 Established 2nd site in NJ – Discovery PK/GLP bioanalytical, LC/MS• 2004 Divested drug testing division – Renamed company to Tandem Labs• 2008 Acquired by Laboratory Corporation of America® Holdings• 2009 Established 3rd site in San Diego, CA – GLP Immunoanalytical• 2010 Acquired BA division of Enthalpy Analytical - RTP, NC (4th Tandem site) – GLP bioanalytical, LC/MS• 200+ scientific/support staff; ~50 mass spectrometers across all sites• Contract Research Organization (CRO) – Regulated Bioanalysis
Company Overview
What regulatory agencies have authority over the work performed at Tandem Labs?
•Not regulated by Clinical Laboratory Improvement Amendments (CLIA)
Regulated Bioanalysis
What regulatory agencies have authority over the work performed at Tandem Labs?
•Not regulated by Clinical Laboratory Improvement Amendments (CLIA)•Are regulated by the Food and Drug Administration (FDA)
Regulated Bioanalysis
What regulatory agencies have authority over the work performed at Tandem Labs?
•Not regulated by Clinical Laboratory Improvement Amendments (CLIA)•Are regulated by the Food and Drug Administration (FDA)•Are subject to the Code of Federal Regulations (CFR)•21 CFR Part 58 – Good Laboratory Practice for Non-Clinical Laboratory Studies•21 CFR Part 11 – Electronic Records, Electronic Signatures
Regulated Bioanalysis
What regulatory agencies have authority over the work performed at Tandem Labs?
•Not regulated by Clinical Laboratory Improvement Amendments (CLIA)•Are regulated by the Food and Drug Administration (FDA)•Are subject to the Code of Federal Regulations (CFR)•21 CFR Part 58 – Good Laboratory Practice for Non-Clinical Laboratory Studies•21 CFR Part 11 – Electronic Records, Electronic Signatures
•Also subject to:•ICH (International Conference on Harmonization) - Guideline for Good Clinical Practice (GCP) – informed consent, patient confidentiality, blinding
Regulated Bioanalysis
What regulatory agencies have authority over the work performed at Tandem Labs?
•Are subject to additional regulations and guidelines from various international regulatory authorities, including:
Regulated Bioanalysis
What regulatory agencies have authority over the work performed at Tandem Labs?
•Are subject to additional regulations and guidelines from various international regulatory authorities, including:
•US FDA – Guidance for Industry: Bioanalytical Method Validation
Regulated Bioanalysis
What regulatory agencies have authority over the work performed at Tandem Labs?
•Are subject to additional regulations and guidelines from various international regulatory authorities, including:
•US FDA – Guidance for Industry: Bioanalytical Method Validation
•European Medicines Agency (EMA): Guideline on Bioanalytical Method Validation
Regulated Bioanalysis
What regulatory agencies have authority over the work performed at Tandem Labs?
•Are subject to additional regulations and guidelines from various international regulatory authorities, including:
•US FDA – Guidance for Industry: Bioanalytical Method Validation
•European Medicines Agency (EMA): Guideline on Bioanalytical Method Validation
•Brazilian Health Surveillance Agency (ANVISA): Bioanalytical Guidance RDC 27/2012
Regulated Bioanalysis
What regulatory agencies have authority over the work performed at Tandem Labs?
•Are subject to additional regulations and guidelines from various international regulatory authorities, including:
•US FDA – Guidance for Industry: Bioanalytical Method Validation
•European Medicines Agency (EMA): Guideline on Bioanalytical Method Validation
•Brazilian Health Surveillance Agency (ANVISA): Bioanalytical Guidance RDC 27/2012
•Japanese Ministry of Health, Labour and Welfare (MHLW): Draft Guideline on Bioanalytical Method Validation in Pharmaceutical Development
Regulated Bioanalysis
• Tandem Labs helps pharmaceutical companies obtain the necessary information to make assessments regarding PD/PK of new drugs that are being developed.
• Pharmacodynamics (PD) is the study of the biochemical and physiological effects of drugs on the body (i.e. what the drug does to a body).
• Pharmacokinetics (PK) describes the drug concentration/time course in body fluids resulting from administration of a certain drug dose (i.e. what the body does to a drug).
• Tandem Labs use mass spectrometry to provide both qualitative and quantitative information to our pharmaceutical partners during all phases of the drug development process.
Pharmacodynamics (PD) and Pharmacokinetics (PK)
Drug Discovery and Development Timeline
Discovery Preclinical Phase I Phase II Phase III Review
1 yr 2 yrs 1-2 yrs2-3 yrs
Phase IV
3 yrs1 - 5+ yrs
Drug Discovery and Development Timeline
NDA to FDAIND to FDA
• Qualitative Analysis (by Mass Spectrometry)• In Vitro• High-throughput screening (lead generation, identification, and
optimization)• Metabolite Identification (cytochrome P450 enzymes)
• Quantitative Analysis (by Mass Spectrometry)• In Vitro• Solubility, plasma protein binding, permeability, plasma stability, metabolic
stability • In Vivo (preliminary animal studies)• Determine basic PK parameters (e.g. half-life, oral bioavailability , clearance
and tissue distribution)• Qualified Assays / “Fit for Purpose”; less stringent acceptance criteria,
“quick and dirty”
DiscoveryDrug Development
• Quantitative Analysis (by Mass Spectrometry)
• Exploratory Toxicology (non-GLP)• Dose range finding studies• Different species and methods of administration• Multiple dosing regimens
• Definitive Toxicology (GLP) – validated assays• General toxicology studies• Different species and methods of administration• Immunogenicity studies with non-human primates (NHPs)• Dose formulation analysis
• Safety is the key focus
PreclinicalDrug Development
• Clinical (Phases I-IV)• Quantitative Analysis (by Mass Spectrometry) • Validated Assays – not GLP; however, conducted under the
principles of GLP• First in Human• Single Ascending Dose (SAD)• Multiple Ascending Dose (MAD)• Food Effects (fed vs. fasted)• Special Populations• Elderly, renal impaired, hepatic impaired• Drug-Drug Interaction (DDI)• Bioequivalence (BE)
Clinical Drug Development
• Method Development• Extraction conditions, chromatography conditions, MS parameters• Very challenging; dictated by the chemistry of the analytes, maximum
sensitivity often required, instability, non-specific binding, tight time pressures.
• Method Validation• Highly regulated; A/P, stability, robustness, selectivity, matrix effects, etc.• Constantly evolving requirements; additional tests
• Sample Analysis• Tight time pressures, sample dilution, sample discrepancies with clinics, ISR
Quantitative Analysisby LC/MS
• ADME (Absorption, Distribution, Metabolism, Excretion)• Dose• Concentration• Area under the curve (AUC)• Accumulation• Bioavailability• Clearance (CL)• Half life (t ½ )• Cmax
PK/PD Parameters
Why is Mass Spectrometry such a good tool for these applications?•Selective•Allows the discrimination of a target analyte to the exclusion of other interferences.•Sensitive•Can routinely detect analytes at ng/mL, pg/mL and sub pg/mL levels.•Compatible with other separation techniques•“hyphenated methods”•GC-MS, LC-MS, UPLC-MS, CE-MS, etc.•Robust / High throughput•Versatile
Mass Spectrometry in Drug Development
Why is Mass Spectrometry such a good tool for these applications?•Selectivity•Biological samples are first extracted (PPE, SPE, LLE, SLE)•Chromatographic Separation (GC, HPLC, UPLC, Microflow LC)•Multiple MS Techniques•Full Scan•SIM•MS/MS (SRM, Product Ion, Precursor Ion, Neutral Loss)•TOF/MS•HRAM
Mass Spectrometry in Drug Development
• MS/MS (tandem MS, triple-quadrupole MS) and Selected Reaction Monitoring (SRM) is by far the most commonly used technique for quantitative bioanalysis for PK/PD testing.
Mass Spectrometry in Drug Development
• LC ionization techniques have also revolutionized quantitative MS bioanalysis for PK/PD testing.
• Ionization is required for mass spectrometry (charged species; m/z)
• GC/MS applications were limited to volatile, thermally stable compounds for ionization.
• Atmospheric ionization techniques (ESI, APCI) removed these limitations, allowing for LC/MS applications to expand to a wider variety of compounds.
Mass Spectrometry in Drug Development
• Types of compounds analyzed with LC/MS techniques:• Small Molecules (MW < 800 amu)• Traditional drugs, NCEs
• Large Molecules (MW > 800 amu; up to 10-40,000 Da)• Biologics• Peptides• Oligonuclieotides• SiRNA• Lipids• Biomarkers• Proteins
Mass Spectrometry in Drug Development
Acknowledgements
Tandem Labs - Salt Lake City, UT• Laixin Wang, PhD• Min Meng, PhD• Troy Voelker, PhD• Juan Rogness, MS
Life Science Cluster, Utah Governor's Office of Economic Development • Kevin Jessing