Utah Life Science Summit
State of the Industry - Growth and Success
through Outsourcing/Partnering
Regulated Bioanalysis for the
Pharmaceutical Industry
Scott A. Reuschel, M.S.F.S
Tandem Labs – Salt Lake City, UT
A Labcorp Company
Who are we?
Who or what is Tandem Labs and what do we do?
Company Overview
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Our 33rd year of operation
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1981 Northwest Toxicology established in SLC, UT (clinical toxicology)
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1985 Certified drugs-of-abuse testing lab (NIDA, DoD, SAMSHA) – GC/MS
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1994 Established bioanalytical division, SLC, UT – GLP bioanalytical, GC/MS, LC/MS
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1998 Established 2nd site in NJ – Discovery PK/GLP bioanalytical, LC/MS
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2004 Divested drug testing division – Renamed company to Tandem Labs
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2008 Acquired by Laboratory Corporation of America® Holdings
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2009 Established 3rd site in San Diego, CA – GLP Immunoanalytical
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2010 Acquired BA division of Enthalpy Analytical - RTP, NC (4th Tandem site) – GLP
bioanalytical, LC/MS
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200+ scientific/support staff; ~50 mass spectrometers across all sites
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Contract Research Organization (CRO) – Regulated Bioanalysis
Tandem Labs Locations
Regulated Bioanalysis
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)
•
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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
What is the purpose of all this regulated bioanalysis?
Pharmacodynamics (PD) and
Pharmacokinetics (PK)
• 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.
Drug Discovery and
Development Timeline
Drug Discovery and Development Timeline
1 - 5+ yrs
2-3 yrs
Discovery Preclinical
1 yr
Phase I
IND to FDA
2 yrs
Phase II
3 yrs
1-2 yrs
Phase III
Review
NDA to FDA
Phase IV
Discovery
Drug Development
• Qualitative Analysis (by Mass Spectrometry)
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In Vitro
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High-throughput screening (lead generation, identification, and
optimization)
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Metabolite Identification (cytochrome P450 enzymes)
• Quantitative Analysis (by Mass Spectrometry)
•
In Vitro
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Solubility, plasma protein binding, permeability, plasma stability,
metabolic stability
In Vivo (preliminary animal studies)
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Determine basic PK parameters (e.g. half-life, oral bioavailability ,
clearance and tissue distribution)
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Qualified Assays / “Fit for Purpose”; less stringent acceptance criteria,
“quick and dirty”
Preclinical
Drug 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
Clinical Drug Development
• Clinical (Phases I-IV)
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Quantitative Analysis (by Mass Spectrometry)
•
Validated Assays – not GLP; however, conducted under
the principles of GLP
•
First in Human
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Single Ascending Dose (SAD)
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Multiple Ascending Dose (MAD)
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Food Effects (fed vs. fasted)
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Special Populations
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Elderly, renal impaired, hepatic impaired
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Drug-Drug Interaction (DDI)
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Bioequivalence (BE)
Quantitative Analysis
by LC/MS
• 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
PK/PD Parameters
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•
•
•
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ADME (Absorption, Distribution, Metabolism, Excretion)
Dose
Concentration
Area under the curve (AUC)
Accumulation
Bioavailability
Clearance (CL)
Half life (t ½ )
Cmax
PK/PD Parameters
PK/PD Parameters
Mass Spectrometry
in Drug Development
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
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
Mass Spectrometry
in Drug Development
Acknowledgements
Tandem Labs - Salt Lake City, UT
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Laixin Wang, PhD
Min Meng, PhD
Troy Voelker, PhD
Juan Rogness, MS
Life Science Cluster, Utah Governor's Office of
Economic Development
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Kevin Jessing
Q&A