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 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

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) 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 1 - 5+ yrs 2-3 yrs 1 yr 2 yrs 3 yrs 1-2 yrs Discovery Preclinical Phase I Phase II Phase III Review Phase IV IND to FDA NDA to FDA

Discovery Drug Development 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) 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”

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 Immunogenicity studies with non-human primates (NHPs) Dose formulation analysis Safety is the key focus

Clinical Drug 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)

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 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 Laixin Wang, PhD Min Meng, PhD Troy Voelker, PhD Juan Rogness, MS Life Science Cluster, Utah Governor's Office of Economic Development Kevin Jessing

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