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

Who are we?

Who or what is Tandem Labs and what do we do?

• 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

Tandem Labs Locations

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

Regulated Bioanalysis

What is the purpose of all this 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

PK/PD Parameters

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

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

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

Q & A