1. 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

2. Who are we?
Who or what is Tandem Labs and what do we do?

3. 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

4. Tandem Labs Locations

5. Regulated Bioanalysis
What regulatory agencies have authority over the work performed at Tandem Labs?
Not regulated by Clinical Laboratory Improvement Amendments (CLIA)

6. 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)

7. 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

8. 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

9. 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:

10. 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

11. 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

12. 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

13. 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

14. Regulated Bioanalysis
What is the purpose of all this regulated bioanalysis?

15. 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.

16. Drug Discovery and Development Timeline
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

17. 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”

18. 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

19. 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)

20. 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

21. PK/PD Parameters
ADME (Absorption, Distribution, Metabolism, Excretion)
Dose
Concentration
Area under the curve (AUC)
Accumulation
Bioavailability
Clearance (CL)
Half life (t ½ )
Cmax

22. PK/PD Parameters

23. PK/PD Parameters

24. 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

25. 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

26. 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.

27. 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.

28. Mass Spectrometry in Drug Development

29. 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

30. Mass Spectrometry in Drug Development

31. Mass Spectrometry in Drug Development

32. 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

33. Q & A 33