PRA International Early Development Services Bioanalytical Laboratory Bioanalytical Laboratories: Retain profitability in a competitive market A View from a Major CRO Houten October 8, 2009 Peter Ketelaar -Vice President
Content PRA International Definition of Bioanalysis Mission & Vision Bioanalytical Laboratory Key Success Factors for Bioanalysis Price Development Investment Strategy Advantages of UPLC-MS: Case Studies Summary & Conclusions
PRA is Supporting Drug Development
Global Presence
Early Development Services LENEXA, KS, USA - 80-bed Phase I unit - Data Support BERLIN, GERMANY - Patient Phase I/IIa studies - 4 operational sites in CEE - Data Support ASSEN, NL - Bioanalytical Laboratory - Small & Large Molecules - 17 LC-MS/MS - MSD, FACS, Luminex ZUIDLAREN/GRONINGEN, NL - 140-bed Phase I/IIa unit - Safety Laboratory - GMP-grade Pharmacy - Data Support
PK/PD Bioanalytical Services
Definition of Bioanalysis The process of quantifying drugs in biological fluids/matrices (e.g. blood, plasma, urine & sputum) for the purposes of defining their pharmacokinetics and pharmacodynamics Pharmacokinetics: what does body do with drug? (safety phase 1) Pharmacodynamics: : what does drug with body? (efficacy phase 2)
PRA International: Vision Vision Bioanalytical Lab: To be a global, high quality preferred partner in complex bioanalytical projects in all phases of drug development making the difference through scientific expertise and full service! Easier said than done?
PRA International: Mission Mission Bioanalytical Lab: Continuously work on quality, efficiency, innovation and as a result customer satisfaction: best in class! The Main Thing: The Main Thing: Our results create your success
KSF s Customer Satisfaction (GLP) Compliance: the qualifier SOP s Validated equipment Trained personnel Project Management: Timelines (deliver according to agreed planning) Open & Frequent Communication & Feedback (PM and BD) Budget (no financial surprises) Quality (no major findings) Innovation: Focused on workable solutions Growth ambition in innovative technologies/equipment Efficiency: Continuously working on a more efficient organization in order to keep the costs as low as possible. Contradiction?
Sample Price Development LC-MS Price ( /sample) 140 120 100 80 60 Average 6 % per year 40 20? 0 2002 2004 2006 2008 2010 Year
Strategy per Segment Maturity Extension: Automate & Diversify! Maximize growth: Innovate & sell! Large molecules Small molecules
How to Innovate? Goal: more business in (growing) market segment not too much driven by pricing KPI s: increasing part of revenue and higher EBITDA Reason: regulatory & product development demand more innovations How, a few examples: Multiplexing: more efficient ELISA assays Immunogenicity: new requirement from FDA/EMEA PK large molecules other than with ELISA Flowcytometry: whole cell biomarker
How to improve Efficiency? Goal: higher productivity lower costs KPI s: revenue/fte, samples/fte and samples/system Reason: price decline over the years How, a few examples: Larger batches First time right More automation of sample preparation Efficient use of equipment: flexibility working hours Faster method development & validation Up-to-date LIMS EFFICIENCY IMPROVING EQUIPMENT: UPLC
Investment Strategy: Innovation & Efficiency Information Management Watson LIMS Minus 4 FTE s Large Molecule Innovation MSD for multiplexing Large Molecules Flow Cytometer (FACS) Biacore for immunogenicity Minus 1.50 Small Molecule Efficiency Automation for pipetting Waters Aquity UPLC API LC-MS 5000
A few Case Studies OR What convinced PRA to buy more UPLC systems? Innovation leads to efficiency!
UPLC versus HPLC 1. Ultra performance liquid chromatography versus high performance liquid chromatography; the higher pressure is a consequence! 2. Smaller particles (1.7 µm versus 3.5 µm) result in higher resolution, an effect further increased by higher flow 3. Higher resolution makes shorter columns possible, combined with higher flow this results in shorter runtimes 4. Higher pressure necessary to operate an UPLC: 1,500 psi versus 12,000 psi 5. The UPLC is delivered with superior injector; less carry-over 6. The use of UPLC considerably lowers solvent consumption per sample
Case I Separation of a pair of late eluting, closely related peaks Original method: HPLC-MS Performed on three monolythic columns at a flow rate of 4.00 ml/min Mobile phase consumption was over 5.5 liter per day. Sample volume: 100µl Injection volume: 30 µl 22 minutes runtime was necessary because of late eluting peaks NB: Chromatograms are related, different mass changes
HPLC-MS chromatograms Chromatograms of LLOQ sample using original method
UPLC-MS method Performed on UPLC column at a flow rate of 0.600 ml/min. Mobile phase consumption 864 ml per day. Sample volume : 100 µl Injection volume : 2 µl
UPLC-MS chromatograms Chromatograms of LLOQ sample using UPLC method
Conclusions Reduction of runtime from 22 to 5.5 minute FOUR TIMES FASTER Better resolution between difficult to separate peaks Less solvent consumption, allowing overnight or over weekend analysis Pay back time of investment in UPLC: one project
General depreciation consideration Price for a HPLC-MS combination = 300,000 Depreciation in five years: 60,000 per year Samples per year per LC-MS system ~ 10,000 Depreciation per sample: 6.00 Price for a UPLC-MS combination = 330,000 Depreciation in five years: 66,000 per year Samples per year per LC-MS system ~ 15,000 Depreciation per sample: 4.40 In addition: More samples per system and FTE More revenue & more margin, or Better able to follow price trend
Case II Sensitivity: Separation of drug from closely related endogenous compound Cytarabine (0.5 ng/ml) and cytidine (50 ng/ml) On HPLC: small peak as shoulder on large peak Only high LLOQ possible On UPLC: baseline separated : Low LLOQ possible
UPLC-MS: sensitivity Endogenous compound Internal standard Analyte
Literature Science Innovation: Practical Comparison of Different Approaches to Improve Analysis Times for LC Systems Nico C. van de Merbel et. al. LC-GC Europe January 2007 Business - Efficiency: Bioanalytical laboratories: facing future challenges Peter Ketelaar & Erik Smaal Pharmaceutical Technology Europe May 2009
Summary 1. The Waters UPLC system is an important tool to innovate and to increase productivity in a bioanalytical laboratory 2. Innovation: Same runtime and improved separation 3. Efficiency: Shorter runtime and same separation 4. UPLC is delivered with superior injector 5. The use of UPLC lowers solvent consumption
PRA International The PeRsonAl Element Thanks for your attention!