Analytical Chemistry @ Roche – Benefits and Hurdles

of ACD Software

Josef Schneider ACD/Labs Symposium on Laboratory Intelligence Jun 19-20, 2013

Drug Discovery "Making discoveries that matter"

Analytical Chemistry

Quality of compounds ?

Structure ? – Purity ? – Concentration ?

Protein Expression & Purification, Biostructure

Compound Depository

In vitro / - vivo screens AD, HTS, FBS, MDO, pre-

formulation, biology

MedChem, Upscaling Chemistry

"Throughput and quality, routine and challenges" "Service and projects"

Allocate routine to non-experts Automate appropriate processes as much as possible Experts for challenges to ensure quality

Analytical Chemistry "Creating knowledge and compounds that matter"

Analytical Chemistry

Routine Challenges

Used by chemists, maintained by

experts

Experts

Open Access Analytical LCMS + NMR Service Analytical GC-,LCMS + NMR

Flash Chromatography, prep LC

Open Access prep LCMS Service analyt./prep RP-, NP-, chiral

and SF chromatograpy

Service IR/Raman/Xray

Open Access Analytical NMR and LC/MS for small molecules - Structural identity and purity

• Throughput

• 60'000 NMR spectra, 120'000 LC/MS spectra p.a. • Sample changer for single samples and racks • Sample preparation by user

• Waiting queue 5 - 30 min, minimal breakdowns • Only fast 1D NMR (1H, 19F, 31P) at daytime • UPLC - LC/MS with 2 min chrom. allow sufficient separation

• Experts maintain machines and guarantee quality of spectra • Automated processing by vendor software, email, data on server accessible • Interpretation by user

• User knows chemistry • User combines LC/MS and NMR results • User has spectra available for all of his compounds and access to spectra of other

compounds • Roche internal MS and NMR training by experts

• Registration and submission to compound depository center • Option to submit samples to Expert Service for analytics and/or purification

• Issues

• Reprocessing and reporting Introduction of ACD Spectrus Processor in Basel and Shanghai

Benefit of ACD Spectrus Processor in Interpretation of Open Access LC/MS Spectra

Optimal mass – and purity determination by manual reprocessing of LC/MS spectra incl. mass spectrum simulation

Improved reporting Only one interface to learn for LC/MS and NMR

Overview page • UV purity table • Peaks show no MS info Every integrated peak has its separate follow-up page

MS spectra in ESI+ and ESI+ mode (fix mass range = 150 – 850)

Vertical MS axis with absolute detector intensity MS peak table with the 10 most intensive signals

(relative) allow determination of isotope pattern MS peak table for reports UV spectrum

Hurdles of ACD Spectrus Processor - LC/MS

Be cautious with structures in combination with "extracted ion current chromatogram (XIC)" and "table of components" The import of chemical structure(s) generates automatically

"extracted ion chromatograms" Opens the table of components Generates a "MS match" for the automated mass confirmation (can be

disabled) Issues (Build 58939, 29.8.2012)

MS match and the XIC's are not reliable False positive results found for mass differences of 1 and 2 Da

Template reporting needs improvement to be compatible and applicable by the

user itself for standard Agilent data formats

Too many parameters for beginners, needs an easy "reset to default" function for all parameters

Benefit of ACD Spectrus Processor in Interpretation of Open Access NMR Spectra

Optimal reprocessing of NMR spectra High performing "multiplet" tool Multiple display and Proton NMR Prediction Improved reporting and multiplet report Only one interface to learn for LC/MS and NMR

Hurdles of ACD Spectrus Processor – NMR and general

"peak analysis auto" usually generates too many or too few multiplets (solvents, impurities, ....) to check and to adjust this mostly needs more effort than using the manual

process instead experience: using the manual tool is much more efficient

"assignment auto" produces a "match factor" for the automated structure

verification by NMR Perfomance is insufficient

Two structure windows "Missing windows"

The challenges • Chemistry samples: regio- and stereoisomers, purity, isotopic labeling,

impurity profiling, metabolites • Quality of HTS libraries, HTS hits and compound profiling samples • Reliable and high quality results, turnaround times 1-3 days (chemistry

samples)

Concentrate resources on interpretation to deliver high quality results Saved resources by

• Automation

• Combination of methods for most efficient process and reliable results • Paperless interpretation

Expert Service Analytical NMR and LC/MS for small molecules

Customer request: cELN

RASPP NMR and GC/LC/MS

AWM

Results ACD

SpecDB

Human Interpretation

Roche Automation in Sample Preparation

Chemistry Samples: Roche Automated Sample Preparation Platform (RASPP) From one delivery sample to three measurement samples

NMR

GC/MS

LC/MS

Library Samples: 8μl@5mM DMSO (d0) – adapted Gilson/Bruker system From one delivery sample to two measurement samples

Highest efficiency by smart combination of methods and paperless interpretation • Standard Approach – cross check between NMR and MS results before reporting

• UPLC-MS (acc. mass, ESI/APCI, MS/MS, Msid + ef, UV purity) • GC-MS (EI) • 600 MHz 1H + 2D DEPT HSQC (10 min overall, cryoprobe) • All spectra from one sample • Chemistry info and knowledge • Paperless interpretation and reporting of GC/LC/MS and NMR by one

Expert About 80% of all requests can be finished with this standard approach The experts gain experience (increased skills and knowledge)

• if standard approach fails,

• more NMR (1H high temp, 1D X NMR, 2D NMR..) • more MS (MS/MS) • X-ray

Expert Service Analytical NMR and LC/MS for small molecules

LC/MS

GC/MS

1H-NMR

2D ed-HSQC

Benefits and hurdles of ACD Spectrus

NMR and GC/LC/MS spectra in one interface Paperless interpretation feasible (for non overlayed spectra) Overlay features are suboptimal for series and 2D NMR, e.g. NMR (TopSpin)

Benefits and hurdles of ACD Spectrus

Workflow by macros and forms, automated generation of pdf's Paperless reporting SpecDB: structure search, detailed results searchable

Avoid effort by redundancy check: AWM Structure Search ACD SpecDB performance

Similarity Search too slow (9 min for multiple search on 103'000 records) Table view

ACD SpecDB Similarity Search quality is good Only one structure per record in DB – chemical reaction is missing in DB

Benefits and hurdles of ACD Spectrus

Acknowledgements

Roche pRED, Discovery Technologies - Michael Hennig

Analytical Chemistry Basel

Markus Bürkler

Philippe Cron

Inken Plitzko

Severine Nnoruka

Caroline Wyss-Gramberg

Christian Bartelmus

Maya Zurfluh

Sophie Brogly

Christian Albrecht

ACD Ryan Sasaki Gerd Rheinwald Oliver Ax

Jörg Hörnschemeyer

Johannes Erny

Siegfried Stolz

David Wechsler

Eric Bald

Thierry Godel

Daniel Zimmerli

Simone Moser

Doing now what patients need next

Drug Discovery Hurdles

Increasing costs "Despite advances in technology and understanding of biological systems, drug discovery is still a lengthy, expensive, difficult, and inefficient process with low rate of new therapeutic discovery. Currently, the research and development cost of each new molecular entity (NME) is approximately US$1.8 billion". Steven M. Paul, et al (2010). "How to improve R&D productivity: the pharmaceutical industry's grand challenge". Nature Reviews Drug Discovery 9 (3): 203–214

Time of market exclusivity for «first in class» diminishes Average period of marketing exclusivity for first entrants to a therapeutic class (time from first-in-class approval to first follow-on drug approval) by period of first-in-class United States marketing approval. DiMasi JA, et al (2011). "Competitiveness in follow-on drug R&D: a race or imitation?" ". Nature Reviews Drug Discovery 10 (1): 23–27

ACD Spectrus automated structure verification

Standard parameter as delivered with Build 58939, 29.8.2012; issues on • Solvent detection • Integral and peak picking

thresholds • Multiplet detection (dt for two

indedendent t at 0.8 ppm)