Analytical Roche Benefits and Hurdles of ACD Software. Josef Schneider ACD/Labs Symposium on Laboratory Intelligence Jun 19-20, 2013

Transcription

1 Analytical Roche Benefits and Hurdles of ACD Software Josef Schneider ACD/Labs Symposium on Laboratory Intelligence Jun 19-20, 2013

2 Drug Discovery "Making discoveries that matter" MedChem, Upscaling Chemistry Compound Depository Protein Expression & Purification, Biostructure In vitro / - vivo screens AD, HTS, FBS, MDO, preformulation, biology Analytical Chemistry Quality of compounds? Structure? Purity? Concentration? "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

3 Analytical Chemistry "Creating knowledge and compounds that matter" Routine Used by chemists, maintained by experts Analytical Chemistry Experts Challenges Open Access Analytical LCMS + NMR Flash Chromatography, prep LC Open Access prep LCMS Service Analytical GC-,LCMS + NMR Service analyt./prep RP-, NP-, chiral and SF chromatograpy Service IR/Raman/Xray

4 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 ( 1 H, 19 F, 31 P) 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, , 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

5 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 = ) 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

6 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, ) 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

7 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

8 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"

9 Expert Service Analytical NMR and LC/MS for small molecules 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 Customer request: celn RASPP NMR and GC/LC/MS AWM Human Interpretation ACD SpecDB Results Combination of methods for most efficient process and reliable results Paperless interpretation

10 Roche Automation in Sample Preparation NMR GC/MS LC/MS Chemistry Samples: Roche Automated Sample Preparation Platform (RASPP) From one delivery sample to three measurement samples Library Samples: DMSO (d 0 ) adapted Gilson/Bruker system From one delivery sample to two measurement samples

11 Expert Service Analytical NMR and LC/MS for small molecules 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

12 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) LC/MS GC/MS 1H-NMR 2D ed-hsqc

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

14 Benefits and hurdles of ACD Spectrus 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

15 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 Jörg Hörnschemeyer Johannes Erny Siegfried Stolz David Wechsler Eric Bald Thierry Godel Daniel Zimmerli Simone Moser ACD Ryan Sasaki Gerd Rheinwald Oliver Ax

16 Doing now what patients need next

17 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): 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

18 ACD Spectrus automated structure verification Standard parameter as delivered with Build 58939, ; issues on Solvent detection Integral and peak picking thresholds Multiplet detection (dt for two indedendent t at 0.8 ppm)