Informatics Plenary Hayward Etal May2012


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Describes the integrated use of several common analytical informatics tools / platforms in the lab and the VM space to maximize access. It also describes a variety of customized additions including links to proprietary databases, barcode utilization, adding value to analytical data, and one stop shopping for data analysis / reporting. The impact is that the same FTEs can produce >3 fold more results!

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Informatics Plenary Hayward Etal May2012

  1. 1. Integrating Informatics Tools to Improve Transparency, Trust, and Productivity Across the Drug Discovery Workflow Mark J. Hayward,* Chi Zhang,* Romel Campbell,** and Qing Ping Han* Lundbeck Research – 215 College Rd. - Paramus, NJ 07652 *Analytical, **IT Chemical & Pharmacokinetic SciencesLundbeck Research
  2. 2. First principles• There’s no substitute for quality science• Informatics cannot change the quality of the science – However, informatics can add significant value to the science output Informatics can extract high value information and conclusions from the scientific data, thereby streamlining scientific processes toward much higher efficiency Informatics can make it much easier to find / view the data Informatics can make it much easier to transfer the data to the next step in the process (next assay or ELN) Informatics can make the data find the scientist The sum of these value added steps is much greater transparency and functional utility of the data for many scientists• The combination of quality science with the transparency and functional utility added with informatics can lead to great trust in the experimental outcomes• Trust in the experimental outcomes results in a much more effective research organization that can focus most on the larger organizational goals*• The impact of trust on productivity has been shown to be many fold at all scales, from individual all the way up to societal* Chemical & *SMR Covey, "The speed of trust," Pharmacokinetic Simon & Schuster, New York, 2006. 2 SciencesLundbeck Research
  3. 3. Where can informatics help trust?• Informatics can support 5 of 7 components of trust• Much of that trust is driven by openness• Thorough transparency allows the 4 other components to be demonstrated (over time) – Ability, competence, integrity, and reliability – Of course, the quality of science must be there to have something to demonstrate (data driven!)• High transparency also can drive toward high quality because Areas where there is no place to transparency can help hide low quality!* build trust Chemical & *It is not uncommon to encounter resistance when shifting to high transparency Pharmacokinetic SMR Covey, "The speed of trust," Simon & 3 *You should do it anyway! Sciences Lundbeck Research Schuster, New York, 2006.
  4. 4. More first principles• Informatics is not an entity unto itself• Informatics must be enabling (i.e. saves steps) without creating barriers or false metrics – it must remove barriers!• Informatics initiatives often fail because: – The input information barrier makes it more work to use informatics Classic mistake: request forms requiring huge amounts of information – The expectation is that the informatics will substitute for F2F communication There is no substitute for F2F communication and this always needs to be promoted more than the informatics – The informatics system was really only intended to generate metrics Users will only use it to game the metrics• Without clear added value, users generally resist learning yet another informatics system – It should be a tool with clear ENABLING benefits that end users want to use Chemical & Pharmacokinetic 4 SciencesLundbeck Research
  5. 5. Still more first principles• No single informatics approach is sufficient – informatics is only part of the picture – other processes must be addressed on a case by case basis• There are many systems and interfaces that must be addressed – Informatics links to ELNs – Informatics links to instruments – Informatics links to other data bases – Instrument links to other data bases – Adding value to instrument data – Informatics links to visualization and reporting tools• Informatics requires customization as does all of the processes – Processes should be viewed holistically and the most effective approach selected Buy informatics package and get vendor to install / set up Outsource customization to vendor or 3rd party In-house programming – Be patient, it’s a multiyear effort to get most pieces in place (always will be more) Chemical & Pharmacokinetic 5 SciencesLundbeck Research
  6. 6. And now the content of this presentation How we used the first principles to address analytical efforts in a drug discovery organization Crucial goal: extract highest overall scientist efficiency in their transition to ELNs Note: notebook #s, compound IDs, and projects are not visible for proprietary compounds, samples, projects, etc. Chemical & Pharmacokinetic SciencesLundbeck Research
  7. 7. Responsibilities of the drug discoveryAnalytical group at Lundbeck Research USA • Analysis – LC/MS, SFC/MS and NMR for structure and purity Challenging compounds done by Analysts QC of compound library done by Analysts Provide tools for Med Chemists to address straight forward compounds and reaction mixtures (Open Access – NMR, LC/MS, SFC/MS, & high res LC/MS) • Purification – LC/MS and SFC/MS based (5 mg to 50 g) • ADME / Physico-Chemical measurements – LogD, permeability, pKa, solubility, stability, water content… • Mechanistic Bioanalysis (and other challenging bioanalysis) – LC & SFC with UV, fluorescence, electrochemical, & MS/MS detection for biomarkers in all fluids and tissues • Formulations – Solubility in excipients and stability / solubility in formulations Chemical & Pharmacokinetic 7 Quality crucial in all areas! SciencesLundbeck Research
  8. 8. Responsibilities from a purely informatics point of view Empower for raw data VM SDMS & email for processed and raw dataworld Pharmacology DB for finished pharma dataCorp IT Sample & ELN DBs for sample & experiment data* (collaboration /trust are crucial) VMs for secure remote accessPC worldRed =Corp ITGreen = Lab PCs: some with Office PCs (>100) barcode readers (28) Home PCs (>50)Analytical Empower TopSpin Xcalibur Sirius MassLynx LCs & SFCs (23) LC/MSs & SFC/MSs (10) NMRs (2) GC/MS (1) & LC/MSs (5) Titrators (2) Corp IT: OS, networking, Office apps, & anti-virus SW. Analytical: instrument SW & SDMS connections Chemical & Effective data access & Pharmacokinetic 8 *LIMS / ELN providers beginning to recognize Sciences resource utilization are crucial! need: R Mullin, C&E News, 90(19), 2012, 11-14. Lundbeck Research
  9. 9. Software used• MassLynx / OpenLynx / FractionLynx (V4.1 SCN798) – Primary drivers of choice: Automation of LC/MS or SFC/MS hardware operation Open Access interface for deploying to non analytical scientists (OpenLynx) Best automation & control of purification hardware (FractionLynx)• Empower (V2 FR5) – Primary drivers of choice: Massive chromatographic data collection – Many instruments (>20) – 10000 chromatograms per month coming mostly from 2 FTEs Most effective automatic peak integration Best system suitability software (an Empower feature) for method development (quality of science) Chemical & Pharmacokinetic 9 SciencesLundbeck Research
  10. 10. Software used • NuGenesis / SDMS (V7.1) – Primary drivers of choice: Automation of a generic way collect, distribute, find, and view analytical data Collects / makes transparent data from Empower, MassLynx, Sirius, TopSpin, and others (for chemists and biologists) Focus is on automatic “printing” (transfer approach) of processed data Some raw data collected too, but not seen as great advantage Primary portal to the chemistry ELN (Symyx) • WDC (Waters Data Converter, an Empower feature) (V2) – Primary drivers of choice: Convert MassLynx (MS) data into Empower data Empower has most effective automatic peak integration Empower has best system suitability software (an Empower feature) for method development (quality of science) Chemical & Pharmacokinetic 10 SciencesLundbeck Research
  11. 11. Ordinary uses of the software Some examples with focus on quality of science Chemical & Pharmacokinetic SciencesLundbeck Research
  12. 12. NMR – TopSpin auto print to SDMS• Used for detailed compound structure analysis• Mostly Med Chemist use in Open Access mode (data finds chemist)• Rich methods set including most 2D experiments• Data easy to find in Vision• Some reprocessing of raw data performed in TopSpin and/or ACD (available on desktop) for publication Chemical & Pharmacokinetic 12 Sciences Lundbeck Research
  13. 13. OA-LC/MS – OpenLynx auto print to SDMS• Used for compound molecular weight and purity analysis• Mostly Med Chemist use in Open Access mode (data finds chemist)*• Frequently used for reaction monitoring• Rich methods set including 2 choices each of column, gradient, and pH.• Data easy to find in Vision• Some reprocessing of raw data performed in MassLynx for publication (on desktop)• Dual UV detectors increases dynamic range and minimizes need to adjust concentration (no rework) *Also used by Compound Management for new compounds going into collection (10-20k/yr) Chemical & Pharmacokinetic 13 Sciences Lundbeck Research
  14. 14. Purification – FractionLynx auto print to SDMS• Purification performed by expert Typical• Big concern of Med OpenLynx Chemists is that none of style report target compound is lost (lots of effort put into making compound)• ELSD quantifies mass purified and 2nd UV detector in waste stream demonstrates none lost (quality of science) Mass of target peak• Data goes into SDMS in real time (inj by inj) and Med Chemists can watch Rack purification in progress as location well as see when it is tracking finished• Med Chemists trust handing Target peak not in waste over hard to make stream compounds to someone else Chemical & Flexible bar-code tracking would be nice here! Pharmacokinetic 14 Sciences Lundbeck Research
  15. 15. Physico-Chemical measurements – Sirius and Empower reports printed to SDMS• Quantitative LC- UV used for most measurements: LogD, membrane permeability, & solubility (Empower)• Acid / base titration used for pKa measurement (Sirius)• Since these assays “rate” the compounds, chemists will question results• Combination of transparency and training results in *Some critical evaluation of the data included in the chemists believing report also helps build trust! results Chemical & *R Galford, AS Drapeau, "The enemies of trust," Galford, Drapeau, Pharmacokinetic HBR, 81(2), 2003, 89-95. 89- 15 Sciences Lundbeck Research
  16. 16. Bioanalysis with challenging separations using MassLynx for data acquisition and Empower for peak integration (transfer via WDC)• MassLynx controls SFC/MS/MS• WDC converts data to Empower• Empower does best automatic peak integration for large number of samples (least amount of rework – i.e. manual integration)• Quantitative analysis of drug enantiomers shown (in plasma)• System suitability parameters show separation not deteriorating despite many hundreds of injections (quality of science) Chemical & Transparency Allows sensitive quantitative process Pharmacokinetic avoids reanalysis. 16 control limits to be monitored / set. Sciences Lundbeck Research
  17. 17. Mechanistic Bioanalysis in Empower• Data shown for LC connected directly to live rat brain• Analytical chemist works directly in same lab with biologists & all are Empower users• Empower does best automatic peak integration for large number of samples (least amount of rework – i.e. manual integration)• Typical experimental output: 4000 chromatograms per month• Empower server (VM) not on same site as lab• Have collected data from 10 LCs in parallel “through the wire”• Empower is best centralized chromatographic data system• Server is readily & routinely accessed from many desktops and home computers Chemical & Reports not going to SDMS, biologists trained in Empower Pharmacokinetic 17 Sciences Lundbeck Research
  18. 18. Customized uses of the software Some examples created in-house and/or by Waters with focus on streamlining processes and getting the most effective use of scientific efforts These examples increase scientist efficiency and reduce human errors. Reducing human errors & getting right answer builds more trust in results! There’s a lot of value in tapping into Waters expertise as well as buying the SDK and sending one of your scientists to a VB and a SQL course! Chemical & Pharmacokinetic SciencesLundbeck Research
  19. 19. Addressing other links to make the workflow efficient • Going from bar-coded samples to analysis sample lists for the instrument & importing analysis sample lists – Empower – MassLynx • Post analysis data processing for physico- chemical assays • Adding value to Open Access LC/MS data • Post analysis data processing for compound QC (MW, purity, concentration) • Automatic emailing of results (Open Access) Chemical & Pharmacokinetic 19 SciencesLundbeck Research
  20. 20. Going from bar-coded samples toanalysis sample lists for the instrument• Physico-chemical assays result in racks of 2D bar-coded tubes with separate racks for each project• Compound management processes compounds on project basis because different biologists handle different assays for each project• Physico-chemical assays are the same regardless of project, so it doesn’t make sense to process on a project by project basis• We backfill racks to streamline physico-chemical assays With a new updated compound ID• Then, we rescan racks and list, we are now ready to create an query compound management DB to get new list of compound instrument analysis list (can be IDs* done in one step) Chemical & Pharmacokinetic 20 *LIMS / ELN providers beginning to recognize Sciences need: R Mullin, C&E News, 90(19), 2012, 11-14. Lundbeck Research
  21. 21. Importing analysis sample lists: Empower• Add-in created to generate lists• Add-in reads file from 2D tube scanner• Allows one to choose use of 1 or 2 LCs• Has multiple templates to address different assays Chemical & Pharmacokinetic Sciences Using Empower SDK 21 Lundbeck Research
  22. 22. Importing analysis sample lists: Empower• Open sample set (analysis list) in the usual way• Analysis list contains all needed information• Just put the plates in autosampler and hit the go button Chemical & Pharmacokinetic 22 SciencesLundbeck Research
  23. 23. Importing analysis sample lists: MassLynx• Handheld bar-code reader used to input rack #• VB / SQL program reads rack of 2D tubes and gets compound IDs from DB• Project, person, and UPLC plate position are added• Hit create button to make MassLynx list with rack bar-code as file name• Import list in usual way and hit the OpenLynx go button Approach also implemented for Xcalibur, Sirius, etc. and all can be performed at instrument computer Chemical & Pharmacokinetic 23 Sciences Lundbeck Research
  24. 24. Post analysis data processing for physico-chemical assays• 6000 chromatograms per month generated / processed by 1 FTE• Sample peaks RT Chromatograms with issues must be matched flagged to standard peaks• Unexpected impurities can confound peak matching• Review of data Data can be unavoidable viewed,• Tools needed to integrations corrected, and achieve this level results of throughput Creates sheet that can be uploaded directly to recalculated all pharmacology DB within same tool Chemical & Pharmacokinetic Sciences Using Empower SDK 24 Lundbeck Research
  25. 25. Adding value to Open Access LC/MS data*• Interpreting mass spectra is fairly easy for trained mass spectrometrists MW inserted into MS• However MS can produce text in report file (.rpt) a variety of peaks from pure compounds and this can be confusing for Med Chemists• Program created to intercept OpenLynx.exe and: – Process in data in normal way without printing – Find molecular weight (MW) of top 3 components in spectrum based on all peaks – Insert MW(s) into text of report and then print (to +/- spectra are treated as arrays and fitted to all known SDMS) adducts to determine MW. Determination cumulatively – Example on right weighted toward most adducts and most peak intensity.* Chemical & Saves lots of time for Med Chemists and Analytical Chemists Pharmacokinetic 25 *Uses technique from: H Tonga, D Bella, K Tabeia, Sciences Lundbeck Research MM Siegel, JASMS, 10(11), 1999, 1174–1187.
  26. 26. Post analysis data processing for compound QC (MW, purity, concentration)• Goals: verify molecular weight (MW), purity, and concentration of DMSO solutions in compound screening collection• MS for MW, UV & ELSD for purity, ELSD for concentration• Off the shelf tools have low success rates (50-70% right answers – threshold based)• Manual examination MW of data unavoidable agreement• Needed to tool to determined by streamline process so 3000 to 10000 adducts compounds per year (previous could be analyzed slide) and quickly with little FTE impact (<0.05 FTE) isotope ratio Chemical & Pharmacokinetic 26 Sciences Lundbeck Research
  27. 27. Post analysis data processing for compound QC (MW, purity, concentration)• Excel report generated with all needed DB* data: – ID & structure (Isis)* – Verification of MW – Purity & concentration – Comments on impurities and/or presence of isomers• Includes SDMS link so data can be immediately viewed (also pdfs) Chemical & Pharmacokinetic 27 *LIMS / ELN providers beginning to recognize Sciences need: R Mullin, C&E News, 90(19), 2012, 11-14. Lundbeck Research
  28. 28. Automatic emailing of results: Open Access data finds chemist• Open Access is an Decision to instant gratification email is by approach, often used by analysis type chemists for reaction (SDMS monitoring (reaction project) complete?) and person• Expectation is result in File name <5 min Emailer set up for pdf is• Worked with Waters to view notebook # create SDMS emailer (no need to• Emailer program change generates / sends email name) as soon as result exists!• pdf can be dragged and dropped anywhere it is allowed (Symyx ELN)• SDMS link can be copied and pasted anywhere text can be Actual email placed Chemical & Pharmacokinetic 28 >30000 drag/drops per year Sciences Lundbeck Research
  29. 29. Summary and Conclusions• Analytical informatics can: – Dramatically increase transparency and access to data – Increased transparency can in turn drive improved quality (because everyone can see it). This facilitates making people more open and has a significant effect! – Enhance the value of data – Significantly increase scientist efficiency through workflow optimization• Combining the benefits of informatics with high quality science and otherwise good communication can build great trust and collaboration among scientists• Achieving high levels of trust in this way can greatly enhance overall productivity (3+ fold improvement) Chemical & Pharmacokinetic 29 SciencesLundbeck Research