Informatics Plenary Hayward Etal May2012

Integrating Informatics Tools to Improve Transparency, Trust, and ProductivityAcross the Drug Discovery Workflow

Chemical & Pharmacokinetic

SciencesLundbeck Research

Mark J. Hayward,* Chi Zhang,* Romel Campbell,** and

Qing Ping Han*

Lundbeck Research – 215 College Rd. - Paramus, NJ 07652

*Analytical, **IT

• 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

First principles



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� 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*

*SMR Covey, "The speed of trust,"

Simon & Schuster, New York, 2006.

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)



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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 there is no place to hide low quality!*

Areas where

transparency can help

build trust*It is not uncommon to encounter resistance when shifting to high transparency

*You should do it anyway!SMR Covey, "The speed of trust," Simon &

Schuster, New York, 2006.

• 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

More first principles



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– 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

• 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

Still more first principles



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– 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)

And now the content of this presentation

How we used the first principles to address



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.

Responsibilities of the drug discovery Analytical 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



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• 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

Quality crucial in all areas!

Responsibilities from a purelyinformatics point of view

Empower for raw data

SDMS & email for processed and raw data

Pharmacology DB for finished pharma data

Sample & ELN DBs for sample & experiment data*

VMs for secure remote access

VMworld

Corp IT(collaboration /trust are crucial)

PC worldRed =



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Titrators (2)LC/MSs & SFC/MSs (10) NMRs (2) GC/MS (1) & LC/MSs (5)

Lab PCs: some with barcode readers (28)

LCs & SFCs (23)

Home PCs (>50) Office PCs (>100)

PC worldRed =Corp ITGreen =Analytical

Empower

MassLynx

TopSpin XcaliburSirius

Corp IT: OS, networking, Office apps, & anti-virus SW. Analytical: instrument SW & SDMS connections

Effective data access &

resource utilization are crucial!*LIMS / ELN providers beginning to recognize

need: R Mullin, C&E News, 90(19), 2012, 11-14.

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



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• 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)

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



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� 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)

Ordinary uses of the software



Some examples with focus on quality of science

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



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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

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,



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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)

Purification – FractionLynx auto print to SDMS

• Purification performed by expert

• Big concern of Med Chemists is that none of target compound is lost (lots of effort put into making compound)

• ELSD quantifies mass purified and 2nd UV detector in waste stream

Typical OpenLynx style report



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in waste stream demonstrates none lost (quality of science)

• Data goes into SDMS in real time (inj by inj) and Med Chemists can watch purification in progress as well as see when it is finished

• Med Chemists trust handing over hard to make compounds to someone else

Target peak not in waste stream

Mass of target peak

Rack location tracking

Flexible bar-code tracking would be nice here!

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 pKameasurement



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measurement (Sirius)

• Since these assays “rate” the compounds, chemists will question results

• Combination of transparency and training results in chemists believing results

*Some critical evaluation of the data included in the

report also helps build trust!

*R *R GalfordGalford, AS , AS DrapeauDrapeau, "The enemies of trust," , "The enemies of trust,"

HBR, 81(2), 2003, 89HBR, 81(2), 2003, 89--95.95.

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 –



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(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)

Allows sensitive quantitative process

control limits to be monitored / set.

Transparency

avoids reanalysis.

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:



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• 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 centralizedchromatographic data system

• Server is readily & routinely accessed from many desktops and home computers

Reports not going to SDMS, biologists trained in Empower

Customized uses of the software

Some examples created in-house and/or by Waters with focus on



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!

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

•



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• 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)

Going from bar-coded samples to analysis 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

•



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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

• Then, we rescan racks and query compound management DB to get new list of compound IDs*

With a new updated compound ID

list, we are now ready to create an

instrument analysis list (can be

done in one step)

*LIMS / ELN providers beginning to recognize


Importing analysis sample lists: Empower

• Add-in created to generate lists

• Add-in reads file from 2D tube scanner



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2D tube scanner

• Allows one to choose use of 1 or 2 LCs

• Has multiple templates to address

different assays

Using Empower SDK

Importing analysis sample lists: Empower

• Open sample set (analysis list) in the usual way

• Analysis list contains all needed



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•contains all needed information

• Just put the plates in autosampler and hit the go button

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



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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

Post analysis data processing for physico-chemical assays

• 6000 chromatograms per month generated / processed by 1 FTE

• Sample peaks RT must be matched to standard peaks

Chromatograms

with issues

flagged



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to standard peaks

• Unexpected impurities can confound peak matching

• Review of data unavoidable

• Tools needed to achieve this level of throughput

flagged

Data can be viewed, integrations corrected, and results recalculated all within same tool

Creates sheet that can be uploaded directly to pharmacology DB

Using Empower SDK

Adding value to Open Access LC/MS data*

• Interpreting mass spectra is fairly easy for trained mass spectrometrists

• However MS can produce a variety of peaks from pure compounds and this can be confusing for Med Chemists

• Program created to

MW inserted into MS

text in report file (.rpt)



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• 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 SDMS)

– Example on right

+/- spectra are treated as arrays and fitted to all known adducts to determine MW. Determination cumulatively weighted toward most adducts and most peak intensity.*

Saves lots of time for Med Chemists and Analytical Chemists*Uses technique from: H Tonga, D Bella, K Tabeia,

MM Siegel, JASMS, 10(11), 1999, 1174–1187.

Post analysis data processing forcompound 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



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concentration

• Off the shelf tools have low success rates (50-70% right answers – threshold based)

• Manual examination of data unavoidable

• Needed to tool to streamline process so 3000 to 10000 compounds per year could be analyzed quickly with little FTE impact (<0.05 FTE)

MW

agreement

determined by

adducts

(previous

slide) and

isotope ratio

Post analysis data processing forcompound QC (MW, purity, concentration)

• Excel report generated with all needed DB* data:– ID & structure (Isis)*

– Verification of MW

– Purity & concentration



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concentration

– Comments on impurities and/or presence of isomers

• Includes SDMS link so data can be immediately viewed (also pdfs)

*LIMS / ELN providers beginning to recognize


Automatic emailing of results:Open Access data finds chemist

• Open Access is an instant gratification approach, often used by chemists for reaction monitoring (reaction complete?)

• Expectation is result in <5 min

• Worked with Waters to

Decision to email is by analysis type (SDMS project) and person

File name for pdf is notebook #

Emailer set up

view



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• Worked with Waters to create SDMS emailer

• Emailer program generates / sends email 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 placed

notebook # (no need to change name)

view

>30000 drag/drops per year

Actual email

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



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– 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)

Informatics Plenary Hayward Etal May2012

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