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Workshop onLean & 6 Sigma Principles for Labs inRegulated Development & QC usingInformatics Case StudiesJohn BearyNordic User Training 2013 2011 Waters Corporation1

Workshop Description In this workshop, the importance of Informatics solutions forlaboratory related Lean Six Sigma projects will be discussed We will explore how our Customers have leveraged Waters'Laboratory Informatics solutions to support these initiatives by:— Eliminating waste and defects— Reducing variability— Improving quality 2011 Waters Corporation2

Pharma Continues to Embrace OperationalExcellence as Profitability is Pressured 2011 Waters Corporation3

Roche - Area of Impact:LaboratoriesChampaneria, Nitin J., Lean Six Sigma and Operational Excellence at Roche, WCBF’s Lean & Six Sigma Summit – Chicago,June 2009 -sigma-and-operational-excellance-at-roche 2011 Waters Corporation4

Roche – List of Selected ProjectsChampaneria, Nitin J., Lean Six Sigma and Operational Excellence at Roche, WCBF’s Lean & Six Sigma Summit – Chicago,June 2009 -sigma-and-operational-excellance-at-roche 2011 Waters Corporation5

Strategies toIncrease Efficiency and QualityLeanIncreasing efficiency by eliminating unnecessarysteps within a process and reducing waste.Six SigmaImprove processes by eliminatingdefects and reducing variability. 2011 Waters Corporation6

Lean & Six SigmaLean Management Eliminate non-value added activities (waste) Reduce complexity Improve flowImprove SpeedSix Sigma Reduce variation Reduce defects Reduce Cost of Poor Quality (COPQ)Improve Quality 2011 Waters Corporation7

Identifying Value and Non-ValueAdded ActivitiesAn Overview of Process Excellence and Lean Thinking at Johnson & Johnson, Edwin Nau, May PE-NauPresentatio98C9BA.pdf 2011 Waters Corporation8

Business y Demands 2011 Waters Corporation9

An Overview of Lean Six SigmaLeanEliminate unnecessary, non-value added stepswithin a process. Principles of “flow” and “pull”.Makes sure we are working on the rightactivitiesSix SigmaImprove processes by eliminatingdefects and reducing variability 2011 Waters Corporation10

Lean is the Elimination of Waste 7 Kinds of WasteProcessingInefficiency dueto poor tool ordesignMotionAny movement thatdoes not added valueWaitingWaiting on parts,or for a machineto finish cycleDefect/ReworkNot doing or makingit right first timeInventoryAny more than theminimum to get thejob doneOverproductionProducing too much,or too soonTransportationAny non-essentialtransport is waste waste elimination can be applied to any process 2011 Waters Corporation11

Laboratory-BasedWorkflows and Systems Harmonization & Standardization Centralization Reduce the Total Number of Software Applications Software Integration and Interoperability Improve Laboratory Efficiencies Lower Total Cost of OwnershipRemoving WASTE, VARIABILITY, and RISK 2011 Waters Corporation12

QC Workflow AnalysisSamplingWorklistCreationSelect SOPFrom sampling instruction tocertificate of analysis creation,where are the largestopportunities to minimize wasteand variability?TestExecutionComplete SOPWorksheetCertificate of AnalysisCreation 2011 Waters Corporation13

Situational Analysis: IdentifyingPotential Areas of Improvement 2011 Waters Corporation14

Situational Analysis: IdentifyingPotential Areas of Improvement 2011 Waters Corporation15

Situational Analysis: IdentifyingPotential Areas of Improvement 2011 Waters Corporation16

Potential Areas of Improvement:Workflow Optimization Examples— Analysis timelines— Customized text and calculations— Processing methods— Asset utilization 2011 Waters Corporation17

Analysis Timelines Use of e-signatures within Empower allows detailed analysis ofresult workflow through the lab Metrics that can be calculated:— First injection to first result processing— First result processing to last result generation— Last result generation to first sign off (level 1)— First sign off to second sign off (level 2 review)— Total time— All metrics measured in days 2011 Waters Corporation18

Discovering Waste and Variabilityin Analysis TimelinesProject 1Project 2Project 3Project 4Project 5Project 6Project 7Project 8Project 9Project 10Project 1Project 2Project 3Project 4Project 5Project 6Project 7Project 8Project 9Project 10 2011 Waters Corporation19

Custom Text and Calculations Text fields (enumerated custom fields)— Provide consistent format and searchability using drop-down lists Calculated fields— Perform custom calculationssuch as percent purity without relyingon external calculations or specializedsoftware programs 2011 Waters Corporation20

Optimize Use of Custom FieldsProject AProject BProject CProject DProject EProject FProject GProject HProject IProject JProject KProject LProject MProject NProject P 2011 Waters Corporation21

Processing Method Optimization Automated processing preferred versus manual integration— Saves time— Provides better result integrity Review number of results per channel Review percentage of results requiring manual integration 2011 Waters Corporation22

Asset Management Asset utilization within the laboratory— Specifically those assets controlled by Empower 3o HPLCo GC— Is asset use optimized to the workload?— Can asset servicing be conducted without impacting labproductivity? 2011 Waters Corporation23

Opportunities with Asset Utilization 2011 Waters Corporation24

Minimizing Wastewith Asset Utilization 2011 Waters Corporation25

Instrument/User ‘Flexibility’ 2011 Waters Corporation26

Lean is the Elimination of Waste ProcessingInformation sent automaticallyeven when not required,printing documents beforethey are required, spreadsheetdata calculations7 Kinds of WasteMotionLooking for data andinformation, re-enteringdata, filing hardcopies,document archivingWaitingWaiting for the next step,system downtime,hardcopy retrieval, auditdelays, review delays,approval delaysDefect/ReworkIncorrect data entry,manual re-integration,incorrect calculations,outdated SOP’s,regenerating dataInventoryFiles and documentsawaiting to beprocessed, materialqueued for release,documents awaitingsignatureOverproductionToo much paperwork,excessive lead time fromapproval delaysTransportationMovement of files anddocuments from onelocation to another,storage of intermediarieswaiting for approvals Waters Informatics can impact these 2011 Waters Corporation27

Case Study ExampleQC & Manufacturing Organization 2011 Waters Corporation28

Consequences ofDelayed Certificate of Analysis Limited shelf life— A 15 day COA delay represents 17% of a 90 day shelf life for apharmaceutical product Late/non-shipment— May translate into millions of dollars of lost revenue per batch— May allow competitors to build market share with similar products 2011 Waters Corporation29

Strategic Need: Making theManufacturing Process More EfficientVP of Operations:: Make a More Efficient ProductManufacturing Process 2011 Waters Corporation30

Strategy for ImprovingOperational EfficiencyLean 2011 Waters e TimeReduction31

Informatics Implementation Steps Used toStreamline Certificate of Analysis Process123 2011 Waters Corporation Standardize Chromatography DataSystem (CDS) Standardize Data Management Implement Electronic SOPDocumentation and WorkflowSystem32

Standardize Testing Equipment onOne Chromatography Data System 2011 Waters Corporation33

Operational Excellence:Advantages of a Common CDS Platform Standardizes data format— Exchange of information easier— Reduces time for review and sign-off Reduces training effort— Training required for only 1 software package Improves compliance— Relational database provides better traceability Promotes collaboration— Easier sharing of methods— Data review from different geographies possible 2011 Waters Corporation34

Empower Enables CDS Standardization bySupporting Multi-Instrument Vendor Control 2011 Waters Corporation35

Standardized Chromatography DataSystem Streamlines Method Validation 2011 Waters Corporation36

Standardized Chromatography DataSystem Streamlines Method Validation 2011 Waters Corporation37

Standardized Chromatography DataSystem Streamlines Method Validation 2011 Waters Corporation38

Business Intelligence for aStandardized CDSEmpower Driven Services 2011 Waters Corporation39

Add LIMS to Manage COA andUse ERP to Manager Orders 2011 Waters Corporation40

Add LIMS to Manage COA andUse ERP to Manager Orders 2011 Waters Corporation41

OpEx: Advantages of IntegratingERP and LIMS Solutions Automates testing requests— Issues QC test requests after receiving request from SAP— Generates sample worklists Single location to store testing results— QC test results stored within single LIMS from regionalEmpower systems— COA stored in LIMS 2011 Waters Corporation42

Centrally Store Laboratory Data toAutomate COA Generation 2011 Waters Corporation43

Centrally Store Laboratory Data toAutomate COA Generation 2011 Waters Corporation44

Centrally Store Laboratory Data toAutomate COA GenerationAn AutomatedCertificate of AnalysisProcessStandardizedLab Data ManagementFocus onScience and Testing 2011 Waters Corporation45

Centralized Data Storage Enablesthe Use of Intelligent Forms 2011 Waters Corporation46

Centralized Data Storage Enablesthe Use of Intelligent Forms 2011 Waters Corporation47

Combine SOP and Data Entryby Using Electronic SOP Forms123456Stock No.34 Maple Street, Milford MA 01757Phone: 1-800-252-4752Fax: 1-508-482-2004Stock PreparationStep 1: Weigh the following into a clean dry 100 mL class "A"volumetric flask.SOPCompoundSourceExpa: DiphenhydramineVMR22-Nov-0740b: Pseudoepherine HCLBayer11-Jan-086006.72c: Dextromethorphan HBrBASF10-Feb-0820024.16Table Continued.Desired (mg)Actual (mg)23.13Batch No.a: DiphenhydramineDIP-003b: Pseudoepherine HCLPSD-02c: Dextromethorphan HBrDextromethorphan Hbr39398.8115751157Step 2: Add 50 mL of purified WaterDextromethorphan HBrCompoundH2O-01SourceWatersExpDesired (mL)10-Feb-08Actual (mL)5049.98Note: Swirl (sonicate if necessary) to dissolve completely.Step 3: Add purified Water to volumetric flask bringing solvent levelto 100 mL.Standard Details:Balance Details:Data Entry 2011 Waters CorporationStd. ABalanceAcceptable (Y/N)Conc (mg/mL)N0.05ID No.SrN-11679-B4Total (mg)54.01Cal/Qual Date4-Nov-07Confidential.48

An Electronic SOP FormCan Integrate with . 2011 Waters Corporation49

Direct Interface with Balances and pHMeters Reduces Transcription Errors9.876 CR unit mg 09/08/2008 wli4345a tare y CR LF 123456Stock No.34 Maple Street, Milford MA 01757Phone: 1-800-252-4752Fax: 1-508-482-2004Stock PreparationStep 1: Weigh the following into a clean dry 100 mL class "A"volumetric flask.Compounda: DiphenhydramineSourceExpVMRDesired (mg)Actual (mg)22-Nov-0740b: Pseudoepherine HCLBayer11-Jan-086006.72c: Dextromethorphan HBrBASF10-Feb-0820024.16Table Continued.Batch No.a: DiphenhydramineDIP-003b: Pseudoepherine HCLPSD-02c: Dextromethorphan HBrDextromethorphan Hbr39398.811575115723.139.876 mgStep 2: Add 50 mL of purified WaterDextromethorphan HBrCompoundH2O-01SourceWatersExpDesired (mL)10-Feb-08Actual (mL)5049.98Note: Swirl (sonicate if necessary) to dissolve completely.Step 3: Add purified Water to volumetric flask bringing solvent levelto 100 mL.Standard Details:Balance Details:Std. ABalanceAcceptable (Y/N)Conc (mg/mL)N0.05ID No.SrN-11679-B4Total (mg)54.01Cal/Qual Date4-Nov-07Confidential. CR 2011 Waters Corporation9.876uni50

Example of an Intelligent SOP FormBalance InterfaceChemical Inventory InterfaceAuto CalculationsFit-for-use InterfaceError Proofing 2011 Waters Corporation51

Operational Excellence:Advantages of Intelligent Forms Reduces errors— Standardizes Data Input and Performs Error Proofing ( 0%)— Reduces Transcription Errors by directly interfacing with other datasources ( 0%) Improves data review and regulatory compliance— Procedure documenting (up to 80% faster)— Easy Review of Centralized Results ( 50% faster)— Compliant-Ready Solution Improves quality— Management has immediate access to data— Promotes collaboration between teams 2011 Waters Corporation52