Heads Up Analysis Vs High Dimensionality Problems: Heads Up Analysis Vs High Dimensionality Problems: Using Data Visualization as an Analytical Tool In Using Data Visualization as an Analytical Tool In

Advanced Solutions Applied toAdvanced Solutions Applied toManufacturing DataManufacturing Data

Gloria Gadea-Lopez, Ph.D., Genzyme CorporationGloria Gadea-Lopez, Ph.D., Genzyme CorporationRobert H. McCafferty, Curvaceous SoftwareRobert H. McCafferty, Curvaceous Software

International Forum for Process Analytical ChemistryInternational Forum for Process Analytical ChemistryJanuary 15, 2004January 15, 2004

IFPAC 2004IFPAC 2004

Application of Parallel Cordinates as Application of Parallel Cordinates as Data Mining Tool at GenzymeData Mining Tool at Genzyme

Gloria Gadea-Lopez, Ph.D.Gloria Gadea-Lopez, Ph.D.

IntroductionIntroduction

Genzyme Corporation is the leading Genzyme Corporation is the leading manufacturer of sterile Sodium Hyaluronatemanufacturer of sterile Sodium Hyaluronate Unique viscoelastic properties that make it the Unique viscoelastic properties that make it the

ingredient of choice for ophtalmic applications ingredient of choice for ophtalmic applications and post-surgery antiadhesion productsand post-surgery antiadhesion products

Produced under a proprietary Genzyme Produced under a proprietary Genzyme fermentation and purification method that fermentation and purification method that yields highly purified, exceptional quality yields highly purified, exceptional quality material.material.

Sodium Hyaluronate (HA)Sodium Hyaluronate (HA) Produced by Genzyme’s Produced by Genzyme’s

Advanced Biomaterials since Advanced Biomaterials since 19841984

In its natural form, HA typically In its natural form, HA typically exists as a sodium salt (sodium exists as a sodium salt (sodium hyaluronate), which can form a hyaluronate), which can form a highly viscous fluid (viscoelastic) highly viscous fluid (viscoelastic) with exceptional lubricating with exceptional lubricating qualities. qualities.

Plays an important role in a Plays an important role in a number of physiological functions number of physiological functions including, cells protection and including, cells protection and lubrication, maintenance of the lubrication, maintenance of the structural integrity of tissues, structural integrity of tissues, transport of molecules, and fluid transport of molecules, and fluid retention and regulation.retention and regulation.

Sodium Hyaluronate - ApplicationsSodium Hyaluronate - Applications

Genzyme's Genzyme's Seprafilm®Seprafilm®, which is used during surgery as an adjunct , which is used during surgery as an adjunct intended to reduce the incidence, extent, and severity of post-surgical intended to reduce the incidence, extent, and severity of post-surgical adhesion formation in the abdominopelvic cavity. adhesion formation in the abdominopelvic cavity.

Genzyme's HA is also being used in commercially available ophthalmic Genzyme's HA is also being used in commercially available ophthalmic products. products.

Established and potential applications for HA include: Established and potential applications for HA include: Ophthalmology Ophthalmology Soft tissue implants Soft tissue implants Wound healing Wound healing Viscosupplementation of joints Viscosupplementation of joints Bone regeneration Bone regeneration Surface coatingsSurface coatings Moisturizing agents Moisturizing agents Adhesion prevention Adhesion prevention Cell preservation Cell preservation Drug delivery Drug delivery Immunomodulation Immunomodulation

Making More and Better HAMaking More and Better HA

Process with a lot of historyProcess with a lot of history Existing legacy of previous facilityExisting legacy of previous facility

Lessons to be applied to new expanded facilityLessons to be applied to new expanded facility Exercise with Curvaceous SoftwareExercise with Curvaceous Software

Data from 150 batches, 70 variablesData from 150 batches, 70 variables• Raw material lot informationRaw material lot information• Process conditions for each unit operationProcess conditions for each unit operation• Cycle times per batchCycle times per batch• Properties of the final product (Quality Control data for Properties of the final product (Quality Control data for

release).release).

Using Parallel Coordinates - ObjectivesUsing Parallel Coordinates - Objectives

Discover “hidden” relationship among process Discover “hidden” relationship among process variables that lead tovariables that lead to Higher yieldHigher yield Viscoelastic properties in optimum rangeViscoelastic properties in optimum range

Prevent process conditions in ranges that lead to Prevent process conditions in ranges that lead to adverse resultsadverse results

Optimize raw material propertiesOptimize raw material properties Work with suppliers to ensure consistent properties of Work with suppliers to ensure consistent properties of

key raw materials.key raw materials.

Collecting the DataCollecting the Data

Information from diverse sourcesInformation from diverse sources Batch recordsBatch records Raw material informationRaw material information Final QC (Certificate of Analysis)Final QC (Certificate of Analysis)

Process history resides in MERLIN, Process history resides in MERLIN, Genzyme’s custom process database.Genzyme’s custom process database.

Biotech Processes are not “Flat Biotech Processes are not “Flat File” FriendlyFile” Friendly

In-Process Data Raw Materials

LOT101

Lot Pooling

Final Product QC Data

Fill/Finish

LOT201

LOT202

Purification

LOT301

LOT302

LOT303

Lot Splitting

Recovery

LOT401

LOT402

LOT403

BioReactor

Effects on Final

Product Quality?

Purification

Typical Data AnalysisTypical Data Analysis

Using ODBC, link Merlin and JMP (SAS), Using ODBC, link Merlin and JMP (SAS), Excel, Chart FX, QC CharterExcel, Chart FX, QC Charter Linear regression modelsLinear regression models Process CapabilityProcess Capability Multivariate with some key propertiesMultivariate with some key properties Control Charts (Shewhart)Control Charts (Shewhart)

Need comprehensive analysis. We know Need comprehensive analysis. We know there is more……there is more……

What N-Space Really Looks Like… And What N-Space Really Looks Like… And How To Make It Pay In SpadesHow To Make It Pay In Spades

Robert H. McCafferty, Curvaceous Software Robert H. McCafferty, Curvaceous Software LimitedLimited

Beyond The Third DimensionBeyond The Third Dimension

Typical Industry PracticeTypical Industry Practice Few High Return Processes Fully UnderstoodFew High Return Processes Fully Understood Complex Chain/Hierarchy Of Intricate Unit ProcessesComplex Chain/Hierarchy Of Intricate Unit Processes Brute Force Numerical Analysis Characterization Method Of Brute Force Numerical Analysis Characterization Method Of

ChoiceChoice Human Intelligence Relegated To Back SeatHuman Intelligence Relegated To Back Seat Jungle Of N-Space ImpenetrableJungle Of N-Space Impenetrable

New Process Knowledge Latent In Existing DataNew Process Knowledge Latent In Existing Data Key To Extraction Engaging Human Mind… Native CuriosityKey To Extraction Engaging Human Mind… Native Curiosity Eyes Primary Path Of Information Input To Human BrainEyes Primary Path Of Information Input To Human Brain N-Dimensional Visualization Breakthrough TechnologyN-Dimensional Visualization Breakthrough Technology 3-Dimensional Status Quo Must Be Broken3-Dimensional Status Quo Must Be Broken

Parallel CoordinatesParallel Coordinates

Substantial Foundation In N-Dimensional GeometrySubstantial Foundation In N-Dimensional Geometry

Map N-D Into 2-D Through Coordinate TransformMap N-D Into 2-D Through Coordinate Transform

Allow Direct Data Visualization And ManipulationAllow Direct Data Visualization And Manipulation Many Process Variables Simultaneously (30+)Many Process Variables Simultaneously (30+) Mathematically Robust… Zero Information LossMathematically Robust… Zero Information Loss No Derived Quantities (Re, Nu, PC, etc.) RequiredNo Derived Quantities (Re, Nu, PC, etc.) Required

True VisualizationTrue Visualization Otherwise Unobservable Phenomena Easily SeenOtherwise Unobservable Phenomena Easily Seen Readily ExplainedReadily Explained

A Single 16-Dimensional Point In Parallel A Single 16-Dimensional Point In Parallel CoordinatesCoordinates

Visual AnalysisVisual Analysis

Patterns Formed When Many Points PlottedPatterns Formed When Many Points Plotted

Human Brain Superlative Pattern RecognizerHuman Brain Superlative Pattern Recognizer Very Good At Seeing The Big PictureVery Good At Seeing The Big Picture Eyes Better Than AlgorithmsEyes Better Than Algorithms

No Absolute Requirement To UnderstandNo Absolute Requirement To Understand Process PhysicsProcess Physics MathematicsMathematics StatisticsStatistics

Process Knowledge Real KeyProcess Knowledge Real Key

Anyone Can ContributeAnyone Can Contribute

Applying Good, Better, Best Criteria Uncovers Patterns Applying Good, Better, Best Criteria Uncovers Patterns

Sweet Spots - Concentrations Of Yellow - AppearingSweet Spots - Concentrations Of Yellow - Appearing High X14 (Biosynthesis End Criteria) Clearly Best For ProductHigh X14 (Biosynthesis End Criteria) Clearly Best For Product Nearly All Premium Production From One X3 Level… High X5 Nearly All Premium Production From One X3 Level… High X5

BestBest

Delving Into More Variables...Delving Into More Variables...

Curious “Hole” In Two Process VariablesCurious “Hole” In Two Process Variables Obvious Bad Range - Poison Zone - For AnotherObvious Bad Range - Poison Zone - For Another Clear Relationship Between Two Others, High Values FavoredClear Relationship Between Two Others, High Values Favored

Looking At Final Process ResultsLooking At Final Process Results

Different Modes Of Process Operation Plainly VisibleDifferent Modes Of Process Operation Plainly Visible Clear Sweet Spot Relationships For Key Time VariablesClear Sweet Spot Relationships For Key Time Variables Fair Correlation Between Lab Measurement & Final RheologyFair Correlation Between Lab Measurement & Final Rheology

Moving To Dynamic Approach… Best Operating ZoneMoving To Dynamic Approach… Best Operating Zone

Selecting Desired Results (X75) Reveals Pattern Of BehaviorSelecting Desired Results (X75) Reveals Pattern Of Behavior Pattern Inherently Incorporates Process Variable InteractionsPattern Inherently Incorporates Process Variable Interactions

Process CameraProcess Camera

Pattern Of Process Variable Interactions (Red Lines) Used To Pattern Of Process Variable Interactions (Red Lines) Used To Derive Working Limits (Green Lines)… Exploited For ControlDerive Working Limits (Green Lines)… Exploited For Control

Genzyme LessonsGenzyme Lessons

Leverage Standing IT InvestmentLeverage Standing IT Investment DatabasesDatabases Network InfrastructureNetwork Infrastructure

Harvest New Knowledge From Existing DataHarvest New Knowledge From Existing Data Engage Complementary Visualization TechnologyEngage Complementary Visualization Technology Analyze Full Span Of Process Data AvailableAnalyze Full Span Of Process Data Available Capitalize On Engineering KnowledgeCapitalize On Engineering Knowledge Effectively Mine Existing RecordsEffectively Mine Existing Records

Exploit GainsExploit Gains Problem ResolutionProblem Resolution Response Surface VisualizationResponse Surface Visualization Process OptimizationProcess Optimization Dynamic ControlDynamic Control