Debugging Finished Goods Manufacture For A Popularly Prescribed Pharmaceutical

Jean-Marie Geoffroy, Xavier Castells Abbott Laboratories

Robert H. McCafferty, Curvaceous Software Limited

Background

• Reasonably Large Database– 106 Variables in Total

– 212 Lots Spanning Full Year’s Manufacture

– Raw Material, Logistical Information Also Tracked

– History Of Issues

• Granulation, Blending, Compression, And Coating Unit Processes Involved

• Yield Loss And Associated Mechanisms Negligible

• Variability Driving:– Test Cost

– Idle Equipment Time

– Dissolution Profile Anxiety

Entire Spreadsheet in One Picture

• Each Black Line An Observation

• Missing Data Clustered At Bottom Of Axes

Querying Against Variability And Yield

• First Pass Approach Given Product Within Specifications

• Considers All Standard Deviations Available In Dataset

Variability Analysis (cont.)

• Clear Temporal Patterns By Month, Possibly Day As Well

Variability Analysis (cont.)

• Adverse Results With Extended Hold Time– Different Gradients For Gran/Blend, Blend/Compress, Compress/Coat Delay

– Also True Of Accumulated Time… Possible Hole In Blend/Compress Delay

Cost Argument Analysis

• Effectively Confirms All Items Discovered By Variability Analysis– No Relationship Between Yield And Tablets Tested (Different Mechanisms)

Cost Analysis (cont.)

• Adverse Signature In Raw Material 1 Characteristics– Map Directly To High Tablet Testing And Variability, Recent And Previous

Dissolution Profile Analysis

• Hardness Range Increases As Min Or Max Diverge From Spec.– Operators Taking Corrective Action (Too Hard/Soft) Only When Warranted

– Standing Procedures Working

Dissolution Profile Analysis (cont.)

• Weight Range Increases As Min Or Max Diverge From Spec.– Operators Taking Corrective Action (Too Light/Heavy) Only When Warranted

– Standing Procedures Working

Dissolution Profile Analysis (cont.)

• Clear Coating Process Sweet Spots – Nozzle To Bed Distance As Well As Pan Loading

Analysis Results

• Holistic View Taken… All Variables Considered Simultaneously

• Clear Shift In Raw Material Constitution Driving High Variability

• Problem Clearly Amplified By Unanticipated Hold Time Influence

• Expected Temporal Patterns (Month and Campaign) Present, Mid- Month Hole In Daily Behavior Under Review

• Manufacturing Procedures Confirmed Operating As Expected– High/Low Hardness Reaction

– High/Low Weight Reaction

Extending to Geometric Model

• All Interactions Considered

• Full Response Surface In Single View

Money In The Bank

• Improved Process Understanding Drives Reduced Variability

• Immediate Manufacturing Savings Possible– Reduced Test Cost

– Elimination Of Excess Idle Time

– Unnecessary WIP/Inventory Cost Elimination

• Much More Certain Planning and Scheduling Feasible

• Entire Factory Throughput Can Now Be Optimized