Critical Steps in Process Design Michel Gigon, Associate, Laporte Consultants September 28, 2006

Agenda Definitions and General Considerations Critical Steps in Process Design

Definitions Product Development : Creation of a new product Process Development : Development of a production method (recipe) Process Design : Design of the equipment required for the production of a product, according to a pre-determined process.

Process Design in the pharmaceutical industry Process Design versus Product Life Cycle

YEARS Discovery Biological Tests Phase I Phase II Phase III NDA Launch & Commercial production PRODUCT DEVELOPMENT -20 0 2 4 6 8 10 YEARS

-20 0 2 4 6 8 10 YEARS Discovery Biological Tests Phase I Phase II Phase III NDA Launch & Commercial production Process Research (1 gr – 1 kg) PRODUCT DEVELOPMENT PROCESS DEVELOPMENT -20 0 2 4 6 8 10 YEARS Commercial Plant Transfer (100 kg- tons) Pilot Development (1 kg-100 kg) Optimisation, Capacity Increase

FACILITY AND EQUIPMENT Discovery Biological Tests Phase I Phase II Phase III NDA Launch & Commercial production Process Research (1 gr – 1 kg) Pilot Plant Operation First Plant Operation Laboratory – Research Laboratory – Development PRODUCT DEVELOPMENT PROCESS DEVELOPMENT FACILITY AND EQUIPMENT -20 0 2 4 6 8 10 YEARS Commercial Plant Transfer (100 kg- tons) Pilot Development (1 kg-100 kg) Plant Operation Optimisation, Capacity Increase

FACILITY AND EQUIPMENT Discovery Biological Tests Phase I Phase II Phase III NDA Launch & Commercial production Process Research (1 gr – 1 kg) Pilot Plant Operation First Plant Operation Laboratory – Research Laboratory – Development PRODUCT DEVELOPMENT PROCESS DEVELOPMENT FACILITY AND EQUIPMENT Design, Build, Validate -20 0 2 4 6 8 10 YEARS Commercial Plant Transfer (100 kg- tons) Pilot Development (1 kg-100 kg) Subsequent Plant Operation Optimisation, Capacity Increase PROCESS DESIGN

The four pivots of process design Mechanical Science Automation Process Validation Pharmaceutical Process

Project Life Cycle Conceptual Design Preliminary Detailed Equipment Manufacturing Construction Validation Support FAT Start-Up SAT

Conceptual design Definition of the user requirements Process Production capacity Product specification Development phase of the product

Conceptual design Definition of the user requirements Process Pilot plant : unit operations, lab procedure example First commercial plant : lab method, preliminary results from pilot plant Subsequent facility : existing process

Conceptual design Definition of the user requirements Production capacity Requirements (kg/year, units/year) Batch size (kg/batch, units/lot) Titre (kg/L) Production time (days/lot) Production schedule (24/7, 8/5) Operation (by campaign, by lots) Production opening (weeks/year) Losses (%) Equipment utilisation (%)

Conceptual design Definition of the user requirements Production capacity Requirements (kg/year, units/year) Batch size (kg/batch, units/lot) Titre (kg/L) Production time (days/lot) Set-up, production process, cleaning, sterilisation, testing, product change-over….

Conceptual design Definition of the user requirements Production capacity …. Equipment utilisation (%) Pilot plant : 20-50% First commercial plant : 70% max Mature process : > 80%

Conceptual design Definition of the user requirements Product specification Sterility Water quality Concentration Impurity levels

Conceptual design Definition of the user requirements Development phase of the product Flexibility Process maturity Laboratory Pilot plant First Plant Subsequentplant

Conceptual design Risks Definition of the user requirements Process Production capacity Product specification Development phase of the product Risks Inability to manufacture the product Inadequate plant capacity Lower quality product Inappropriate flexibility

Preliminary design Facility definition and sizing Preliminary specifications of the process equipment Sizing of utilities Sizing of spaces Preliminary specifications of the automation system

Preliminary design Facility definition and sizing Preliminary specification of the process equipment Volume, capacity Material Functionality Process paramaters Design and operation range (pressure, temperature, etc…)

Preliminary design Facility definition and sizing Sizing of utilities and spaces Process equipment Spaces production, mechanical rooms, warehouse… Process support CIP, solution prep… Building utilities HVAC, Steam, chilled water, power… Process Utilities water, effluent treatment…

Preliminary design Facility definition and sizing Preliminary specification of the automation system Manual vs automated operation Transfer panel vs manifold… Level of automation Local controller, unit operation control, batching, archiving General architecture

Preliminary design Risks Facility definition and sizing Inadequate process equipment Insufficient space and utilities Inadequate control and automation => Production capacity cannot be met => Difficulties of operation

Detailed design Detailed specification of all components of the installation Mechanical components Fabrication specification Installation specification Automation Hardware Software

Detailed design P&ID Components List I/O List Sequences of operation Mechanical components specification Automation components specifications Alarms Interlocks Access rights Installation drawing (3D, isometrics) Control panel drawings loop diagram wiring diagram Programming

Detailed design Detailed specification of all components of the installation Risks Inappropriate installation Cleaning and sterilisation issues Corrosion issues Operational difficulties Maintenance difficulties Accessibility issues

Construction and Fabrication Construction follow-up Documentation follow-up Start-up and testing (FAT, SAT)

Construction and Fabrication Construction follow-up Ergonomy and accessibility Slopes Dead legs Weld quality Etc…

Construction and Fabrication Documentation follow-up Update of design document (P&ID, specifications) Data Sheets Isometrics Test Certificates Turn-Over Package Validation Maintenance

Construction and Fabrication Start-up and testing Verification of the quality of fabrication Verification of all design hypothesis Control of process parameters Process sequences are achievable Equipment drainable, cleanable and sterilisable

Construction and Fabrication Construction follow-up Documentation follow-up Start-up and testing (FAT, SAT) Risks Inadequate installation Cleaning and contamination issues Ergonomic and operational issues Inadequate documentation Validation issues Maintenance issues

Validation Adequate documentation facilitates protocol preparation and execution Review of validation criterion can avoid unnecessary deviation Participation in protocol execution facilitates and accelerates protocol execution

Questions ?