PLANT/FACILITIES ENGINEERING IN THE PHARMACEUTICAL INDUSTRY

1. PLANT/FACILITIES ENGINEERING IN THE PHARMACEUTICAL INDUSTRY

2. FUNCTIONS OF THE PLANT ENGINEERING DEPT • Design and construction of facilities and systems • Maintenance of facilities and systems • Operation of system • Environmental, Health & safety • Regulatory compliance • Energy management • Technology • Validation • Administration, supervision, organization, planning

3. OFFICE PRODUCTION WAREHOUSE EXTERNAL INFRASTRUCTURES UTILITIES BUILDING INFRASTRUCTURES COLDROOM PHARMA FACILITY LABORATORIES FACILITY BIOTECH ASEPTIC & STERILE FILLING AREA DESIGN OF FACILITIES NEW PHARMACEUTICAL PROJECT FUNCTION ENGINEERING / PROCUREMENT / CONSTRUCTION / COMMISSIONING /START-UP / (VALIDATION)

4. PROJECT PHASES • Conceptual • Long range plan development (1-5 years in advance) • Planning • Project scope development for next year (6-12 months in advance) • Request for capital expenditures (RCE) • Develop RCE documentation 2-4 months in advance • Execution • Immediately pre & post funding • Closeout • Upon completion

5. TYPES OF PROJECT • New water for injection system • Chilled water upgrade • Clean rooms upgrade • Installation of a second bag printer • Optimize clave cycles • Install thermal oxidizers • Electrical bussway upgrade • Upgrade hot stamp system • Overhaul blow mold deflasher

6. PROJECT INDICATORS • Did you meet project scope? • Did you meet project timeline? • Did the project was within budget?

7. PREVENTIVE MAINTENANCE • New equipment or changes are added to PM program via VCR (validation change request) • Master PM describes: • Equipment identification • Frequency • Tasks to be performed • Master PM approved by Maintenance coordinator, Engineering manager, Production manager, and Quality manager.

8. PREVENTIVE MAINTENANCE REQUIREMENTS • Tasks and frequency determined by: • Manufacturer’s recommendation • Historical data • Department supervisor and maintenance coordinator verifies completion of PM tasks • PM records maintained by the engineering department

9. SHUTDOWN • Include routine activity and projects • Require project management tools • Involve all department and contractors • Training is critical to avoid safety issues • Require maintenance resource availability

10. SPARE PARTS • Increased focus on better utilization of our stockroom dollars • Plants are making progress in reducing the cost and number of spare parts in inventory • Alternate suppliers are being identified to reduce the cost of parts • In-house & local machine shops are being utilized where possible to fabricate parts for less than OEM cost

11. DOWNTIME ANALYSIS Sample report:

12. AUTONOMOUS MAINTENANCE Line Operator Example

13. SWAT TEAMS-PROCESS IMPROVEMENTS • SWAT teams are used in some form at all sites • Involves Six Sigma, Cost Reduction teams and Maintenance Productivity teams • Team Targets Lines based on Labor Performance, Material Performance, and Standard Units Produced • Line Improvement Projects are selected based on Cost vs. Return just like RCE projects • Team evaluates mechanical performance, processes and procedures • Team tracks effectiveness and strives to make permanent fixes

14. DMAIC Process • Define Problem • Problem Statement • Pareto Charts • Form Team • Charter • Monitor • Process Management Plan • Control Charts • Scope Project • SIPOC Map • Align w/Customer • VOC • Affinity Diagram Train • Standardize • Juran’s Pyramid • Flow Charting • What Data? • “Five Points of View” Control Define Remedial Journey • How to Measure • Operational Def’s • Measurements System Analysis • Anticipate • Failure Mode • Process FMEA • Which Units? • Representative Samples • Contextual Data (Implement) • Address • Human Side • Leadership Tools Diagnostic Journey Measure • Plot Data • Time Plots & • Control Charts • Frequency Plots • (Histo & Pareto) Improve • Plan • Implementation • Planning Tools Estimate Sigma Analyze (Create) • Map Process • Activity Flowchart • Deployment Flowchart • Anticipate • Failure Mode • Design FMEA • Choose Solution • Priority Matrix • Pugh Matrix • Focused Prob. Statement • (Problem Specification) • Set Criteria • Multi Voting • List Probable Causes • Is vs. Is Not • Fishbone/Fault Tree (Why) • Develop Solutions • Brainstorming • Idea Box, etc. Implementation Problem • Test (Verify) Causes • Scatter Diagram • Strat Freq. Plots • Tables Decision Problem • Analyze Map • Cycle Times • Wastes 6/14/2004

15. MANAGEMENT STANDARDS • EHS Global Management • Strategic Planning • Self Assessment / Risk Assessment • Business Integration • Training and Awareness • Communication and Information • Performance Measures • Assurance Review

16. TECHNICAL STANDARDS • Confined Spaces Entry • Underground Storage Tanks • Dangerous Goods / Hazardous Material • Waste Facility Selection • Machine Guarding • Spill Prevention • Hazardous Process • Waste Management • Ergonomics • Water

17. TECHNICAL STANDARDS(continued) • Emergency Preparedness Planning • Air Emissions • Significant EHS Incident Reporting • Contractor EHS Management • Reproductive Hazard Management • Chemical Hazard Communication • Capital Project Review • Occupational Health Services

18. REGULATORY AUDITS • The Audit criteria includes: • Federal & Local Environmental, Health and Safety Regulations, Good manufacturing practices • Audit approach: • Facility tour • Inspections • Employee interviews • Documentation / records • Site programs and procedures • System design

19. Steam - natural gas Steam trap maintenance Pipes and valves insulation More efficient equipment Steam pressure adjustment Sanitation frequency Boiler economizer Electricity High efficiency motors Equipement operation schedules Low consumption fluorescent lamps Repair of compressed air leaks ENERGY SAVING INITIATIVES

20. Preliminary Data

21. PROCESS ENGINEERING • Lyophilization Equipment Engineering • Solution Preparation and Delivery System Engineering • Pharmaceutical Water Systems Engineering • CIP (clean in place) Systems Engineering • SIP (steam in place) Systems Engineering • Utility Systems Engineering • Automation Engineering & Design • Filtration Selection & Qualification Support

22. STERILIZATION ENGINEERING • Terminal Sterilization of Final Product (Steam, Gamma, ETO) • Sterilization of Commodities (Steam, Dry Heat, Gamma, ETO) • Sterilization of Aseptic Filling Equipment (Steam, VHP, Dry Heat) • Sterilization Cycle Development • Sterilizer Equipment Design • Sterilizer Tray/Rack Design • New Product Submission Generation and Support

23. PAT “Systems for analysis and control of manufacturing processes based on timely measurements of critical quality parameters and performance attributes of raw materials and in-process products, to assure end-product quality at the completion of the process”

24. PAT OBJECTIVES • Produce • The right quality • In the shortest time • At the lowest cost • Predictable fashion • Pharmaceutical Manufacturing • Does not always meet all criteria • Efficiency is lower than comparable industries • Lots of room for improvement but improvement was almost discouraged

25. PAT-TECHNOLOGIES • Simple sensors • pH, temperature, pressure, etc • Spectroscopic • Near-IR, Imagers, Mid-IR, Raman, UV-Vis, etc • Physical properties • Particle size and shape, thermal effusivity, acoustics, etc • Classical analytical techniques • HPLC, GC, LOD, etc

26. VALIDATION LIFE CYCLE

27. VALIDATION IN THE FUTURE • Shift to “continuous validation” concepts from up-front 3 batch concept (this comes with PAT) • Increased usage of Commissioning activities and documentation to reduce IQ/OQ activities • Focus validation efforts on “product quality” attributes • Increased usage of documented “Risk Assessments” to streamline the validation testing

28. ADMINISTRATION • Preparation of plant/facilities budget • Management of capital projects and expenditures • Support production goals • Solicitation, preparation and administration of contracts • Contracting and overseeing the activities of various contractors and consultants • Maintenance of current as built drawings • Hiring and coaching of the engineering employees • Supervision of employees • Maintain appropriate training and certification