Biotech Facilities: Regulatory and Design Approaches

1. Biotech Facilities:Regulatory and Design Approaches Dr. Trent Carrier

2. Presentation Outline • Manufacturing Strategies • Concept and Design • Construction and Qualification • Citation Examples • Regulatory References 2

3. Manufacturing Strategies • New manufacturing facilities can….. • Be very expensive - costing tens/hundreds of millions of dollars • Take a long time to construct, startup, validate & license • For a new product, may require significant spending at risk • Having product supply ready at licensure requires spending before final clinical trial data • May have uncertainties in product demand - but have to build to a defined capacity 3

4. Product Profiles Fermentation Vaccines (protein, polysaccharide) - micrograms of API/dose, initial plus 1-2 booster doses - up to tens of million patients per year - bulk facilities at thousands of liters scale Viral Vaccines - tens of thousand of virus units/dose, initial plus 1-2 booster doses - up to tens of million patients per year - bulk facilities at hundreds of liters scale Therapeutic Proteins (enzymes, antibodies) - milligrams of API/dose, repeat administration (multiple doses/yr) - less than 1MM patients per year - bulk facilities at tens of thousand of liters scale Cell Therapy & Gene Therapy (TBD) 4

5. Case Study: Style-ogen® • Condition: Enzyme deficiency identified in professors. Linked with uncontrollable desire to wear brown polyester. Symptoms begin to appear around age 50. • Product Profile: Injectable recombinant enzyme • Timing: Launch the product in 2010 • Dose: 5 mg/ml, 10 mg/70 kg body weight, 1 treatment per month • Target Markets: US, EU, Japan • Patient Population: 16MM • Filled Product Requirements: 2,000 kg/yr • Bulk Requirements: 5,000 kg/yr (adjusted for overage and losses) • Process Scale: 2 fermentors at 5,000L scale (10 g/L titers) 5

6. Integrating with Product Timelines • What to build? • When to start? 6

7. Facility Influences Begin Early 7

8. Competing Project Goals/Information…... Uncertainty in clinical data and market demand Must define project scope & facility capacity • Timely Licensure • Launch product supply available • Defer capital spending as long as possible • Minimize spending at risk Robust GMP Manufacturing Minimize capital spending 8

9. What Do You Need??? Options for Manufacturing • Outsource • Avoid capital spending • Requires technology transfer to outside company • Launch/Pilot Facilities • FDA guidance on use of pilot facilities • Make validation/phase III/launch lots in small scale facility • Transition to full scale mfg facility to meet supply needs • Final manufacturing facility • Dedicated or multi-product? • Scale/capacity? • Evaluate ALL options before proceeding! 9

10. Product: Style-ogen® • Management decides that they want to build a manufacturing facility dedicated to this critically important product. • Based on your experience, the project might cost ~ $30-60MM. • When should we start? 10

11. Typical Project Schedule YEAR Launch 2010 means we need to start today Phase III APPROVAL Scope Design Procurement Construction IQ/OQ Startup / Validation 100% APPROVAL % Spent 11

12. Presentation Outline • Integrating Product and Facility Strategies • Concept and Design • Construction and Qualification • Case Study Follow-up • Regulatory References 12

13. Concept and Design • Layouts • Flows • Classification • Specifications • Diagrams 13

14. Links Between Regulations and Facility – Concept and Design Buildings of suitable size for cleaning, maintenance, and ops. Adequate space and flows for equipment and materials to prevent mixups -> Room size Premises laid out to allow production in logical order corresponding to sequence and cleanliness. -> Room organization and movement Equipment of appropriate design, size, constructed of non-reactive materials–> Equipment specifications Measuring equipment of appropriate range and precision-> Instrument specifications Computer equipment has controls to ensure master production and control records are accurate -> Automation Equipment located to suit intended purpose-> Equipment layouts Control of ventilation temp, pressure, dust, microorganisms adequate for manufacturing -> Room environment 14

15. Conceptual Plans • Process Conceptual Plans • Inputs: • Research / development final process (Phase II clinical process?) • Marketing Sales Forecast • Outputs: • Process Flow Diagrams (PFDs) with equipment sizes and mass balance • Equipment List • Facility Architectural Plans • Inputs: • PFDs and process equipment size estimates • Utility and Material Handling / Storage • Quality / cGMP Philosophy • Staffing Plan • Outputs: • Architectural Conceptual Plans • Cost Estimate (+/- 25%) 15

16. Early Concepts – Starting Point Process Flow Diagrams Architectural Bubble Diagrams Step 1 Mat In Fermentation People In Storage Step 2 Ferm Area Out Step 3 Purif Area People In Purification Step 4 16

17. “Rules of Thumb” • Process Area vs. Total Building Area: • Process Support (Labs, Wash/Prep, Autoclaves) 5%-10% • Building Circulation (Corridors and Airlocks) 8%-17% • Personnel (Lockers, Offices, etc) 5%-15% • Material Handling (Storage) 5%-15% • Mechanical (HVAC, Utilities, Elec., Chases) 35%-50% • Process Areas (Ferm, Purif., Buffer/Media) 15%-20% • Facility Cost ~$1000 to $1500 / square foot Style-ogen ® • 7000 sq. ft. Process Area estimated (2 rooms of 3500 each) • 7000 / 17.5% = 40,000 square foot building • 40,000 x $1250 = $50MM !!!! 17

18. Building Architectural Plan Purif Lockers, Support Ferm Ferm vs Mechanical Mechanical Lockers, Support Purif 18

19. Design • Process Design • Piping and Instrumentation Diagrams (P&IDs) • Equipment Specifications and Bid Packages • Automation Functional Requirement Specifications • Facility Design • Architectural Drawings with Equipment • Facility Specifications (Finishes, Electrical, HVAC, etc.) • All detail design drawings complete (CADD, 3D modeling, etc) • Cost Estimate (+/- 10%) 19

20. Process Scaleup From Lab 20

21. Pressure Control Vent Vent PI TI Cln Stm T Add TI Sparge TI Tank T T TI Gas FC Gas flow T Agitator Process Equipment Design A P&ID is a representation of process elements 21

22. Material Selection Material Charging Pressure Control Mix Temperature Control Discharge and Recirc Pump Equipment Functionality Via Design FT M PT TT FT 22

23. Suite Layouts Based on Equipment and Bubble Diagrams 23

24. 100% Industry range 90% 80% 70% 60% 50% 40% 30% 20% <10% Grade A Grade B Grade C Controlled Uncontrolled Mechanical Unclassified Room Classification Costs • Area classification remains topic of debate • Balance of product quality risks vs. cost Relative Cost ($/square foot) 24

25. Area Classification for Style-ogen® Process Steps • Tank Fermentation • Non Sterile Purification • Buffer/Media Hold Unclassified Space Open Processing Closed Equipment Grade A • Solution Prep • Equipment Assembly • Sterile Purification Classified Space • Open Sterile Sampling • Open Sterile Transfers • Open Aseptic Transfers 25 Lighter shading signifies more stringent area classification

26. Presentation Outline • Integrating Product and Facility Strategies • Concept and Design • Construction and Qualification • Case Study Follow-up • Regulatory References 26

27. Construction and Qualification • Fabrication and Assembly • Fits/Finishes • Installation • Operation 27

28. Links Between Regulations and Facility – Construction and Qualification Buildings of suitable construction for cleaning, maintenance, and operations-> Facility finishes, assembly Equipment installed in such a way to prevent risk of error or contamination -> Equipment fabrication Equipment designed to suit intended purpose. -> Qualification Input to and output from computer systems shall be checked for accuracy. -> Qualification 28

29. Fabrication and Construction • Facility Assembly and Equipment Fabrication • On-site (Stick-built) – Assemble piping, steel, walls, etc • Modular (off-site) – Build elsewhere and ship to site • Hybrid approaches may be used • Facility “stick-built” on-site • Process Equipment built at equipment vendor (Skids) • Allows for concurrent facility and equipment construction 29

30. Style-ogen® Facility Assembly + 30

31. Styleogen® Equipment Fabrication 31

32. Style-ogen® Process Area 32

33. Qualification Steps • Factory Acceptance Testing / Site Acceptance Testing (FAT/SAT) ensures that equipment is fabricated according to engineering designs prior to IQ • Installation Qualification (IQ) verifies that the equipment is the correct piece of equipment by design and has been installed properly. • Operational Qualification (OQ) verifies that the piece of equipment will operate as designed, for example the valves open and close as designed, the agitator functions correctly, etc... • Automation Qualification (AOQ)ensures that computer hardware and software systems used to automate processes, complete calculations, etc. can consistently perform their intended function. • Performance Qualification • Cleaning Validation • Sterilization Validation • Process Validation Subject of another class 33

34. Qualification Tiered by Product Impact Temp controller Fermentor Waste neutralization Air handlers Water generator Increasing Level of Qualification Vacuum system Autoclave Power station 34

35. Style-ogen® Qualification 4 Process Steps / 12 Pieces of Equipment 6600 pages of IQ/OQ protocols + 9 months x 15 people equipment and testing 35

36. Next Steps for Style-ogen® • Validation • Environmental Testing • cGMP Operations 36

37. Presentation Outline • Integrating Product and Facility Strategies • Concept and Design • Construction and Qualification • Case Study Follow-up • Regulatory References 37

38. Style-ogen® Follow-ups Concept -> Design -> Construction -> Qualification • You finish the project and are happy to report that you were able to build the facility for $40MM, a savings of 20% on the initial estimate. Your boss asks how you were able to save so much? Concept – Efficiencies through combining process areas Design – Reducing area classifications and re-using equipment designs Construction – Off-site fabrication of equipment at a new vendor Qualification – Risk-based qualification approaches Your boss says that is a great story and suggests that your next project should be able to save 40% because you are so good. 38

39. Style-ogen® Follow-ups Concept -> Design -> Construction -> Qualification • A production supervisor calls you and says that they can’t get the pump to run at the flowrates they need. What happened? Design – Perhaps the equipment specifications were wrong? Construction – Perhaps the wrong pump was installed? Qualification – Why didn’t the qualification testing catch it? The specs were right, the right pump was installed, and the qualification did test the pump flowrate…. You find that the wrong valve was installed in the pipe that caused a lower flowrate from the pump. 39

40. Style-ogen® Follow-ups Concept -> Design -> Construction -> Qualification • An FDA inspector arrived to perform an audit of your new facility. They question how you know that your product is protected from microbes from outside. What are your safeguards? Concept – People and material flows Design – Area classifications and equipment designs Qualification – Testing of the equipment The inspector is impressed with the thoroughness of your response and determines that your facility should be approved…. and you get a raise! 40

41. Conclusion • Regulatory guidance is major influence in facility design, but is open for interpretation. • Facility design requires an integrated view of product, process, and operations. • The lifecycle of a project is a progression of activities that build on each other. • The successful completion of a manufacturing facility is a tremendous accomplishment But it’s only the start…. 41

42. Presentation Outline • Integrating Product and Facility Strategies • Concept and Design • Construction and Qualification • Case Study Follow-up • Regulatory References 42

43. Regulatory References • Guidance for Bulk Biologics • Facilities: CFR 211.42-211.58, 600.10; EudraLex Chapter 3 • HVAC: 600.11, 211.46, EudraLex Chapter 3 • Equipment: 211.63-211.72, 600.11, EudraLex Chapter 3 • EU Annex 2 (WHO) • ISPE Baseline Guide for Biopharmaceuticals (excludes vaccines) • ASME-BPE 2002 43