ISPE Biopharmaceutical Baseline Guide Chapter 6 - Facilities Omaha, April 14, 2005
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ISPE Biopharmaceutical Baseline Guide Chapter 6 - Facilities Omaha, April 14, 2005 Mark von Stwolinski, CRB So who is Mark von Stwolinski? Biopharmaceutical Baseline Guide – Steering Committee member and author PACLAW Baseline Guide – author and Facilities Chapter lead 2 Two Part Presentation Part 1 – The New Bioguide concepts Paradigm Shift: product does not equal facility Part 2 – What can be done now? editorial Optional Futures Shift Rate of Change Shift Attitude Shift 3 ISPE Biopharmaceutical Guide This Guide presents a major shift in thinking for facility designs The ‘closed system’ verses ‘open system’ production approach results in two very different facilities This presentation is an overview of this major concept 4 Closed verses Open processing These are both cGMP 5 Facility Layout Items Fully closed system process design is a major technology shift over open processing Facility design for closed processing now needs to shift to adapt to the process technology Many of the “open processing” facility design features such as supply and return corridors and unidirectional flows are not needed in “closed processing” facilities 6 Biopharmaceutical Paradigm Shift Product = Process = Facility for “open systems”. Typical for past facilities Product = Process and not equal to Facility for “closed systems”. Current standard Product does not equal equipment and does not equal process 7 Paradigm Shift Product = Process = Facility Product = Process ≠ Facility Product ≠ Process ≠ Facility 1985-2005 2005 2010 8 Spatial Segregation with a Single Production Line and Dual Production Hallways A ‘Supply/Return’ Hallway System A common design solution for early biotech facilities with all open processing. This approach is still used today for closed processes. 9 Single Product/Min Segregation Single Product / Minimal Segregation Access Co ntrol Ra w Ma te rials Ma te rials & Solutions Ino cul um Prep. Produc t Flow A Produc t Media Pre p. Ferm /C C + Ha rve st/Rec ov ery Upstre am Processing A Dispensa ry Downstream Processing Buffer Pre p. Raw Mate rials In For mula ted Bulk Product Out 10 Purific ation Mate rials Ce nte r A Bulk For mula tion Single Product/Mod Segregation Single Product / Moderate Segregation Access Co ntrol Ra w Ma te rials Ma te rials & Solutions Ino cul um Prep. Produc t Flow A Ferm /C C Media Pre p. Produc t Ha rve st/ Re cover y A Upstre am Processing Dispensa ry Raw Mate rials In For mula ted Bulk Product Out 11 Buffer Pre p. Mate rials Ce nte r Downstream Processing Cr ude Pur ifica tion A Final Pur ifica tion A Bulk For mula tion Multi-Product/Mod Segregation Mul ti -Pro du ct / Mo d erate Segr ega tion Acc ess Co nt rol Ra w Ma te rial s Materials & Solutions Pr oduc t Fl ow A Medi a Prep. Pr oduc t Upstream Processing Ino cu lum Prep . Ferm/C C Ha r vest/ Re cov ery Harvest/ Recovery A+B A B Di spensary Buffer Prep. Raw Mat e ri al s In For mula te d Bul k Produc t O ut 12 Material s Center Crude Purifi cation Fina l Purifi cation A or B A or B Downstream Processing Bul k For mulation Multi-Product/Mod Segregation Multi-Product / Moderate Segregation Access Co ntrol Ra w Ma te rials Ma te rials & Solutions Ino cul um Prep. Ferm /C C + Ha rve st/ Re cover y Ferm /C C + Ha rve st/ Re cover y Ino cul um Prep. Produc t Flow A Media Pre p. Produc t A B Cr ude Pur ifica tion Cr ude Pur ifica tion Dispensa ry Raw Mate rials In For mula ted Bulk Product Out Buffer Pre p. Mate rials Ce nte r A Final Pur ifica tion A 13 Upstre am Processing Downstream Processing B Final Pur ifica tion B Bulk For mula tion Facility Layout - Overview What determines how areas are segregated? What is segregation? Without this knowledge, many will say company “x” did it, so we should too. This results in solutions applied out of context. 14 Basic Processing Steps Why, What, Where, When and How to cut 15 Facility Layout Key Factors Closed or Open Processing Closed or Open Equipment Cleaning Additional Segregation Approaches 16 Closed and Open Processing Closed Processing = Controlled Non-Classified (CNC) Environment Open Processing mitigated to closed = CNC 17 Open Processing = Classified Space Open Processing The room environment is part of the product protection equation 18 Closed Processing Product protection is by closed systems and is independent of the room environment 19 Open and Closed Processing Typical open process in a series of separate rooms Inoculum to harvest is typically upstream Purification to bulk formation is typically downstream 20 Open and Closed Processing Validated Closed Processing allows for multiprocess steps to occur in the same room, including Pre and Post Viral Inactivation Open Process steps are still segregated 21 Open and Closed Processing 22 This works for Single Production Lines and for Multi-Product concurrent production, including concurrent cell culture and microbial closed system processing. Open and Closed Processing The facility is organized around “open and closed” The traditional division of upstream and downstream facility separation for open processing becomes less of a factor for validated closed processing. 23 Closed Processing Cell Culture Harvest Utilities Purif 2 Hold Purif 1 A possible future? The “McFusion” or the “McProcess”. For closed processing, this guide does not preclude this Ballroom approach. 24 Closed Processing Multi-product concurrent production for validated closed processing and closed equipment cleaning 25 Facility Layout Key Factors Closed or Open Processing Closed or Open Equipment Cleaning Additional Segregation Approaches 26 Open and Closed Equipment Cleaning But Equipment Cleaning is not always closed Impact factors include: production scheduling, personnel protection, environmental protection and room cleaning for residual contamination prevention 27 Open and Closed Equipment Cleaning Non-closed product contact equipment, portable vessels and utensils can be addressed by spatial segregation The result may be the return of a series of separate rooms 28 Open and Closed Comparison 29 Open and Closed Comparison 30 Facility Layout Approach 31 Possible Two Level Vertical Concept Large scale ‘horizontal’ concept 32 Possible Four Level Vertical Concept Large scale, gravity feed media and buffers 33 Possible Five Level Vertical Concept Large scale, gravity feed process 34 3-D Facility Planning 35 Facility Concept 36 Facility Concept Graphic 37 Facility Concept Art 38 Facility Layout Key Factors Closed or Open Processing Closed or Open Equipment Cleaning Additional Segregation Approaches 39 Segregation and Flow The concept of “Segregation” reflects a need for the design to protect the open product from environmental contamination as it progresses through a series of unit operations. The avenues to accomplish segregation include, among others, procedural, physical, environmental and chronological (temporal) separation. Open processing requires segregation which drives “flow”. 40 Segregation and Flow Segregation by space (spatial) may include built-in paths of travel Segregation by time (temporal) may include sequencing clean and dirty items or materials at different stages of cleanliness through the same area, but separated by time 41 Segregation and Flow Segregation by environmental control may include the protection of an open system by the use of a classified area. Segregation by ‘closed processing’ (a form of physical segregation) avoids the additional measures identified above to protect an open process. 42 CNC Areas Can look like bulk pharmaceutical and chemical production facilities Exposed utilities are acceptable 43 CNC Environment Ventilated with filtered air – ARHRAE 85% filtration. HEPA filtration is not required Some differential pressure to reduce outdoor contamination Routine environmental monitoring is not required 44 Closed verses Open processing These are both cGMP 45 Facility Layout Summary Protect the product by ‘closed’ system processing and avoid elaborate and expensive facility designs. Once a process step is ‘open’ then the facility environment, production flows and personnel gowning are required to protect the product. Discretionary upgrades are anything that are beyond product protection. 46 Facility Layout Summary There is no single way to approach facility design There is no single way to design a facility The Guide should not be used to develop an ‘ideal’ facility outside of the context of reality 47 Part 1 Conclusion The goal is to protect the product. Everything else is discretionary. 48 Two Part Presentation Part 1 – The New Bioguide concepts Paradigm Shift: product does not equal facility Part 2 – What can be done now? editorial Optional Futures Shift Rate of Change Shift Attitude Shift 49 Optional Futures Based on a solid understanding of the regulatory requirements, there is a freedom to implement rational and creative facility solutions The ‘same old way’ does not have to be ‘the same old way’ 50 The GMP Compass Step 1: orientation Step 2: path forward Develop your internal GMP compass 51 Creating Possible Futures What are the possible futures of biopharmaceutical facility design? Anything you want them to be It is creation that integrates the process technology and regulatory requirements into a viable facility These are discretionary opportunities 52 Production Rough 53 Production Slick 54 Grim 55 Light 56 Open 57 Heidelberg 58 Modules 59 Editorial Comment The GMPs do not make ugly or grim facilities, people do GMPs are like a building code, there are requirements, but the variations are endless The industry has a choice 60 A Bright Future With what the industry knows now, if we could start with a clean sheet of paper, what would we do? But sometimes thinking can be locked in time 61 Current Negative Layout Drivers Fear (the greatest hindrance to reason & innovation) Unclear understanding of regulatory intent Concepts applied out of context One-upmanship Belts and suspenders Funds spent on items that have no bearing on product protection 62 Two Part Presentation Part 1 – The New Bioguide concepts Paradigm Shift: product does not equal facility Part 2 – What can be done now? Optional Futures Shift Rate of Change Shift Attitude Shift 63 Rate of Change Shift Changes from start to 2000 < 2000-2020 < 2020-2030 64 The rate of change is compressing Facility design needs to accommodate these shifts Rate of Change Shift The rate of process technology change is compressing The rate of equipment technology is compressing The rate of process analytical technology is increasing The rate of facility design needs to adapt to keep up 65 Rate Of Change Shifts The Biopharm Industry is Changing 66 Rate Of Change Shifts The Biopharm Industry is Changing “It is safer to assume all processes are open” 67 “Reduce the clean area by remoting some equipment into gray space” “Design the equipment for all closed processing for a flexible facility” “We have well characterized proteins – keep the equipment flexible” “McProcess run in your garage like the washing machine” Rate of Change Shifts People tend to “design in” obsolescence Fueled by: Regulatory Uncertainty Good ideas applied out of context or out “of current” People tend to repeat what they have seen Adaptation is essential to remain market viable Anticipate and facilitate change 68 Rate Of Change Shifts The Biopharm Industry is Changing “It is safer to assume all processes are open” “Reduce the clean area by remoting some equipment into gray space” Less competitive 69 “Design the equipment for all closed processing for a flexible facility” Facility Cost “We have well characterized proteins – keep the equipment flexible” “McProcess run in your garage like the washing machine” More competitive Two Part Presentation Part 1 – The New Bioguide concepts Paradigm Shift: product does not equal facility Part 2 – What can be done now? Optional Futures Shift Rate of Change Shift Attitude Shift: humans, what to do with them? 70 Human Factors What? Who let the human in here? Many industries have an unfortunate view of personnel - in two classes The creative class, those who use machines to create wealth The commodity class, those who service machines that create wealth 71 The Beginning - Choices Understanding The Corporate values and mission Understanding the Project goals, objectives and tasks This is a counter-offshoring optional future 72 Begin with Corporate Values Time Expended The How Tasks The When Objectives The What Goals The Why Mission The Who Values 73 This is what you will do These are what Define your company Corporate Goals Example To provide a working environment that will: •Attract and retain the best employees in a highly competitive market. •Encourage a large and diversified product portfolio. •Incorporate Technologies for the 21st Century. •Provide flexibility and accommodate future growth. •Create and foster a collaborative cross team environment, reflecting the way people use facilities today. 74 Facility Concepts To provide a working environment that will provide: •Group Interaction •Facility Integration •Collaborative Environment •Excitement •Employee Enjoyment •Corporate Image 75 Next Generation Facilities Next Generation Facilities 76 Next Generation Facilities An overview of the change in thinking in biopharm facility design What is ‘current’ 77 Generation One •Isolated Production •No Visual Relief The Generation Dial Functional Groups Interaction 1 2 3 4 5 4 5 Facility Integration 1 2 3 Collaborative Environment 1 2 3 4 5 3 4 5 Excitement 1 2 Employee Enjoyment 1 2 3 4 5 4 5 Corporate Image 1 78 2 3 Generation One •Isolated Production •No Visual Relief 79 Generation Two •German Daylight View Guide •FDA observation from a non-clean area The Generation Dial Functional Groups Interaction 1 2 3 4 5 4 5 Facility Integration 1 2 3 Collaborative Environment 1 2 3 4 5 3 4 5 Excitement 1 2 Employee Enjoyment 1 2 3 4 5 4 5 Corporate Image 1 80 2 3 Generation Two •German Daylight View Guide •FDA observation from a non-clean area 81 Generation Three Loop circulation •Dislodged from building exterior •Color 82 Generation Three Loop circulation •Dislodged from building exterior •Color 83 Generation Three 84 Generation Three 85 Generation Four The Generation Dial Functional Groups Interaction 1 2 3 4 5 4 5 Facility Integration 1 2 3 Collaborative Environment 1 2 3 4 5 3 4 5 4 5 4 5 Excitement 1 2 Employee Enjoyment 1 2 3 Corporate Image 1 86 2 3 Generation 5 87 Generation Five The Generation Dial Functional Groups Interaction 1 2 3 4 5 3 4 5 Facility Integration An Innovative Solution that Celebrates the values of the Client 1 2 Collaborative Environment 1 2 3 4 5 2 3 4 5 3 4 5 3 4 5 Excitement 1 Employee Enjoyment 1 2 Corporate Image 1 88 2 A Sense of Place Place is: Particular Somewhere Meaningful Unique Refreshing Space is: General Everywhere Meaningless Generic Fatiguing “Place” exists from the executive suites to admin to labs – everywhere but manufacturing Do manufacturing personnel have the same right to “place?” 89 Arrival 90 A Sense of Place 91 A Path 92 Functional Art 93 Open 94 One Future 95 Another Future 96 Creating Possible Futures What are the possible futures of biopharmaceutical facility design? Anything you want them to be It is creation that integrates the process technology and regulatory requirements into a viable facility 97 Creating Futures Requires Change Closing thoughts on change Change is never a complete replacement. There are always remnants; Reminders of how things used to be All new principals and ideas, however dynamic, are never wholly accepted by everyone Different views have their adherents, either on the grounds of vested interests, principled support or inertia 98 Creating Futures Requires Change Radicals encounter conservatives in their attempts to reconfigure existing situations to new criteria Radicals are driven by the search for new futures 99 Attitude Shift Conclusion Can production find a place in the sun Is it still ‘just manufacturing’ The attitude toward manufacturing personnel Attract and retain qualified staff The introduction of a sense of place in manufacturing 100 Two Part Presentation Part 1 – The New Bioguide concepts Paradigm Shift: product does not equal facility Part 2 – What can be done now? Optional Futures Shift Rate of Change Shift Attitude Shift The end 101 ISPE Biopharmaceutical Baseline Guide Chapter 6 - Facilities Omaha, April 14, 2005 Mark von Stwolinski, CRB
