Biotech Facilities: Regulatory and Design Approaches
Dr. Trent Carrier
Presentation Outline
Manufacturing Strategies Concept and Design Construction and Qualification Citation Examples Regulatory References
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 3 have to build to a defined capacity
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)
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)
Integrating with Product Timelines
What to build? When to start?
Facility Influences Begin Early
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
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!
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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?
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Typical Project YEAR Schedule
1 2 3 4 5 6
Phase III to start today Launch 2010 means we need APPROVAL Design Procurement Construction IQ/OQ Startup / Validation 100% % Spent APPROVAL
Scope
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Presentation Outline
Integrating Product and Facility Strategies Concept and Design Construction and Qualification Case Study Follow-up Regulatory References
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Concept and Design
Layouts Flows Classification Specifications Diagrams
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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
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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
PFDs and process equipment size estimates Utility and Material Handling / Storage Quality / cGMP Philosophy Staffing Plan
Inputs:
Outputs:
Cost
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Architectural Conceptual Plans
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Early Concepts Starting Point
Process Flow Diagrams
Step 1
Architectural Bubble Diagrams
People Mat In In Ferm Area Storage
Fermentation
Step 2
Step 3
Purification
Step 4
People In
Purif Area
Out
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Rules of Thumb
Process
Area vs. Total Building Area:
5%-10% 8%-17% 5%-15% 5%-15% 35%-50% 15%-20%
Process Support (Labs, Wash/Prep, Autoclaves) Building Circulation (Corridors and Airlocks) Personnel (Lockers, Offices, etc) Material Handling (Storage) Mechanical (HVAC, Utilities, Elec., Chases) Process Areas (Ferm, Purif., Buffer/Media)
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
17 40,000 x $1250 = $50MM !!!!
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Building Architectural Plan
ort p p Su , s r ke c o L Ferm
f P ur i
vs
Ferm
h Mec
al c i n a
f P ur i
ical n a h ort c p e p M u S , s ker c o L
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Design
Process
Design
Piping and Instrumentation Diagrams (P&IDs) Equipment Specifications and Bid Packages Automation Functional Requirement Specifications
Facility
Design
Architectural Drawings with Equipment Facility Specifications (Finishes, Electrical, HVAC, etc.) All detail design drawings complete (CADD, 3D modeling, etc)
Cost
Estimate (+/- 10%)
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Process Scaleup From Lab
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Process Equipment Design
A P&ID is a representation of process elements
Pressure Control Vent Vent TI T Add Cln Stm TI T PI
TI
Sparge T
Tank
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Gas
FC Gas flow
TI T Agitator
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Equipment Functionality Via Design
Material Selection Material Charging Pressure Control
FT
Mix
M
Temperature Control
TT
PT
Discharge and Recirc
Pump
FT
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Suite Layouts Based on Equipment and Bubble Diagrams
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Room Classification Costs
Area classification remains topic of debate Balance of product quality risks vs. cost
Relative Cost ($/square foot)
100% 90% 80% 70% 60% 50% 40% 30% 20% <10%
Grade A Grade B Grade C Controlled Unclassified Uncontrolled Mechanical
Industry range
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Area Classification for Style-ogen Process Steps
Tank Fermentation Non Sterile Purification Buffer/Media Hold
Unclassified Space Closed Equipment Open Processing
Open Sterile Sampling Open Sterile Transfers
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Grade A
Solution Prep Equipment Assembly Sterile Purification
Classified Space
Open Aseptic Transfers
Lighter shading signifies more stringent area classification
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Presentation Outline
Integrating Product and Facility Strategies Concept and Design Construction and Qualification Case Study Follow-up Regulatory References
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Construction and Qualification
Fabrication and Assembly Fits/Finishes Installation Operation
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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
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Fabrication and Construction
Facility On-site
Assembly and Equipment Fabrication (Stick-built) Assemble piping, steel, walls, etc (off-site) Build elsewhere and ship to site
Modular Hybrid
approaches may be used
Facility stick-built on-site Process Equipment built at equipment vendor (Skids) Allows for concurrent facility and equipment construction
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Style-ogen Facility Assembly
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Styleogen Equipment Fabrication
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Style-ogen Process Area
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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
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Qualification Tiered by Product Impact
Temp controller Waste neutralization
ng i s Power station re a c n I tio a Air handlers c i al i f u fQ o l e Lev n
Fermentor
Water generator
Vacuum system
Autoclave
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Style-ogen Qualification
4 Process Steps / 12 Pieces of Equipment
6600 pages of IQ/OQ protocols + 9 months x 15 people equipment and testing
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Next Steps for Style-ogen
Validation Environmental Testing cGMP Operations
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Presentation Outline
Integrating Product and Facility Strategies Concept and Design Construction and Qualification Case Study Follow-up Regulatory References
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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.
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Style-ogen Follow-ups
Concept -> Design -> Construction -> Qualification
A production supervisor calls you and says that they cant 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 didnt 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.
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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!
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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 its only the start.
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Presentation Outline
Integrating Product and Facility Strategies Concept and Design Construction and Qualification Case Study Follow-up Regulatory References
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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
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