strategies to introduce single-use technology in legacy facilities
TRANSCRIPT
2/5/2016
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Strategies to Introduce Single-Use Technology in Legacy Facilities
• Alan Powell, DME Consultant• Eric Sipe, DME Senior Process Engineer• David M. Marks, P.E., DME Principal
ISPE-DVC 26th Annual Symposium & Exhibition
Agenda
• Introduction (Marks)• Process Design with SUS (Sipe)• Hybrid SS/SUS Systems (Powell)• Facility Design with SUS (Marks)
– Regulatory/References– Strategic Approaches to Manufacturing with SUS– Facility Requirements for Manufacturing with SUS– Introducing SUS to Legacy Facilities
• Q&A
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StainlessSteel
Single-UseDisposable
Single-Use / Disposables
4
20%
20%
20%
20%
20%
Process Closure Single-Use/Disp Cont. Bioproc. Modular Other
1. Process closure.2. Single-Use /
disposables.3. Continuous
bioprocessing.4. Modular Construction.5. Other.
Survey of ~70 Professionals
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DRIVERS
• Markets• Competition• Regulatory
ENABLERS
• Process Technologies• Equipment Technologies• Facility Delivery Technologies
STRATEGIES
• Business Approach• Process Equipment• Facility Design
Why is this happening?
6
LowerCapital Cost
FasterSchedule
ROI Need forFlexibility
Other
20% 20% 20%20%20%
1. Lower capital cost.2. Faster schedule.3. Return on
Investment.4. Need for Flexibility.5. Other.
Survey of ~70 Professionals
2/5/2016
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Biopharm Manufacturer’s
Portfolio
More Flexible Facilities
Facility Flexibility Improves UtilizationFacilities for emerging markets, small volume therapeutics and personalized medicine will require less capacity and more flexibility to be fully utilized.
Facility Utilization
COGS • Utilization has a large impact on Cost of Goods Sold.
Quality• Facilities operating near full capacity
typically produce better product quality.
Legacy
• Many biomanufacturing facilities today are underutilized because they are unable to accommodate demand diversity (i.e. they lack flexibility in the right areas).
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How SUS Improves Flexibility & Adaptability
CIP/SIP infrastructure reduced or eliminated
Process systems are mobile and can be easily exchanged or modified
Product transfer is not hard-piped and can be easily reconfigured
Process change-over is relatively quick
Process Design with Single-Use
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ERIC SIPE, PMP/E.I.T.Senior Process Engineer
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Basic Design TenetsThink
Linearly Bags can travel man
Think Connectivity
Where am I going next?Who am I going to
connect with?
Think Product
Protection in an open
space
You don’t need a hood to make a clean connection!
Bags have limitations
Think Linearly
Bags can move, but can connections be reused?
What are the operations that will be performed with this bag through its life?
Can we use this bag for more than one operation?
What will be added to and subtracted from the bag?
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Process Definition
Process Flow
DiagramUnit
Operations
Material & Energy
Balances
Sequence of Operations
Material & Equipment Movement Waste
Processing Requirements
Auxiliary Requirements
Equipment Sizing
Design Process
PFD
P&IDs
Process Transfers
Facility / Process
Fit
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SUS Unit Operations
• Mixing • Heat Transfer• Filtration• Chromatography• Product Isolation• Product Manipulation• Waste Inactivation• Cell Lysis
( from GE with permission)
Investigate Availability of SU Equipment
• Mixers• Seed Bioreactors (Wave Bags)• Bioreactors (Larger Scale Bags)• Filters• Centrifuges• Chromatography Units• Product Storage Bags• Filler Product Transfer Path
( from Nunc with permission)
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Identify Auxiliary Requirements
Auxiliary Process Needs
• Buffer Needs• Nutrient Needs• Waste Removal Needs• Gas Addition Needs• Venting Requirements• Heating/Cooling
Requirements• Material Transfers
Methods to Supply Auxiliary Needs
• Single Use Bag Mixing Station
• Waste Collection Bag• Gas Addition Nozzles &
Gas Distribution Panel• Single Use Filter• Single Use Bag
Heating/Cooling Station• Tubing Sets and
Peristaltic Pumps
Material and Energy Balances
• Example: UF / DF (TFF)
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Equipment Sizing
Material/Equipment Movement
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Process Flow Diagrams• Prepare Symbolic
Representation of Unit Operations & Material Movements
• Define Material & Energy Balance for Unit Operations and Transfers
• Prepare Stepwise Description of Activities to be performed
• Determine size and quantity of single use containers/unit operations needed
Process Flow Diagrams• Identify Container
Movements on PFDs• Identify waste
streams and waste treatment mechanism
• Determine Buffer, Nutrient and Gas Requirements
• Define Waste Collection and Storage Approach
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Process Connectors
• Disposable Tubing• Sterile Tube welders / sealers • Disposable sterile connectors• Disposable SIP’able connectors• Septum sampling systems• Non-sterile connectors
– (e.g. luer locks, quick-connects, hose barb)
– not acceptable for aseptic
• No-drip chemical connectors
P&IDs
Develop detailed connection diagrams for each unit operation.
Define Utility System for each unit operation.
Show movement of materials and single use units.
Define hose assemblies needed for each single use bag.
Identify equipment size for all unit operations on P&IDs.
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Evaluate Facility / Process Fit
• Create Equipment Blocks.• Insert Utility Panels/Unit Ops
Stations into the Facility Foot Print.
• Prepare Time Based Room Layouts of the Facility.
• Confirm that the Fixed Equipment and Support Single Use Bags Fit.
• Assess the Movement of Single Use Resources Into and Out of the Bioprocessing Suite.
Hybrid SS/SUS Systems
ALAN POWELLEngineering Consultant
Bioprocess & Hygienic Design
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Fixed Systems:
• Process related is very simple system (black) • CIP and SIP greatly add to complexity (red).
2"
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ATAI
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CONTAINED DRAIN
DRAIN
COND
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CLEAN STEAMCIP SUPPLY
PRODUCT
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TRANSFER LINE CIP
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ProcessSolution
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TETITTI
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MIN MIN
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FEFITFI
AT
XXX1801
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Bag
Transfer Panel PRODUCT
Pump
Vent Filter
Vent Filter
CIP
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TEMP
FLOW
PRESSURE
COND
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Single Use Simplifies
• Single use (SU) systems – Supplied clean and sterile (if required)– Replace stainless vessel and tubing in many applications– Eliminate need for CIP and SIP
• Utilities• Process system piping and instrumentation
– Reduce or eliminate utilities• CIP system
• Pure steam
• Compendial water
– Few connections– Rapid implementation
• Construction• Validation
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Single Use: Not always the Silver Bullet
When planning a facility: • Compare SU and Fixed Equipment with respect to factors that affect feasibility
and total cost of ownership• Feasibility
– Is equipment available at the required scale?– Are SU components suitable for process requirements?
• E.g. temperature, pressure, composition …
• Operating and capital cost– Typically lower capital for single use
• Compared to fabrication, installation, and C&Q of stainless systems• Utilities: spares clean utilities (e.g. clean steam and pure water)
However, if any clean utility is required, only incremental cost is spared.• Equipment preparation areas (autoclaves, parts washers)
– Operating cost varies with process, scale, operating rate, etc.• Greater unit cost more complex SU equipment (Mixing systems, bioreactors)
– Facility footprint• Staging and moving SU bags vs. utility space
Bags
I1
X
O
I2
ProcessSolution
BagsBags
Tank
Hybrid Single Use and Fixed Systems
• Often the optimal solution is a hybrid system.• Selective application of SU components to
reduce complexity of fixed systems– Reduce piping between and within systems– Reduce CIP and SIP
• Time and number of routes validated– Reduce instrumentation and automation effort
• In this example: Sacrifice ability to change components after SIP.
TE
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ProcessSolution
2"3/4
"
3/4
"
3/4
"
3/4"
I3
Bag
TEMP
Stm/CIP
Tank
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Simplification of a Fermentor
• Typical fermentation system includes many hard-piped components
• Direct and indirect product contact surfaces must be clean and sterilized– CIP and steam connect to
• All liquid transfer lines• Sparge and vent lines• Vessel
• Hybrid solution to meet challenge to simplify as much as possible– Rapid deployment– Reduced cost– Reduce C&Q effort
VentTransfers in
Transfers out
Sample
Additions
Sparge
Drive & Mech Seal
CIP
Fermentor Schematic
Steam sample and outlet valves closed from port valves
Port valve
Port valve
Steam Path
Steam in (controlled or pulsed)
Steam Mech Seal
Concept Plan for Hybrid Fermentor• Features enabled by SU
– 2 CIP routes (sprayballs & Sparge
– All transfers to/from bags • Replace add ports w/ SU
valves– SU valve and tubing for
product transfer– CIP by local recirculation
• Chemical adds manual• Capabilities enabled by fixed
vessel– Empty SIP and media
sterilization– Pressurization and high
temperature– High OTR
• Limited size
Product/Local CIP Recirc/ Steam trap
CIP Circ / Water(opt)
Coolant Supp (Heating for FVSIP opt.)
Coolant Ret
Air / CIP/ CS
Exhaust
Bag
Nozzles for Connection of SU Addition Assemblies
Hybrid Bioreactor/Fermentor
Mech Seal Steam Supply
Bags
Bags
Bags
SU sampleAssy
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Facility Design Implications
DAVID M. MARKS, P.E.Principal
Key Questions to Answer before Implementing
Single-Use Technology
Supply Chain Management?
Extractables and
Leachables?
Sterility of Connections?
Cost of SU Components +
Disposal?
Scalability?
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• CFR 21 § 211.65 Equipment construction.– (a) Equipment shall be constructed so that surfaces that
contact components, in-process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.
• CFR 21 § 211.63 Equipment design, size, and location.– Equipment used in the manufacture, processing, packing, or
holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.
Regulatory Requirements for Licensed Facilities
Bio-Process Systems Alliance (BPSA)
• Industry-led corporate member trade association dedicated to encouraging and accelerating the adoption of single use manufacturing technologies used in the production of biopharmaceuticals and vaccines.
• www.bpsalliance.org
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BPE Part PM: Single-Use Components
• Leachable / Extractable• Gamma Irradiation• Joining Methods• Storage/Expiration
PDA Technical Report No. 66
• Application of Single-Use Systems in Pharmaceutical Manufacturing– Points to Consider for
Single-Use System Manufacturing Strategy
– Single-Use Technologies and System Integration
– Qualification and Verification of Suppliers, Materials, Components, and Completed Assemblies
– Business Drivers for the Adoption of Single-Use Systems
– Implementation of a Single-Use System
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Single-Use Technology:Constrained by Process Scale
Unit Operations / Pooling: bag size limitations ~2000 liters
Product Transfer: Weld-able polymeric tube & aseptic connector size limitations ~1”
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Traditional Blended Scale-Out Continuous Other
20% 20% 20%20%20%1. Traditional SS
Facilities.2. Blended SS / SUS
Facilities.3. “Scale-Out” SUS,
Multiple SUS Facilities.4. Continuous
Biomanufacturing5. Other.
Survey of ~70 Professionals
2/5/2016
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Options for Large-Scale BioManufacturing
Scale Up• Traditional SS Approach• Capital Intensive; Flexibility = Complexity
Scale Out• Next Gen SUD Approach• Flexible; Fast; Labor Intensive
Continuous• SS or SUD Approach• Best of Both Worlds?
Continuous Bioprocessing: Limitations
• Requires significant process development.
• Requires more integrated process monitoring.
• Requires a different approach to product release (e.g. parametric release).
• Requires closed processing for long-term, robust axenic/aseptic operations.
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A Synergy of Technologies
Single Use Technology• Facilitates closed
processing for robust axenic & aseptic operations.
Continuous Bioprocessing• Provides large
manufacturing capacity with relatively small-scale operations.
PROCESS CLOSURE
PROCESS SCALE
100% SUS: The Future of Bioprocessing?
Photo courtesy of GE
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Facility Cost of Goods
• Example showing impact of demand/utilization
Biogen Idec Flexible Volume Manufacturing Facility (FVM)
2013 ISPE Facility of the Year winner – Facility Integration
Equipment
• Process Scale• Manual Operations• Ergonomics• Tube Routing• Spills & Containment
Utilities
• CIP systems• Clean steam, SIP• Compendial water• HVAC/mechanical• SUS utility panels
Logistics
• Receiving, storage & disposal of SU waste
• Materials dispensing• Warehousing,
halls/doors
How SU Technology Affects Facility Design
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Facility Design Impact: Equipment
• Transport ergonomics• Bag handling• Spills & containment
(cross-contamination, biosafety)• Materials compatibility• Scaling Up • Connections to stainless steel
equipment; Hybrid systems • Automation (no CIP/SIP)
Photo courtesy of GE
Facility Design Impact: Plant Utilities
• CIP Systems
• Clean Steam Systems
• CIP/SIP Stations
• Process piping, transfer panels
• Automation
• HVAC
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Facility Design Impact: Logistics
• Receiving, storage & disposal of single-use components.
• Big demands on loading docks, hallways & doorways.
• Increased warehousing & cold storage requirements.
• Higher demands on autoclaves.
• Provisions for tote storage & maintenance.
Warehousing
Distribution
Receiving
Legacy Facility Challenges
• Removal/Relocation of Legacy SS Equipment• Configuration of Equipment & Staging in Confined Space• Routing and Support of Flexible Tubing • Process Automation, Data Acquisition, MES
Equipment
• Abandoned in Place Utility Systems• Utility Stations for Flexible SUS Operations• Cold Storage of Process Intermediates
Utilities
• Transport & Staging of Totes through Legacy A/L & Halls• Structural Requirements for Shifting Floor Loads• Facility Flows and Segregation from Other Operations• Storage for Mobile Equipment and Consumables• Biohazards (A/L, HVAC, drains, berm)
Facility
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Legacy Facility/Process Fit
• Segregation
• Circulation; Design of A/L, Doors, Corridors.
• Drains, waste treatment.
• Structural support.
• Storage for mobile skids, consumables
A/L
bioreactor
Clean Corridor
bioreactor
harvest
Think About Transport & Staging of Materials
• Product, Buffer & Waste Totes
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Think About Adjacencies
• Within Processing Suite.
Photo of Biogen Flexible Volume Manufacturing Project; from CRB website; https://www.crbusa.com/our-work/by-service/view-all-projects/715-flexible-volume-manufacturing-project/715-flexible-volume-manufacturing-project
Think About Adjacencies
• Between classified spaces.– Adjacent processing suites.– Staging areas outside the
processing suite..
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• Facility Unknowns: Develop Contingencies
• Ongoing GMP Ops: Develop Execution Approach with Minimal Disruption
• Segregation & Flows:Develop Rational Circulation Patterns, Cleanroom Transitions & HVAC Zones
Lessons Learned: Plan for Success
Project Plan
Facility Segregation
& Flows
Ongoing cGMP
Operations
Legacy Facility
Unknowns
Questions!
• For Further Information:– David M. Marks, P.E.