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POSSIBILITIES FOR FLEXIBLE MANUFACTURING CAPABILITIES FOR V ACCINE PRODUCTION KIM L. NELSON, PH.D. CRB CONSULTING ENGINEERS INTERPHEX 2011 30 MARCH 2011 NEW YORK
POSSIBILITIES FOR FLEXIBLEMANUFACTURING CAPABILITIES FOR
VACCINE PRODUCTION
KIM L. NELSON, PH.D.CRB CONSULTING ENGINEERS
INTERPHEX 2011
30 MARCH 2011NEW YORK
TOPICS
Current gaps in vaccine manufacturing capacity Enabling Technologies FutureFacility
• Responsive facilities providing increased flexibility / adaptability, providing a fast response to changing needs such as number of doses, titer, strain or process
• Reduced capital cost • Reduced time to market
Sustainable vaccine production capacity.
BEING MORE COMPETITIVE
Flexibility: Easy to Modify Adaptable for Multiple Products Adaptable for Multiple Business Units Accommodate Future Technologies Easy to Expand
High Value:
Initial Capital Cost & Operating Cost Reusable / Adaptable Asset Fits Changing Business Needs Adjustable Supply Chain Capacity
Lower Risk:
Project Risk Business Risk Compliance Risk Supply Chain Risk Process Risk Time-to-Market Speed to Adapt
CURRENT GAPS IN VACCINE CAPACITY
Egg-based throughput constraints Fundable initial capital investment costs Acceptable cost of goods Flexibility
• Adaptability for deploying of new processes• Expandability for surge demands
Experience with available enabling technologies
SYSTEM CLOSURE:AN ENABLING TECHNOLOGY
Very important principle Adopted in ISPE Baseline Guide for Biopharmaceutical
Facilities With a closed process, you can lower the room classification
SOURCES OF POTENTIAL PRODUCT ADULTERATION
Batch 1
CARRYOVER
ENVIRONMENTALCONTAMINATION
PROCESS AREA
Batch 2
Product1
Product2
CROSSCONTAMINATION
Batch
RAWMATERIALS
SO LET’S LOOK AT THE ENVIRONMENT⋯.
ISO VS EU GRADE CLASSIFICATIONS
ISO does not distinguish “At Rest” vs. “In-Operation”• e.g. ISO 7 is Grade C at rest
and Grade B in operation…
EU Grade particle counts are NOT exactly equal to corresponding ISO classes. • e.g. Grade A permits only
3500 particles 0.5 per m3
vs. 3520 particles per m3 for ISO 5
• Similar differences are seen in other ISO classes vs EU Grades
WHAT IS THE IMPACT OF THE ROOM ENVIRONMENT
If you have an OPEN operation, which is not subsequently filtered, it makes a difference by decreasing the probability of a contamination entering from the room air.
If the processes is RENDERED CLOSED (such as by filtration into a closed tank or bag), it makes no difference.
If you have a CLOSED processes, the environment makes no difference at all.
WHICH HAS HIGHER RISK OF CONTAMINATION ?
CLOSED OPEN
IS LIKELIHOOD OR IN ISO 7 VS CNC ?
CLOSED OPEN
IS SEVERITY OR IN ISO 7 VS CNC ?
CLOSED OPEN
IS DETECTABILITY OR IN ISO 7 VS CNC ?
CLOSED OPEN
Clean Rooms Isolators
Virgin Closed SystemsCIP and/or SIP of
System After Closure
To Mitigate Risk of Product
Adulteration
Improve Equipment
Integrity
Improve Environment
Quality
OR
AND(until now!?)
SOURCES OF POTENTIAL PRODUCT ADULTERATION
ARE ISO 7 COVING, AIR CHANGES & GOWNINGEFFECTIVE FOR CLOSED ASEPTIC OPERATIONS?
This is commonly done and approved by regulatory agencies.
Why??? BECAUSE THEY ARE CLOSED SYSTEMS
BIOREACTORS IN CLEANROOM AREAS….. WHAT DO YOU GAIN?
Low Risk High Risk
112,32,3
55
2525
1111
13-1713-17
7,87,8 99
1818 1919
22,2322,232424
29-3129-31
1212
2020 2121
1010
44
66
2626
27,2827,28
E.G. CHROMATOGRAPHY
FAULT TREE ANALYSIS OF RISK ELEMENTS
QUESTION (1)DOES THE CONNECTION EFFECTIVELY ISOLATE THE
PROCESS FROM THE ENVIRONMENT
QUESTION (1)DOES THE CONNECTION EFFECTIVELY ISOLATE THE
PROCESS FROM THE ENVIRONMENT
QUESTION (2)IS THE SYSTEM CLOSURE CONSISTENT WITH THE USEROR PROCESS REQUIREMENTS ?
QUESTION (2)IS THE SYSTEM CLOSURE CONSISTENT WITH THE USEROR PROCESS REQUIREMENTS ?
QUESTION (3)ARE THERE DOWNSTREAM CONTROLS THATEFFECTIVELY MITIGATE THE RISK?
QUESTION (3)ARE THERE DOWNSTREAM CONTROLS THATEFFECTIVELY MITIGATE THE RISK?
UPGRADE SURROUNDINGENVIRONMENTUPGRADE SURROUNDINGENVIRONMENT
REDESIGN CLOSURESYSTEMREDESIGN CLOSURESYSTEM
MITIGATE USING DOWNSTREAM STEPMITIGATE USING DOWNSTREAM STEP
QUESTION (1)DOES THE CONNECTION EFFECTIVELY ISOLATE THE
PROCESS FROM THE ENVIRONMENT
QUESTION (2)IS THE SYSTEM CLOSURE CONSISTENT WITH THE USEROR PROCESS REQUIREMENTS ?
QUESTION (3)ARE THERE DOWNSTREAM CONTROLS THATEFFECTIVELY MITIGATE THE RISK?
UPGRADE SURROUNDINGENVIRONMENT
REDESIGN CLOSURESYSTEM
MITIGATE USING DOWNSTREAM STEP
SUMMARIZE CLOSURE BREAKDOWN
IMPACT OF CLOSED PROCESSING
Traditional FutureFacility(GLSP Biotech)
FutureFacility(BSL / Containment)
Inoculum Prep
Upstream Processing
Initial Purification
Final Purification
Bulk Fill
MediaPrep /
Hold
Single Ballroom(Closed Processing)
Inoculum Prep(Open Processing)
Virus / ActiveCell Processing
(Closed Processing)
Cell Scale-up
InactivatedCell Processing /
Support Operations(Closed Processing)
BufferPrep /
Hold
IS0 7
IS0 8
Controlled Non Classified (CNC)
DECREASED CAPITAL $$$
INCREASED FLEXIBILITY / ADAPTABILITY
INCREASED VALUE
DECREASED RISK
SINGLE USE SYSTEMSAN ENABLING TECHNOLOGY
Advantages of Disposables Reduces capital cost Provides great flexibility in volumes
and changing processes Speeds delivery of facility Reduces labor and validation
associated with CIP and SIP Reduces water usage Reduces wastewater discharge reduces maintenance and calibration
costs with decreased number of I/O points
VALUE-ADDED SOLUTIONS - DISPOSABLES
Drawbacks risk of major leakage or breach of the
bag integrity which could result in discarding product
Not a”Copy Exactly”of existing Leachable/Extractable Testing Cost of bags Cost of waste disposal Limited volumes Warehouse stocking Movement of bags through facility complex supply chains for high
number of components that make up systems
Increased staging space required
VALUE-ADDED SOLUTIONS - DISPOSABLES
Buffer Hold
Buffer PrepMedia Prep
L1
L2
L3Cell
Growth
B1CIP Skid
CIP Skid
CIP Skid
CIP Skid
Tote
BufferPrep Tank
Media Prep Tank
Platform
NutrientFeed
Clarification
CIP Skid
CIP Skid
VirusInactivation
ToFill /
Finish
0.22filtrationHarvest
Tank
Seed Biorxt
Seed Biorxt
5,000 L Bioreactor
Seed Biorxt
5,000 L Bioreactor
BreakTank
Virus Production
Centrifugation InactivationMix Tank
2nd DNA Digestion
HarvestTank
InactivationHold Tank
1st DNA DigestionPrior to Harvest
BufferHold
Tanks
Detergent Disruption
HarvestTank
DetergentTank
Chromatography
Homogenization
ZonalUltracentrifuge
HarvestTank
Zonal LoadTank
Detergent
ResinFor Batchdetergentremoval
CIP Skid
CIP Skid
CellInoc
VirusInoc Purification
OPPORTUNITIES FOR SINGLE-USE SYSTEMS IN INFLUENZA VACCINE MFGR
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HANDLING BIOCONTAINMENT
RESPONSIVE FACILITIES
Modularity of Plug-and-Play Operation provides great manufacturing flexibility
BENEFITS OF CLOSED PROCESSING & FUTURE FACILITY CONCEPTS
Reduced manufacturing area (15-30%) Reduced HVAC
• Reduced room classifications• Reduced cleanroom areas• Reduced air changes per hours• Reduced fan power demand• Reduced number of air handling units• Reduced maintenance
BENEFITS OF CLOSED PROCESSING & FUTURE FACILITY CONCEPTS
Reduced Utilities• Using single use systems can reduce clean steam and WFI requirements (up to 80-90% reductions)
• Reduced chilled water and steam demands (up to 60% savings)
• Reduced wastewater Reduced Construction & Start-up Schedule
• Up to 50% schedule savings Reduced COGs (situation dependent)
REDUCED TIME TO MARKET
FutureFacilityFutureFacility
T = 23 mo.
Engineering/ Design
Engineering/ Design ConstructionConstruction
CommissioningCommissioning
Start upStart up ValidationValidation
MechanicallyComplete
MechanicallyComplete
Engineering/ Design
Engineering/ Design ConstructionConstruction
CommissioningCommissioning
Start upStart up ValidationValidation
MechanicallyComplete
MechanicallyComplete
TraditionalFacility
TraditionalFacility
Traditional FutureFacility % ChangeSCHEDULE Months Months
Engineering / Design 9 6 -33%
Construction / Mech Completion 18 6 -67%
Start-up 3 2 -33%
Commissioning 6 2 -67%
Validation 12 9 -25%
Totals 48 25 -48%
QUICKER PROJECT TIMELINE ALLOWS OPTIONS
Improved Timeto Market
Additional Timefor Process Developmentand Business Planning
Strategy AStrategy A
Strategy BStrategy B
Process / Clinical Development
Process / Clinical Development
Process / Clinical Development
Traditional Project
FutureFacilityProject
Facility Licensing
Facility Licensing
Facility Licensing
SUSTAINABLE IMPROVEMENT
75-95% Water Usage Reduction 50-95% Chemical Reduction 50%+ Energy Reduction 25-50% Smaller Carbon Footprint 30-40% Smaller Land Requirement
Future Facility concepts can reduce footprint, lower energy costs and use less water, making the FutureFacility much more green ⋯
SUMMARY
Flexible, Adaptable & Expandable facilities are possible and cost effective
Process Closure provides superior product protectionAND allows lower room classifications
Single-Use systems offer process flexibility, shortened construction schedule and start-up/validation schedule, and decreased utilities
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ACKNOWLEDGEMENTS
Lee Emel Mark von Stwolinski Marc Pelletier Avi Page and many others at CRB
THANK YOU FOR YOUR ATTENTION !
Kim L. Nelson, Ph.D.Director, Strategic ConsultingCRB Consulting Engineers220 W. Germantown Pike, Suite 170Plymouth Meeting, PA 19462USA
(610)-278-7644 office(215)-435-0390 [email protected]
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