Presentation to Engineering Conference International Integrated Continuous Biomanufacturing Conference Implementing process closure and continuous processing into the modern biopharmaceutical facility Oct 23, 2013 Castelldefels, Spain
Dec 16, 2015
Presentation to
Engineering Conference InternationalIntegrated Continuous Biomanufacturing Conference
Implementing process closure and continuous processing into the modern biopharmaceutical facility
Oct 23, 2013 Castelldefels, Spain
THE BIOPHARMACEUTICAL INDUSTRY IS CHANGING
FINALLY!
THE SAFEST PROCESS IS CLOSED, WHERE THE ENVIRONMENT IS A PARAMETER WITHOUT CRITICAL ASPECT
WE HAVE THE TECHNOLOGY
Closed Process Defined
• Environment does not represent a Critical Aspect (No Impact)
• Product is not exposed to the surrounding environment
• Additions and withdrawals performed in closed fashion
• Validated to show sufficient layers of protection against risk of contamination from the environment
• Risk of contamination is not mitigated by housing operation in bioburden-free or particulate-free environment
• Contamination of closed system = breach of integrity
NOTE: Closed Sterile (although sterile is one form)
ALSO: Closed Single Use Systems (although one form)
1980s Traditional Multiproduct Facility
Buffer Hold
Purification 1 V+
Purification 2 V+
Purifica tion V-
Men’s Locker Room
Women’s Locker Room
Inoc
Inoc
Seed Cell Culture
Equipment Wash
Cell Culture 1 Harvest and Clarification 1
Cell Culture 2 Harvest and Clarification 2
Weigh DispenseDispensed Kit StorageMedia Prep
Buffer Prep
Centrifuge
Corridor
Buffer Hold
Centrifuge
Seed Cell Culture
Corridor
PAL
PAL MAL
MAL
Inoc
Inoc
PAL
PAL
PAL
MAL
PAL
PAL
MAL
MAL
ALALPAL
MAL
PAL
MAL
PAL MAL
PAL MALPAL MAL
PAL PALPAL MAL
PAL MAL
PAL MAL
PAL MALPAL MALCorridor
Clean Equipment
Storage
CorridorCorridor
Clean Equipment
Storage
Corridor
Corridor
Corridor
7
8
9
= ISO 7, Grade B5
= ISO 8, Grade C= ISO “9”, Grade D
= ISO 5, Grade A
e8
CNC= Controlled Non-Classified
UC
= ISO 8, Grade C
= Uncontrolled Unclassified
BSC
BSC
BSC
BSC PAL
PAL
DFB DFB DFB DFB
MAL
MAL
PALMAL PAL MAL
JC
JC
15K
15K
15K
15K
15K
15K
CF-100 CF-100
CF-100 CF-100
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
Media Hold
Media Hold
Downstream Equip Wash
Column Packing
Warehouse
Cell Bank
Dewar
e.g. 2 products
1980s Traditional Facility
Buffer Hold
Purification 1 V+
Purification 2 V+
Purifica tion V-
Men’s Locker Room
Women’s Locker Room
Inoc
Inoc
Seed Cell Culture
Equipment Wash
Cell Culture 1 Harvest and Clarification 1
Cell Culture 2 Harvest and Clarification 2
Weigh DispenseDispensed Kit StorageMedia Prep
Buffer Prep
Centrifuge
Corridor
Buffer Hold
Centrifuge
Seed Cell Culture
Corridor
PAL
PAL MAL
MAL
Inoc
Inoc
PAL
PAL
PAL
MAL
PAL
PAL
MAL
MAL
ALALPAL
MAL
PAL
MAL
PAL MAL
PAL MALPAL MAL
PAL PALPAL MAL
PAL MAL
PAL MAL
PAL MALPAL MALCorridor
Clean Equipment
Storage
CorridorCorridor
Clean Equipment
Storage
Corridor
Corridor
Corridor
7
8
9
= ISO 7, Grade B5
= ISO 8, Grade C= ISO “9”, Grade D
= ISO 5, Grade A
e8
CNC= Controlled Non-Classified
UC
= ISO 8, Grade C
= Uncontrolled Unclassified
BSC
BSC
BSC
BSC PAL
PAL
DFB DFB DFB DFB
MAL
MAL
PALMAL PAL MAL
JC
JC
15K
15K
15K
15K
15K
15K
CF-100 CF-100
CF-100 CF-100
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
Media Hold
Media Hold
Downstream Equip Wash
Column Packing
Warehouse
Cell Bank
Dewar
2 X 3 production BRX Redundant centrifuges
Redundant downstream
Redundant upstream
Many silos Highly classified (to reduce “risk” of bioburden)
1980s Traditional Facility
Buffer Hold
Purification 1 V+
Purification 2 V+
Purifica tion V-
Men’s Locker Room
Women’s Locker Room
Inoc
Inoc
Seed Cell Culture
Equipment Wash
Cell Culture 1 Harvest and Clarification 1
Cell Culture 2 Harvest and Clarification 2
Weigh DispenseDispensed Kit StorageMedia Prep
Buffer Prep
Centrifuge
Corridor
Buffer Hold
Centrifuge
Seed Cell Culture
Corridor
PAL
PAL MAL
MAL
Inoc
Inoc
PAL
PAL
PAL
MAL
PAL
PAL
MAL
MAL
ALALPAL
MAL
PAL
MAL
PAL MAL
PAL MALPAL MAL
PAL PALPAL MAL
PAL MAL
PAL MAL
PAL MALPAL MALCorridor
Clean Equipment
Storage
CorridorCorridor
Clean Equipment
Storage
Corridor
Corridor
Corridor
7
8
9
= ISO 7, Grade B5
= ISO 8, Grade C= ISO “9”, Grade D
= ISO 5, Grade A
e8
CNC= Controlled Non-Classified
UC
= ISO 8, Grade C
= Uncontrolled Unclassified
BSC
BSC
BSC
BSC PAL
PAL
DFB DFB DFB DFB
MAL
MAL
PALMAL PAL MAL
JC
JC
15K
15K
15K
15K
15K
15K
CF-100 CF-100
CF-100 CF-100
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
Media Hold
Media Hold
Downstream Equip Wash
Column Packing
Warehouse
Cell Bank
Dewar
Product 1
Product 2
Product 1
Product 2UPSTREAM CELL (+) DOWNSTREAM CELL (-)
Shared Shared
1980s Traditional Facility SharedMultiproductUnclassified!
And regulatory agencies know about this “secret”
EUROPE/ USA FDA (approx)
GRADE ISO CLASS IN OPERATION
MAX # PARTICLES
0.5 µ & LARGER / M3MAX # OF VIABLE MICROORGANISMS
(CFUs) / M3
A 5 3500 <1
N/A 6 35000 7
B 7 350000 10
C 8 3500000 100
D "9" 3500000 (at rest) 200
Risk Management
Eureka! Bioreactors are closed!
Buffer Hold
Purification 1 V+
Purification 2 V+
Purifica tion V-
Men’s Locker Room
Women’s Locker Room
Inoc
Inoc
Seed Cell Culture
Equipment Wash
Cell Culture 1 Harvest and Clarification 1
Cell Culture 2 Harvest and Clarification 2
Weigh DispenseDispensed Kit StorageMedia Prep
Buffer Prep
Centrifuge
Corridor
Buffer Hold
Centrifuge
Seed Cell Culture
Corridor
PAL
PAL MAL
MAL
Inoc
Inoc
PAL
PAL
PAL
MAL
PAL
PAL
MAL
MAL
ALALPAL
MAL
PAL
MAL
PAL MAL
PAL MALPAL MAL
PAL PALPAL MAL
PAL MAL
PAL MAL
PAL MALPAL MALCorridor
Clean Equipment
Storage
CorridorCorridor
Clean Equipment
Storage
Corridor
Corridor
Corridor
7
8
9
= ISO 7, Grade B5
= ISO 8, Grade C= ISO “9”, Grade D
= ISO 5, Grade A
e8
CNC= Controlled Non-Classified
UC
= ISO 8, Grade C
= Uncontrolled Unclassified
BSC
BSC
BSC
BSC PAL
PAL
DFB DFB DFB DFB
MAL
MAL
PALMAL PAL MAL
JC
JC
15K
15K
15K
15K
15K
15K
CF-100 CF-100
CF-100 CF-100
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
Media Hold
Media Hold
Downstream Equip Wash
Column Packing
Warehouse
Cell Bank
Dewar
DECLASSIFY
REMOVE WALL
Solution for Successful Cell Culture:
AIRLOCKS NOT REQUIRED
Closed Media Containers
Buffer Hold
Purification 1 V+
Purification 2 V+
Purifica tion V-
Men’s Locker Room
Women’s Locker Room
Inoc
Inoc
Equipment Wash
Cell Culture 1 Harvest and Clarification 1
Cell Culture 2 Harvest and Clarification 2
Weigh DispenseDispensed Kit StorageMedia Prep
Buffer Prep
Centrifuge
Corridor
Buffer Hold
Centrifuge
Corridor
PAL
PAL MAL
MAL
Inoc
Inoc
PAL
PAL
PAL
MAL
PAL
PAL
MAL
MAL
ALALPAL
MAL
PAL
MAL
PAL MAL
PAL MALPAL MAL
PAL PALPAL MAL
PAL MAL
PAL MAL
PAL MALPAL MALCorridor
Clean Equipment
Storage
CorridorCorridor
Clean Equipment
Storage
Corridor
Corridor
Corridor
7
8
9
= ISO 7, Grade B5
= ISO 8, Grade C= ISO “9”, Grade D
= ISO 5, Grade A
e8
CNC= Controlled Non-Classified
UC
= ISO 8, Grade C
= Uncontrolled Unclassified
BSC
BSC
BSC
BSC PAL
PAL
DFB DFB DFB DFB
MAL
MAL
PALMAL PAL MAL
JC
JC
15K
15K
15K
15K
15K
15K
CF-100 CF-100
CF-100 CF-100
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
Media Hold
Media Hold
Downstream Equip Wash
Column Packing
Warehouse
Cell Bank
Dewar
Close the Bioreactor NOT cove corners!
Sterile filter clarified broth = briefly exposed
0.2µ filter after CENTRIFUGATION to close
Buffer Hold
Purification 1 V+
Purification 2 V+
Purifica tion V-
Men’s Locker Room
Women’s Locker Room
Inoc
Inoc
Equipment Wash
Cell Culture 1 Harvest and Clarification 1
Cell Culture 2 Harvest and Clarification 2
Weigh DispenseDispensed Kit StorageMedia Prep
Buffer Prep
Centrifuge
Corridor
Buffer Hold
Centrifuge
Corridor
Inoc
Inoc
PAL
PAL
PAL
MAL
PAL
PAL
MAL
MAL
ALALPAL
MALMedia Hold
PAL PALPAL MAL
PAL MAL
PAL MAL
PAL MALPAL MALCorridor
Clean Equipment
Storage
CorridorCorridor
Clean Equipment
Storage
Corridor
Corridor
Corridor
7
8
9
= ISO 7, Grade B5
= ISO 8, Grade C= ISO “9”, Grade D
= ISO 5, Grade A
e8
CNC= Controlled Non-Classified
UC
= ISO 8, Grade C
= Uncontrolled Unclassified
BSC
BSC
BSC
BSC PAL
PAL
DFB DFB DFB DFB
MAL
MAL
PALMAL PAL MAL
JC
JC
15K
15K
15K
15K
15K
15K
CF-100 CF-100
CF-100 CF-100
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
Downstream Equip Wash
Column Packing
Warehouse
Cell Bank
Dewar
Media Hold
Logistical segregation
Sterile filter clarified broth = briefly exposed
Buffer Hold
Purification 1 V+
Purification 2 V+
Purifica tion V-
Men’s Locker Room
Women’s Locker Room
Inoc
Inoc
Equipment Wash
Cell Culture 1 Harvest and Clarification 1
Cell Culture 2 Harvest and Clarification 2
Weigh DispenseDispensed Kit StorageMedia Prep
Buffer Prep
Centrifuge
Corridor
Buffer Hold
Centrifuge
Corridor
Inoc
Inoc
PAL
PAL
PAL
PAL
MAL
MAL
ALALMedia Hold
PAL PAL
PAL MAL
PAL MAL
PAL MAL
Corridor
Clean Equipment
Storage
CorridorCorridor
Clean Equipment
Storage
Corridor
Corridor
Corridor
7
8
9
= ISO 7, Grade B5
= ISO 8, Grade C= ISO “9”, Grade D
= ISO 5, Grade A
e8
CNC= Controlled Non-Classified
UC
= ISO 8, Grade C
= Uncontrolled Unclassified
BSC
BSC
BSC
BSC PAL
PAL
DFB DFB DFB DFB
MAL
MAL
PALMAL PAL MAL
JC
JC
15K
15K
15K
15K
15K
15K
CF-100 CF-100
CF-100 CF-100
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
Downstream Equip Wash
Column Packing
Warehouse
Cell Bank
Dewar
Media Hold
Airlocks no longer requiredDeclassified; HVAC segregation no longer required
When Environment = No Critical Aspect
Product 1 is closedProduct 2 is closed
Buffer Hold
Purification 1 V+
Purification 2 V+
Purifica tion V-
Men’s Locker Room
Women’s Locker Room
Inoc
Inoc
Equipment Wash
Cell Culture 1 Harvest and Clarification 1
Cell Culture 2 Harvest and Clarification 2
Weigh DispenseDispensed Kit StorageMedia Prep
Buffer Prep
Centrifuge
Corridor
Buffer Hold
Centrifuge
Corridor
Inoc
Inoc
PAL
PAL
PAL
PAL
MAL
MAL
ALALMedia Hold
PAL PAL
PAL MAL
PAL MAL
PAL MAL
Corridor
Clean Equipment
Storage
CorridorCorridor
Clean Equipment
Storage
Corridor
Corridor
Corridor
7
8
9
= ISO 7, Grade B5
= ISO 8, Grade C= ISO “9”, Grade D
= ISO 5, Grade A
e8
CNC= Controlled Non-Classified
UC
= ISO 8, Grade C
= Uncontrolled Unclassified
BSC
BSC
BSC
BSC PAL
PAL
DFB DFB DFB DFB
MAL
MAL
PALMAL PAL MAL
JC
JC
15K
15K
15K
15K
15K
15K
CF-100 CF-100
CF-100 CF-100
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
Downstream Equip Wash
Column Packing
Warehouse
Cell Bank
Dewar
Media Hold
Physical segregation not required
If Environment = No Critical Aspect
Efficiency in Inoc Prep Likely:Cadence of 1 BRX every 2 days
Buffer Hold
Purification 1 V+
Purification 2 V+
Purifica tion V-
Men’s Locker Room
Women’s Locker Room
Inoc
Inoc
Equipment Wash
Cell Culture 1 Harvest and Clarification 1
Cell Culture 2 Harvest and Clarification 2
Weigh DispenseDispensed Kit StorageMedia Prep
Buffer Prep
Centrifuge
Corridor
Buffer Hold
CentrifugeCorridor
Inoc
Inoc
PAL
PAL
PAL
PAL
MAL
MAL
ALAL
PAL PAL
PAL MAL
PAL MAL
PAL MAL
Corridor
Clean Equipment
Storage
CorridorCorridor
Clean Equipment
Storage
Corridor
Corridor
Corridor
7
8
9
= ISO 7, Grade B5
= ISO 8, Grade C= ISO “9”, Grade D
= ISO 5, Grade A
e8
CNC= Controlled Non-Classified
UC
= ISO 8, Grade C
= Uncontrolled Unclassified
BSC
BSC
BSC
BSC PAL
PAL
DFB DFB DFB DFB
MAL
MAL
PALMAL PAL MAL
JC
JC
15K
15K
15K
15K
15K
15K
CF-100 CF-100
CF-100 CF-100
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
Downstream Equip Wash
Column Packing
Warehouse
Cell Bank
Dewar
Media Hold
Corridor
Efficiency in Centrifugation Use LikelyBallroomMultipurpose Room
If Environment = No Critical Aspect
Buffer Hold
Purification 1 V+
Purification 2 V+
Purifica tion V-
Men’s Locker Room
Women’s Locker Room
Inoc
Inoc
Equipment Wash
Cell Culture Harvest and Clarification
Cell Culture
Weigh DispenseDispensed Kit StorageMedia Prep
Buffer Prep
Centrifuge
Corridor
Buffer Hold
Corridor
PAL
PAL
PAL
MAL
MAL
ALAL
PAL PAL
PAL MAL
PAL MAL
PAL MAL
Corridor
Clean Equipment
Storage
CorridorCorridor
Clean Equipment
Storage
Corridor
Corridor
Corridor
7
8
9
= ISO 7, Grade B5
= ISO 8, Grade C= ISO “9”, Grade D
= ISO 5, Grade A
e8
CNC= Controlled Non-Classified
UC
= ISO 8, Grade C
= Uncontrolled UnclassifiedBSC
BSC PAL
PAL
DFB DFB DFB DFB
MAL
MAL
PALMAL PAL MAL
JC
JC
15K
15K
15K
15K
15K
15K
CF-100 CF-100 CF-100
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
Downstream Equip Wash
Column Packing
Warehouse
Cell Bank
Dewar
Media Hold
Corridor
Single redundancy likely sufficient
If Environment = No Critical AspectSterile Filter all Buffers or Use < 24 hours
Buffer Hold
Purification 1 V+
Purification 2 V+
Purifica tion V-
Men’s Locker Room
Women’s Locker Room
Inoc
Inoc
Equipment Wash
Cell Culture Harvest and Clarification
Cell Culture
Weigh DispenseDispensed Kit StorageMedia Prep
Buffer Prep
Centrifuge
Corridor
Buffer Hold
Corridor
PAL
PAL
PAL
MAL
MAL
ALAL
PAL PAL
PAL MAL
PAL MAL
PAL MAL
Corridor
Clean Equipment
Storage
CorridorCorridorCorridor
Corridor
7
8
9
= ISO 7, Grade B5
= ISO 8, Grade C= ISO “9”, Grade D
= ISO 5, Grade A
e8
CNC= Controlled Non-Classified
UC
= ISO 8, Grade C
= Uncontrolled Unclassified
BSC
BSC PAL
PAL
DFB DFB DFB DFB
MAL
MAL
PALMAL PAL MAL
JC
JC
15K
15K
15K
15K
15K
15K
CF-100 CF-100 CF-100
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
Downstream Equip Wash
Column Packing
Warehouse
Cell Bank
Dewar
Media Hold
Use Protected Powder Additions and Closed Liquid Additions
If Environment = No Critical Aspect
Buffer Hold
Purification 1 V+
Purification 2 V+
Purifica tion V-
Men’s Locker Room
Women’s Locker Room Inoc
Inoc
Equipment Wash
Cell Culture Harvest and Clarification
Cell Culture
Weigh DispenseDispensed Kit StorageMedia Prep
Buffer Prep
Centrifuge
Corridor
Buffer Hold
Corridor
PAL
PAL
PAL
MAL
MAL
ALAL
PAL PAL
PAL MAL
PAL MAL
PAL MAL
Corridor
Clean Equipment
Storage
CorridorCorridor
Corridor
Corridor
7
8
9
= ISO 7, Grade B5
= ISO 8, Grade C= ISO “9”, Grade D
= ISO 5, Grade A
e8
CNC= Controlled Non-Classified
UC
= ISO 8, Grade C
= Uncontrolled Unclassified
BSC
BSC PAL
PAL
DFB DFB DFB DFB
MAL
MAL
JC
JC
15K
15K
15K
15K
15K
15K
CF-100 CF-100 CF-100
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
Downstream Equip Wash
Column Packing
Warehouse
Cell Bank
Dewar
Media Hold
Close SystemsSanitize skidsBlind runs
If Environment = No Critical Aspect
Buffer Hold
Purification 1 V+
Purification 2 V+
Purifica tion V-
Men’s Locker Room
Women’s Locker Room Inoc
Inoc
Equipment Wash
Cell Culture Harvest and Clarification
Cell Culture
Weigh DispenseDispensed Kit StorageMedia Prep
Buffer Prep
Centrifuge
Corridor
Buffer Hold
Corridor
PAL
MAL
MAL
AL
PAL MAL
PAL MAL
Corridor
Clean Equipment
Storage
CorridorCorridor
Corridor
Corridor
7
8
9
= ISO 7, Grade B5
= ISO 8, Grade C= ISO “9”, Grade D
= ISO 5, Grade A
e8
CNC= Controlled Non-Classified
UC
= ISO 8, Grade C
= Uncontrolled Unclassified
BSC
BSC PAL
PAL
DFB DFB DFB DFB
JC
JC
15K
15K
15K
15K
15K
15K
CF-100 CF-100 CF-100
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
Downstream Equip Wash
Column Packing
Warehouse
Cell Bank
Dewar
Media Hold
Use Single Use Systems
If Environment = No Critical Aspect
Buffer Hold
Purification 1 V+
Purification 2 V+
Men’s Locker Room
Women’s Locker Room Inoc
Inoc
Equipment Wash
Cell Culture Harvest and Clarification
Cell Culture
Weigh DispenseDispensed Kit StorageMedia Prep
Buffer Prep
Centrifuge
Corridor
Buffer Hold
Corridor
PAL
MAL
MAL
AL
Corridor
Clean Equipment
Storage
CorridorCorridor
Corridor
Corridor
7
8
9
= ISO 7, Grade B5
= ISO 8, Grade C= ISO “9”, Grade D
= ISO 5, Grade A
e8
CNC= Controlled Non-Classified
UC
= ISO 8, Grade C
= Uncontrolled Unclassified
BSC
BSC
DFB DFB DFB DFB
JC
JC
15K
15K
15K
15K
15K
15K
CF-100 CF-100 CF-100
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
Downstream Equip Wash
Column Packing
Warehouse
Cell Bank
Dewar
Media Hold
Purifica tion V-
PAL MAL
PAL MAL
Regulatory Concern
If closed
With Technology Improvements
Buffer Hold
Purification V+
Men’s Locker Room
Women’s Locker Room Inoc
Inoc
Equipment Wash
Cell Culture Harvest and Clarification
Cell Culture
Weigh DispenseDispensed Kit StorageMedia Prep
Buffer Prep
Centrifuge
Corridor
Corridor
PAL
AL
AL
Clean Equipment
Storage
CorridorCorridor
Corridor
Corridor
7
8
9
= ISO 7, Grade B5
= ISO 8, Grade C= ISO “9”, Grade D
= ISO 5, Grade A
e8
CNC= Controlled Non-ClassifiedUC
= ISO 8, Grade C
= Uncontrolled Unclassified
BSC
BSC
DFB DFB DFB DFB
JC
JC
15K
15K
15K
15K
15K
15K
CF-100 CF-100 CF-100
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
Column Wash &Packing
Warehouse
Cell Bank
Dewar
Media Hold
Purifica tion V-
PAL MAL
If concern overcome
If in line dilution usedIf cytocentric isolator used
If Environment = No Critical Aspect
Buffer Hold
Purification V+/V-Men’s Locker Room
Women’s Locker Room
Equipment Wash
Cell Culture Harvest and Clarification
Cell Culture
Weigh DispenseDispensed Kit Storage
Media Prep Buffer Prep
Centrifuge
Corridor
Corridor
AL
AL
Clean Equipment
StorageCorridor
Corridor
Corridor
7
8
9
= ISO 7, Grade B5
= ISO 8, Grade C= ISO “9”, Grade D
= ISO 5, Grade A
e8
CNC= Controlled Non-ClassifiedUC
= ISO 8, Grade C
= Uncontrolled Unclassified
ISOL
ISOL
DFB DFB DFB DFB
JC
JC
15K
15K
15K
15K
15K
15K
CF-100 CF-100
15K
15K
15K
15K 15
K
15K
15K
15K
Column Wash &Packing
Warehouse
Cell Bank
Dewar
Media Hold
2K 2K 2K 2K 2K
2K 2K 2K 2K 2K
2K 2K 2K 2K 2K
2K 2K 2K 2K 2K
ISOL
Consolidated V+ / V-
Note fewer staff
Smaller volumes required
If Environment = No Critical Aspect
Buffer Hold
Purification V+/V-Men’s Locker Room
Women’s Locker Room
Equipment Wash
Cell Culture Harvest and Clarification
Cell Culture
Weigh DispenseDispensed Kit Storage
Media Prep Buffer Prep
Centrifuge
Corridor
Corridor
AL
AL
Clean Equipment
StorageCorridor
Corridor
Corridor
7
8
9
= ISO 7, Grade B5
= ISO 8, Grade C= ISO “9”, Grade D
= ISO 5, Grade A
e8
CNC= Controlled Non-ClassifiedUC
= ISO 8, Grade C
= Uncontrolled Unclassified
ISOL
ISOL
DFB DFB DFB DFB
JC
JC
15K
15K
15K
15K
15K
15K
CF-100 CF-100
15K
15K
15K
15K 15
K
15K
15K
15K
Column Wash &Packing
Warehouse
Cell Bank
Dewar
Media Hold
2K 2K 2K 2K 2K
2K 2K 2K 2K 2K
2K 2K 2K 2K 2K
2K 2K 2K 2K 2K
ISOL
If all SS: UC space above
If Environment = No Critical Aspect
Buffer Hold
Purification 1 V+
Purification 2 V+
Purifica tion V-
Men’s Locker Room
Women’s Locker Room
Inoc
Inoc
Seed Cell Culture
Equipment Wash
Cell Culture 1 Harvest and Clarification 1
Cell Culture 2 Harvest and Clarification 2
Weigh DispenseDispensed Kit StorageMedia Prep
Buffer Prep
Centrifuge
Corridor
Buffer Hold
Centrifuge
Seed Cell Culture
Corridor
PAL
PAL MAL
MAL
Inoc
Inoc
PAL
PAL
PAL
MAL
PAL
PAL
MAL
MAL
ALALPAL
MAL
PAL
MAL
PAL MAL
PAL MALPAL MAL
PAL PALPAL MAL
PAL MAL
PAL MAL
PAL MALPAL MALCorridor
Clean Equipment
Storage
CorridorCorridor
Clean Equipment
Storage
Corridor
Corridor
Corridor
BSC
BSC
BSC
BSC PAL
PAL
DFB DFB DFB DFB
MAL
MAL
PALMAL PAL MAL
JC
JC
15K
15K
15K
15K
15K
15K
CF-100 CF-100
CF-100 CF-100
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
15K
Media Hold
Media Hold
Downstream Equip Wash
Column Packing
Warehouse
Cell Bank
Dewar
Purification V+/V-Men’s Locker Room
Women’s Locker Room
Equipment Wash
Cell Culture Harvest and Clarification
Cell Culture
Weigh DispenseDispensed Kit Storage
Media Prep Buffer Prep
Centrifuge
CorridorAL
AL
Clean Equipment
StorageCorridor
Corridor
Corridor
ISOL
ISOL
DFB DFB DFB DFB
JC
JC
15K
15K
15K
15K
15K
15K
CF-100 CF-100
15K
15K
15K
15K
Column Wash &Packing
Warehouse
Cell Bank
Dewar
Media Hold
ISOL
Buffer Hold
15K
15K
15K
15K
2K 2K 2K 2K 2K
2K 2K 2K 2K 2K
2K 2K 2K 2K 2K
2K 2K 2K 2K 2K9900 m2 5400 m2 + 380 m2 buffer hold UC
If Environment = No Critical Aspect
Purification V+/V-Men’s Locker Room
Women’s Locker Room
Equipment Wash
Cell Culture Harvest and Clarification
Cell Culture
Weigh DispenseDispensed Kit Storage
Media Prep Buffer Prep
Centrifuge
CorridorAL
AL
Clean Equipment
StorageCorridor
Corridor
Corridor
ISOL
ISOL
DFB DFB DFB DFB
JC
JC
15K
15K
15K
15K
15K
15K
CF-100 CF-100
15K
15K
15K
15K
Column Wash &Packing
Warehouse
Cell Bank
Dewar
Media Hold
ISOL
Buffer Hold
15K
15K
15K
15K
2K 2K 2K 2K 2K
2K 2K 2K 2K 2K
2K 2K 2K 2K 2K
2K 2K 2K 2K 2K4000 m2 ISO 8, 1000 m2 ISO 7 500 m2 ISO 8
How might this look?
Batch Continuous
Purification V+/V-Men’s Locker Room
Women’s Locker Room
Equipment Wash
Cell Culture Harvest and Clarification
Cell Culture
Weigh DispenseDispensed Kit Storage
Media Prep Buffer Prep
Centrifuge
CorridorAL
AL
Clean Equipment
StorageCorridor
Corridor
Corridor
ISOL
ISOL
DFB DFB DFB DFB
JC
JC
15K
15K
15K
15K
15K
15K
CF-100 CF-100
15K
15K
15K
15K
Column Wash &Packing
Warehouse
Cell Bank
Dewar
Media Hold
ISOL
Buffer Hold
15K
15K
15K
15K
2K 2K 2K 2K 2K
2K 2K 2K 2K 2K
2K 2K 2K 2K 2K
2K 2K 2K 2K 2KSmaller volumes & areas required
Batch Continuous
Mabs Model:
• Perfusion versus Batch Cell culture
• Continuous Harvest/Clarification (ATF, centrifuge, etc
• Continuous Capture (SMCC Protein A)
• SMB/SMCC where possible in multi-chrom operation
• Nanofiltration
• UF/DF & Bulk Fill
Batch Continuous
Requirements:
• All operations must be closed and synchronized for long term operations
• Cell Culture must be “bpsterile”
• Clarification cannot contaminate upstream (but…)
• Capture must be closed (but…)
• Any static hold steps must be “bacteriostatic”
• If continuous, UF/DF & Bulk Fill must be bacteriostatic
Batch ContinuousMetrics from benchmark projects and models:
• Assuming 5:1 lower titer in Perfusion versus Batch
• 15K batch BRX for 1000 kg protein
• 1K to 4K perfusion BRX for 1000 kg protein
• Harvest batch 20K in 4-6 hours after 12-14 days
• Harvest continuous 24/7 (1-3 BRX volumes/day)
5000 m2 batch 3000 to 3800 m2 continuous ( -24 to -40%)
Batch Continuous
Purification V+/V-Men’s Locker Room
Women’s Locker Room
Equipment Wash
Cell Culture Harvest and Clarification
Cell Culture
Weigh DispenseDispensed Kit Storage
Media Prep Buffer Prep
Centrifuge
CorridorAL
AL
Clean Equipment
StorageCorridor
Corridor
Corridor
ISOL
ISOL
DFB DFB DFB DFB
JC
JC
15K
15K
15K
15K
15K
15K
CF-100 CF-100
15K
15K
15K
15K
Column Wash &Packing
Warehouse
Cell Bank
Dewar
Media Hold
ISOL
Buffer Hold
15K
15K
15K
15K
2K 2K 2K 2K 2K
2K 2K 2K 2K 2K
2K 2K 2K 2K 2K
2K 2K 2K 2K 2KAssume 24% reduction
Assume no change
Batch Continuous
Purification V+/V-Men’s Locker Room
Women’s Locker Room
Equipment Wash
Cell Culture Harvest and Clarification
Cell Culture
Weigh DispenseDispensed Kit Storage
Media Prep Buffer Prep
Centrifuge
CorridorAL
AL
Clean Equipment
StorageCorridor
Corridor
Corridor
ISOL
ISOL
DFB DFB DFB DFB
JC
JC
15K
15K
15K
15K
15K
15K
CF-100 CF-100
15K
15K
15K
15K
Column Wash &Packing
Warehouse
Cell Bank
Dewar
Media Hold
ISOL
Buffer Hold
15K
15K
15K
15K
2K 2K 2K 2K 2K
2K 2K 2K 2K 2K
2K 2K 2K 2K 2K
2K 2K 2K 2K 2K
Buffer Hold
Purification V+/V-Men’s Locker Room
Women’s Locker Room
Equipment Wash
Cell Culture Harvest and Clarification
Weigh DispenseDispensed Kit Storage
Media PrepBuffer Prep
CorridorAL
AL
Equipment Storage
Corridor
Corridor
Corridor
ISOL
DFB DFB DFB DFB
JC
JC
15K
15K
15K
15K
Column Wash &Packing
Warehouse
Cell Bank
Dewar
Media Hold
2K 2K 2K 2K 2K
2K 2K 2K 2K 2K
2K 2K 2K 2K 2K
2K 2K 2K 2K 2K
Further 1000 m2 space savings or more achievable
Closed + Continuous = Low Cost
Facility Cost
Less competitiveHigher costLess flexible
Lower costMore competitive
Highly flexible
Buffer Hold
Purification V+/V-Men’s Locker Room
Women’s Locker Room
Equipment Wash
Cell Culture Harvest and Clarification
Weigh DispenseDispensed Kit Storage
Media PrepBuffer Prep
CorridorAL
AL
Equipment Storage
Corridor
Corridor
Corridor
ISOL
DFB DFB DFB DFB
JC
JC
15K
15K
15K
15K
Column Wash &Packing
Warehouse
Cell Bank
Dewar
Media Hold
2K 2K 2K 2K 2K
2K 2K 2K 2K 2K
2K 2K 2K 2K 2K
2K 2K 2K 2K 2K
Closing #1
Closed & Continuous
Project Risk