Automating Fermentation
INTERPHEX2007
April 24-26, 2007
Presenters
Todd Ham
– Automation Engineer
Emerson Process Management, Life
Sciences, Food, and Beverage
Todd Edgington
– Automation Engineer
Genentech
NIMO Facility, Oceanside, CA
INTERPHEX2007
April 24-26, 2007
The NIMO Project Overview
• NIMO is a large scale, multi-product biopharmaceutical
complex.
• Fermentation/Recovery process
– Fermentation
– Centrifuges, Chromatography, UF/DF, …
– CIP/SIP
• Fully automated
–
–
–
–
Recipe-level batch control
Warehouse management
Electronic signatures
Electronic records
INTERPHEX2007
April 24-26, 2007
The NIMO Project Timeline
2000
2002
2004
2006
2008
NIMO Engineering Kick-Off
Engineering and Design
Procurement
Construction
Commissioning
Validation
BLA Enabling Runs
BLA Submission
FDA Review
BLA Approval
INTERPHEX2007
April 24-26, 2007
NIMO Philosophy
• Fully automated
• Paperless, dock-to-dock
– Electronic record
– Handheld units for plant operations
– Barcode scanning for material additions, filters
• Consistency for operator / Use of industry standards
– Bus technologies
– S88 / S95
• Fermentation was integral to entire project
– Project philosophy impacted fermentation
– Fermentation impacted project philosophy
INTERPHEX2007
April 24-26, 2007
The Fermentation Process Overview
Feed Vessel (for Large Fermenters)
XV
023
CIP/SIP
Pressure Control
CIPS/CSL
311-R2-1560-B
XV
411
XV
168
Inoculation
312
sidewal
l
F-15X0.A
CIPS/CSL
303
XV
161
TE
162
XV
150
Inoculum
Media
XV
164
TE
165
T
XV
152
Vent
through
roof
XV
167
XV
160
XV
154
PV
002
T
VA-15X0.D
P
P
XV
151
XV
050
XV
054
P
P
TO MEDIA
FILTER
T
XV
051
XV
071
XV
148
P
XV
070
T
P
TE
053
T
VA-15X0.E
P
XV
215
T
P
XV
218
P
MV
071
MV
110
OVERLAY
GAS (CA)
P
XV
216
P
Additive
CIPS/CSL
308
XV
110
XV
108
VA-15X0.F
P
P
VA-15X0.B
XV
103
P
XV
225
XV
100
XV
228
P
SPARGE GAS
(CA)
P
P
P
XV
226
XV
101
MV
104
P
XV
106
P
P
XV
104
TE
102
T
TE
105
CIPS/CSL
312
XV
086
P
TE
227
T
P
XV
235
T
T
TE
217
T
P
TE
107
P
T
VA-15X0.G
P
XV
238
P
CIPS/CSL
310
XV
025
XV
024
FERMENTER
XV
032
XV
033
CIPS/CSL
311
P
SPARGE GAS
(CA)
XV
236
P
MV
135
P
TE
237
T
CIPS/CSL
309
XV
135
XV
133
T
XV
026
Sparge
XV
034
VA-15X0.C
P
XV
128
P
P
P
XV
129
TE
130
TE
132
T
P
XV
028
XV
036
XV
015
T
XV
126
MV
129
XV
131
XV
12
5
T
XV
016
P
T
TE
127
XV
047
XV
048
XV
019
T
Sampling
T
T
Base
Product/Inoculum
INTERPHEX2007
April 24-26, 2007
S88 Control Modules
• Identify the “common” modules and instances.
XV
023
CIPS/CSL
VA-15X0.A
P
Feed Media
P
XV
079
XV
076
P
XV
168
XV
071
XV
077
XV
080
P
XV
411
P
P
312
sidewall
TE
078
CIPR
Vent
XV
167
XV
070
T
PV
002
F-15X0.A
VA-15X0.D
CIPS/CSL
303
XV
160
P
XV
050
T
XV
150
XV
154
Inoculum
XV
161
TE
162
MV
071
XV
152
XV
054
TE
165
T
XV
151
P
P
XV
164
T
P
P
XV
148
VA-15X0.E
T
CIPS/CSL
308
XV
110
XV
108
P
XV
215
P
XV
103
P
P
XV
100
P
P
Overlay
TE
217
T
P
P
XV
101
MV
104
P
XV
106
XV
218
XV
216
VA-15X0.B
VA-15X0.F
P
XV
104
T
TE
105
TE
107
P
P
T
F-15X0.F
P
TE
102
P
XV
225
XV
228
P
P
Sparge1
XV
226
T
T
Media
TE
053
T
T
MV
110
P
XV
051
P
P
TE
227
T
MV
135
VA-15X0.G
CIPS/CSL
309
XV
135
XV
133
P
XV
235
T
F-15X0.E
CIPS/CSL
312
XV
128
P
XV
125
P
XV
129
TE
130
TE
132
T
T
P
CIPS/CSL
310
XV
025
XV
032
XV
024
XV
033
CIPS/CSL
311
P
Sparge2
TE
237
T
XV
126
MV
129
XV
131
P
P
P
XV
238
XV
236
VA-15X0.C
P
P
P
XV
086
P
T
TE
127
XV
026
XV
034
XV
015
XV
016
XV
047
XV
028
T
XV
048
XV
019
T
XV
036
T
T
Product
CMB 3/3/03
INTERPHEX2007
April 24-26, 2007
Examples:
Motors
Valves
S88 Equipment Modules
XV
168
F-15X0.A
PV
002
Vent
XV
167
– Fermentation Agitator Control
– Fermentation Pressure Control
– Fermentation Temperature
Control
– pH Control
– Dissolved Oxygen Control
– Foam Control
CIPS/CSL
303
XV
160
XV
161
TE
162
T
XV
164
TE
165
T
• Used some project-wide
module templates
– Sampling System
– Sparger Control
• Added some area-specific
module templates
• Added unique (one-time
use) equipment modules
– Transfer Panels
– Valve Assembly (VA) Control
INTERPHEX2007
April 24-26, 2007
Transfer Panel
INTERPHEX2007
April 24-26, 2007
S88 Units
• Identify classes and instances based on..
– Physical similarity
– Phases that they use
•
•
•
•
Batch Media
Inoculate
Ferment
Etc.
VA
Unit Class: Inoc
Fermenter
Unit Class: Seed Fermenter
TP A
INTERPHEX2007
April 24-26, 2007
Unit Class:
Production
Fermenter
Unit
Class:
Feed
Vessel
TP B
Phase Control
•
•
•
•
•
•
•
•
•
•
•
•
Batch Feed Vessel
Batch Fermenter
Pre-inoculation Prep
Inoculate
Ferment
Sample
Add Additive
Add Base
Add Feed Media
Transfer
Pressure Test
The following CIP
Phases for Feed
Vessel, Production
Fermenter, Seed
Fermenter, Discharge
Line, and Media Line
– CIP Setup
– CIP Circuit
– CIP Complete
•
•
•
•
•
•
INTERPHEX2007
April 24-26, 2007
Pre-SIP Pressure Test
Seed Fermenter
Pre-SIP Pressure Test
Production Fermenter
Pre-SIP Setup
SIP Sample Line
SIP Production
Fermenter
SIP Inoculation Line
Production Fermenter Procedure
Recipes
From Media
MEDIA TRANSFER
From Media
VESSEL/TRANSFER LINE
WFI FLUSH
1) Group Phases into
Operations
Batch
Fermenter
Vessel/Transfer
Line WFI Flush
Wait Until Feed
Vessel Fill
Procedure
Completes
Pre-Inoculation
Prepare
SIP Inoculum Line
2) Group Operations into
Unit Procedures
Prompt Operator
to Run:
Feed Vessel Fill
Procedure
Prompt Operator
to Run:
Media Feed CIP/
SIP Procedure
From Seed
Fermenter
TRANSFER
Inoculation
Wait Until Media
Feed CIP/SIP
Procedure
Completes
Base Addition
From Media
MEDIA TRANSFER
Feed Addition
3) Group Unit Procedures
into Procedures
Additive Addition
Fermentation
Feed Media
Addition
From Media
VESSEL/TRANSFER
LINE WFI FLUSH
Vessel/Transfer
Line WFI Flush
Transfer
To Harvest
HARVEST VESSEL
HARVEST
INTERPHEX2007
April 24-26, 2007
Vessel to Vessel Communication
Are you ready to receive?
Here comes the transfer.
SEED
FERMENTER
XV
015
XV
016
XV
047
XV
048
XV
019
T
T
TP
XV
150
XV
154
XV
152
Yes. Bring it on.
XV
151
T
XV
148
T
I got it.
XV
070
T
MV
071
PRODUCTION
FERMENTER
XV
015
XV
016
XV
047
XV
048
T
INTERPHEX2007
April 24-26, 2007
XV
019
T
Manufacturing Procedures
• Material Management
• Container Management
• Filter Management
• Sampling
INTERPHEX2007
April 24-26, 2007
MAT 2.
200 GR
Testing
• Emerson and Genentech
worked together closely on
requirements
• Emerson performed modulelevel and integration–level
testing
• Emerson and Genentech ran a
full Customer Acceptance Test
(CAT) prior to delivery
INTERPHEX2007
April 24-26, 2007
Lessons Learned – Modularity
• As much as possible, keep
process units the same.
• With similar units, make sure
operations are as uniform as
possible as well!
• Beware of alias over-load.
• Enforcement of classes can be
a negative thing.
INTERPHEX2007
April 24-26, 2007
Unit Class: Seed Fermenter
Lessons Learned –
Level of Automation
• High levels of automation
are a double edged sword.
• With high levels of
automation and modularity,
documents can become
very numerous.
INTERPHEX2007
April 24-26, 2007
Lessons Learned –
Up-Front Testing
• Time spent upfront saves on back
end effort.
• Easier to fix problems off-site
when you are in control of the
software.
• Risk based software validation
works.
• No level of testing will capture all
mistakes or prevent changes.
INTERPHEX2007
April 24-26, 2007
Lessons Learned – Raw Material Handling
and other Manufacturing Procedures
• Make sure everyone is on the
same page from the start.
• Make sure everyone uses the
same language.
• Get operators time on the
equipment.
INTERPHEX2007
April 24-26, 2007
Conclusion
• Leverage the S88 model as
much as possible.
• Take as much time as possible
upfront.
• Prepare for an effort
commensurate with your level of
automation.
INTERPHEX2007
April 24-26, 2007
Acknowledgements
Genentech
• Johannes Roebers
• Christoph Lebl
• Dave Stewart
• Sean Stephan
• Debi Marshall
• Christopher Birnie
• Leonidas Castaneda
• Jim Merrit
• Dirk Ellison
Emerson
• Christie Deitz
• Craig Bieda
• Brian Crandall
• Molly Firkins
• Dick Seeman
• Chen Yang
• Shelley Richards
• Ajay Savargaonkar
• Ketaki Raste
INTERPHEX2007
April 24-26, 2007