Flexible Biochemical Manufacturing:
Strategic Considerations
April 18, 2002
Robert Bottome
1
Preparing for the Future…
the Next Revenue Wave
Potential
Launches
Xolair
Xanelim
Avastin
Genentech
Founded
‘76
‘85
‘87
‘93
‘96
‘97
‘98
‘99
‘00
‘01
‘02
‘03
‘04
(for use with the Nutropin AQ Pen Cartridge)
2
Abstract

The strategic value of the SSF Biochemical
manufacturing facility

Flexibility
• Ability to rapidly reconfigure shrinks development timelines
• Maximizes return on asset



Offsets the risk, limitations





Proximity to Development organization
Able to make any known biotech molecule
High cost of living
Disaster risk
Multi-product, mixed facility (GMP and clinical) inspection risks
Challenge to continuous improvement and standardization
efforts
The De-coupled paradigm enabled

Engaged, dedicated cross-trained technicians
3
Generic Process
Packaging
Filling
Large Scale Fermentation
(12,000 L)
Purification
4
Major Process
Steps
Major groups and pieces of
equipment
Released Materials (Kits)
fromweigh and dispense
vial thaw
Process Map
stock spinner
small volume media prep
supports Seed Train and CCM
20L batch refeed fermentor
SeedTrain
seed train
Cell Culture Manufacturing
portable spinner cart
80LFermentor
410
411
119
410 100L
portable
412
TP481.1
500L
media prep
100 105
F 481.1
400LFermentor
CCMmedia prep
200L
media prep
400L fermentors
421 422
420
TP482.1 TP485.1
2,000L fermentors
2000LFermentor
430
431
432
H150
TP 116.1
H153
H155
TP486.2
TP486.1
12,000LFermentor
11801, Operation 30
441
12000Lharvest Stage
11801, Operation 40
Tangential FlowFiltration
3000L media prep
H151
H152
TP483.1
442
TP116.1
U470
470.8 470.9
440
443
Primatone
130 131
101 102 103
103
13,000L media prep
104
140 141141
carbonate
TP142.1
12,000L fermentors
444
445
446
447
200
10Kbuffer prep
246
220
241System
T-200
(1b)
10K
10K
5
12000Lharvest Stage
11801, Operation 40
Tangential FlowFiltration
470.3
470.4
201
Aseptic Filtration
470.6
Harvested Cell Culture Fluid
470.7
c510.1
c510.3
513
512 8000L
513
Pool
3000L 8000L
pool pool
c520.1
CationExchange
Chromotography
SPSepharose
11801, Operation 60
AnionExchange
Chromotography
QSepharose
11801, Operation 70
Hydrophobic Interaction
Phenyl Sepherose
chromotography
11801, Operation 80
m220.1
229
T201
system222
(3a)
5K
5K
16,000L HCCF
472
AffinityChromotography
ProteinA
11801, Operation 50
10Kbuffer prep
246
220
241System
T-200
(1b)
10K
10K
8K
U470
470.8 470.9
Depth Filtration
Process Map
200
TP116.1
c520.3
521
3000L
Pool
c530.1
531
5000L
Pool
c530.3
c540.1
c540.3
541 542
5000L 500L
Pool pool
bay
5
ring
5K
202
m221.1
bay
2
ring
3Kbuffer prep
225
231
237
223
T202 system(2b)
3K
3K
3K
3K
bay
3
ring
bay
4
ring
550
10KDformulationTFF
Operation 90
bay
1
ring
8Kbuffer prep
221
203 prep
urea
260
3Kbuffer prep
236
3K
3K
230
224 (1a)242
T203 system
3K
3K
urea
dist.
system
1000L buffer prep
204
m230.1
227
m224.1
226
238 m242.1
232
244
T204 system(2a)
x550.1
m232.1
551
m244.1
Product Recovery
Filtrationof rhuAMABHER2
bulk for storage
11870, Operation 95
freze thawskid
Genentech
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Genentech Approx. Theoretical Capacity
Tanks
Porriño
~Revenues
CHO
4 x 10k
~85
0.7 bn
CHO
12 x 12k
~240
2.4 bn
8 x 12k
~160
1.6 bn
e. coli
2 x 1k
~100
clinical
400-12k
~20
Vacaville
SSF
~Runs / yr*
CHO
Filling
Pack
>0.3bn
N/a
>200 fills
> 200
7
B3A/3B Fermentation
8
Portable Skids Used to Purify
Growth Hormone
9
Top of Buffer Prep
10
Bottom of Pool
tanks, chrom
skid is behind
you
11
Today’s Situation at SSF: Challenges

Current LRP says 7 years,
 Development
Org moved to revise to 9 years
as realistic;
 PPC and EC held line at 7 years

Development Operating Team Productivity
Initiative has set a timeline compression
goal
 down
to 5.5 years
12
Today’s Situation at SSF: Challenges

Compliance Challenges:


Simultaneous Multi-product Licensure (“4 plants”);
Mixed plant / Multiple Flow Paths:
• Research, Clinical, Marketed
• Inter-path tensions, validation, asset management
• Highly utilized critical constraint utilities

Complex Manufacturing Plant:

Mixture of
• Old & New, Traditional & State-of-the-art
• Fully automated, Semi-automated and Manual
– Manual valves lead to errors

Inconsistencies burden technicians
• Controls, automation / HMI’s

Low standardization complicates improvement efforts
• Poorly defined labor model, takt times
• Not all skids equipped with comparable defenses
Footnotes: Slides 52-53
13
SSF B3 Complex, “4
plants in one”
1: Monoclonal
2 Fermentation
4 Initial Purification
1 Final Purification
Raw Materials,
Media etc
E.coli
“purification”
2: Lytics
3: Pulmozyme
Process
Development
CHO
ferm
4: GH
E.coli & CHO
ferm
Multi-product purification
Utilities
14
Changeover

As plant ramped up production volume and
variety of products (tPA and Pulmozyme to
Antibodies)

Original arbitrary window of 21 days between campaigns
inadequate
• Pressure to do more in the same amount of time
• Effort to decrease change-over
– 3 weeks to 2 weeks, pilot
– Equipment, process start up varies by product
– Optimize changeover by combining low overlap product
» Activase to c2b8 in one day
» Eliminate overlap, focus on single shared asset
» Pulmozyme uses everything, high overlap
» 10 days current max
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Fermentation
CCP Ferm
CMF Ferm
3720
3B130
B3 Ferm
C2B8
AX 215
AX 213
BTPX 205
BTAX 215
Dnase
Area
Fermentation
Product
Area
CCP Ferm
CMF Ferm
3720
3B130
B3 Ferm
AX 215
AX 213
BTPX 205
BTAX 215
Nutropin Iso
3517
3554
3510
3606
3500
3519
3555
COF
3600
3505
rtPA
3640
Mexico I
Nutropin Final
Protropin Iso
3810
B3A/B
Recovery
3B110
3700
3B120
3B110
B3 Isolation
3810
Her2
3B120
B3 Isolation
B3A/B
Recovery
E25
3700
3517
3554
3510
3606
3500
3519
3555
COF
3600
3505
rtPA
3640
Mexico I
MFP
3651
3659
MFP
3651
3659
LSFP/Mexico III
TPA
Product
Area
Fermentation
B3 Final
TNK
LSFP/Mexico III
CCP Ferm
CMF Ferm
3720
3B130
B3 Ferm
C2B8
AX 215
AX 213
BTPX 205
BTAX 215
Dnase
Area
Fermentation
B3 Final
Protropin Final
CCP Ferm
CMF Ferm
3720
3B130
B3 Ferm
AX 215
AX 213
BTPX 205
BTAX 215
3B110
Nutropin Iso
3517
3554
3510
3606
3500
3519
3555
COF
3600
3505
Nutropin Final
Protropin Iso
3810
Her2
3B120
B3A/B
Recovery
3810
3700
B3 Isolation
B3 Isolation
B3A/B
Recovery
E25
3700
3B120
3B110
3517
3554
3510
3606
3500
3519
3555
COF
3600
3505
rtPA
3640
Mexico I
MFP
3651
3659
rtPA
3640
Mexico I
LSFP/Mexico III
MFP
3651
3659
TNK
TPA
B3 Final
B3 Final
Protropin Final
LSFP/Mexico III
16
Lost Product Scenario’s

‘Cracked’ Manual Valve

Product flowing to drain, masked
• Detected late

Non standard skid design

Buffer made and held, not transferred
• Salt collected in dead leg

Pumped onto column through pool filter
• Not around through buffer filter

Non standard automation

‘Acknowledge’ has dwell on some not others
• Technician left room, and product pumped to floor

Inconsistent mixing

Variety of vessel sizes, impeller lengths, mixing times
17
Today’s Situation at SSF: Challenges

Optimize fit: Process vs Plant
 To
what degree does the ‘ideal’ process have
to be sub-optimized to match the constraints in
the plant
• Can we successfully challenge these constraints?
 Cost
control
• Can we learn everything we need at 1000L vs 12K?
 QC
test and validation
• Standard tests, uniform turn-around times
• Validation philosophy to enable reliable
manufacturing
18
Today’s Situation at SSF: Strengths






Only site capable of producing all products
Strategic back-up to other sites
Sole supplier for Pulmozyme, Lytics and Growth
Hormone
Only site for E.coli production
Production of Clinical Material & Launching pad for
Development projects
Flexible: best Development time 5.5 years (Pulmozyme)
Can schedule complex Development campaigns & changes etc.

Flexible = competitive advantage (e.g. Enbrel)
19
Today’s Situation at SSF: Strengths

CHO processes remarkably similar


Ferm; Purification = 3 chromatographies and 1 formulation
Resins and membranes standardized
• Long lead times, high expense

Decoupled

Concurrent processing possible
• Build buffers to cushion impact of process variability
• Changeover begins before routing complete

Redundant

Parallel paths available
• Equipment availability issues
NOTE: Vacaville plant is tightly coupled and highly automated—one large
routing with few parallel paths available. Changeovers take weeks (e.g.
recipes need to be re-written for each product); problems become preemptive outages.
20
DE-COUPLED
COUPLED
Tightly Coupled vs De-coupled
A
B
C
A
B
C
A
B
Parallel option
A
D
E
C
D
E
C
D
B
D
E
Start changeover prior to completing routing
21
SSF Manufacturing Paradigm
T1
T2
x
x
Re-configurable skids,
product specific—can be
changed over in days
Skid is isolated
from upstream
& downstream
vessels; little if
any automation,
interlocks etc
x
T3
System depends
on engaged/alert
technician to
monitor process
22
Technician Engagement

Recruitment and Retention



Wear & Tear issues




Transport
Parts, tools
Automation design for support
Ownership



Career path
Cross-trained vs silo’d
Recognition
Mastery
Readiness rituals
23
Aspects of Flexibility

Product Range

Excellent, able to make all molecules
• Optimum for Dnase and Activase
• Less ideal for others

Mobility

Higher in some areas
• Final was designed for flexibility
– Central core, ample floor space

Uniformity of Performance

Variable / vulnerable
• Utility constraints
• Latent errors—automation needs to support operator
– Not mask failures
24