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Flexible Biochemical Manufacturing: Strategic Considerations. April 18, 2002. Robert Bottome. (for use with the Nutropin AQ Pen Cartridge). Preparing for the Future… the Next Revenue Wave. Potential Launches Xolair Xanelim Avastin. Genentech Founded. - PowerPoint PPT Presentation
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1
April 18, 2002 Robert Bottome
Flexible Biochemical Manufacturing: Flexible Biochemical Manufacturing: Strategic ConsiderationsStrategic Considerations
2
Preparing for the Future…the Next Revenue Wave
Potential Launches
Xolair XanelimAvastin
Potential Launches
Xolair XanelimAvastinGenentech
Founded
‘76 ‘85 ‘87 ‘93 ‘96 ‘97 ‘98 ‘99 ‘00 ‘01 ‘02 ‘03 ‘04
(for use with the Nutropin AQ Pen Cartridge)
3
Abstract
The strategic value of the SSF Biochemical manufacturing facility Flexibility
• Ability to rapidly reconfigure shrinks development timelines• Maximizes return on asset
Proximity to Development organization Able to make any known biotech molecule
Offsets the risk, limitations 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
4
Generic Process
Large Scale Fermentation (12,000 L)
Packaging
PurificationFilling
5
G enentech
ureadist.
sys tem
Cell Culture M anufacturing
1000L buffe r prep
TP 116.1
103
141
440
410
16,000L H C C F
472
H150
H 152H 151
H 153H 155
P rim atone
100Lportab le 200L
m edia prep
500Lm ed ia prep
3000L m ed ia prep
13 ,000L m ed ia prep104
101 102
130 131100 105
140carbona te
12,000L ferm ento rs441 442 443 444 445 446 447
TP 486.2
TP 483 .1
2 ,000L fe rm entors
431 432
TP 482.1
400L fe rm ento rs421 422
TP 116 .1
TP 481 .1
TP 486.1 TP 142.1
TP 485.1
F 481.1
5138000LPool
241 246 220
200
10K10K 8KT-200 S ystem (1b)
10K bu ffer p rep
229 222 221
201
5K5K5KT201 sys tem (3a)
8K bu ffer p rep
3K
227 238 232 244226T204 sys tem (2a)
3KT202 sys tem (2b)
5213000LPool
bay3
ring
bay2
ring
bay1
ring
m 220.1
m 221.13K bu ffer prep
urea prep
202
3K
225 231 237 223
3K
m 244.1m 232.1
3K204
T203 system (1a)
260203
236 230 224 242
3K 3K3K
3K buffe r p rep
5315000LPool
5415000LPool
bay4
ring
bay5
ringm 242.1
m 230.1 m 224.1550
551
sm a ll vo lum e m edia p repsupports S eed Tra in and C C M
C CM m edia p rep
seed tra in
freze thaw skid
vial thaw
stock sp inner
20L batch refeed ferm entor
portable spinner cart
Tangen tia l F low F iltration
H arvested C ell C ulture F luid
Seed Train
80L Fermentor
400L Fermentor
2000L Fermentor
Depth F iltration
A septic Filtration
Affinity ChromotographyProte in A
11801, Operation 50
Cation ExchangeChrom otography
SP Sepharose11801, Operation 60
Anion ExchangeChrom otography
Q Sepharose11801, Operation 70
Hydrophobic InteractionPhenyl Sepherose chromotography
11801, Operation 80
10KD formulation TFFO peration 90
Filtration of rhuAMAB HER2bulk for storage
11870, O pera tion 95
12000L harvest Stage11801, O peration 40
12,000L Fermentor11801, O pera tion 30
M ajor groups and pieces ofequipm ent
M ajor ProcessSteps Released M aterials (K its)
from weigh and dispense
Product Recovery
x550.1
c510.1c510 .3
c540.1c540 .3
c530 .3c530.1
c520 .3c520.1
430
412
420
410 411119
U 470470.8 470 .9
470.3 470.4
470.6 470.7
5123000Lpool
5138000Lpool
542500Lpool
103
141
Pro
cess
Map
6
G enentech
ureadist.
sys tem
Cell Culture M anufacturing
1000L buffe r prep
TP 116.1
103
141
440
410
16,000L H C C F
472
H150
H 152H 151
H 153H 155
P rim atone
100Lportab le 200L
m edia prep
500Lm ed ia prep
3000L m ed ia prep
13 ,000L m ed ia prep104
101 102
130 131100 105
140carbona te
12,000L ferm ento rs441 442 443 444 445 446 447
TP 486.2
TP 483 .1
2 ,000L fe rm entors
431 432
TP 482.1
400L fe rm ento rs421 422
TP 116 .1
TP 481 .1
TP 486.1 TP 142.1
TP 485.1
F 481.1
5138000LPool
241 246 220
200
10K10K 8KT-200 S ystem (1b)
10K bu ffer p rep
229 222 221
201
5K5K5KT201 sys tem (3a)
8K bu ffer p rep
3K
227 238 232 244226T204 sys tem (2a)
3KT202 sys tem (2b)
5213000LPool
bay3
ring
bay2
ring
bay1
ring
m 220.1
m 221.13K bu ffer prep
urea prep
202
3K
225 231 237 223
3K
m 244.1m 232.1
3K204
T203 system (1a)
260203
236 230 224 242
3K 3K3K
3K buffe r p rep
5315000LPool
5415000LPool
bay4
ring
bay5
ringm 242.1
m 230.1 m 224.1550
551
sm all vo lum e m edia p repsupports S eed Tra in and C C M
C CM m edia p rep
seed tra in
freze thaw skid
vial thaw
stock sp inner
20L batch refeed ferm entor
portable spinner cart
Tangen tia l F low F iltration
H arvested C ell C ulture F luid
Seed Train
80L Fermentor
400L Fermentor
2000L Fermentor
Depth F iltration
A septic Filtration
Affinity ChromotographyProte in A
11801, Operation 50
Cation ExchangeChrom otography
SP Sepharose11801, Operation 60
Anion ExchangeChrom otography
Q Sepharose11801, Operation 70
Hydrophobic InteractionPhenyl Sepherose chromotography
11801, Operation 80
10KD formulation TFFO peration 90
Filtration of rhuAMAB HER2bulk for storage
11870, O pera tion 95
12000L harvest Stage11801, O peration 40
12,000L Fermentor11801, O pera tion 30
M ajor groups and pieces ofequipm ent
M ajor ProcessSteps Released M aterials (K its)
from weigh and dispense
Product Recovery
x550.1
c510.1c510 .3
c540.1c540 .3
c530 .3c530.1
c520 .3c520.1
430
412
420
410 411119
U 470470.8 470 .9
470.3 470.4
470.6 470.7
5123000Lpool
5138000Lpool
542500Lpool
103
141
Pro
cess
Map
7
FillingPack
>200 fills> 200
2.4 bn
1.6 bn
>0.3bn
N/a
~Revenues
0.7 bn
12 x 12k ~240CHO
400-12k ~20
2 x 1k ~100
clinical
e. coli
8 x 12k ~160CHO
4 x 10k ~85CHO
Vacaville
SSF
Porriño
~Runs / yr*Tanks
Genentech Approx. Theoretical Capacity
8
B3A/3B Fermentation
9
Portable Skids Used to Purify Growth Hormone
10
Top of Buffer Prep
11
Bottom of Pool tanks, chrom skid is behind you
12
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
Today’s Situation at SSF: Challenges
13
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
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E.coli & CHOferm
CHOferm
Utilities
Multi-product purification
E.coli “purification”
Raw Materials, Media etc
2: Lytics
Process Development
SSF B3 Complex, “4 plants in one” 1: Monoclonal
3: Pulmozyme
4: GH
2 Fermentation4 Initial Purification1 Final Purification
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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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AX 215
BTPX 205
3700
3600
CMF FermCCP Ferm
3720 3B130 BTAX 215
AX 213
Area
Fer
men
tati
on
B3 Ferm
B3A
/B
Rec
over
y3519 3555
Product
Protropin Final
Protropin Iso
C2B8
Dnase
E25
Her2
Nutropin Iso
TNK
TPA
Nutropin Final3500
3505
rtPA 3640
B3
Isol
atio
n
3517 3554 3510
MFP 3651 3659
3B120
3B110
3810
B3
Fin
al Mexico I
LSFP/Mexico III
COF
3606
CMF Ferm
AX 213
3B120
3B110
3810
3519
3720
3555
3B130
AX 215
BTPX 205
3700
BTAX 215
Area
CCP Ferm B3 Ferm
B3A
/B
Rec
over
y
3500
COF 3600
Fer
men
tati
on
3505
rtPA 3640
B3
Isol
atio
n
3517 3554 36063510
B3
Fin
al Mexico I
MFP 3651 3659
LSFP/Mexico III
CMF Ferm
AX 213
3B120
3B110
3810
3519
3720
3555
3B130
AX 215
BTPX 205
3700
BTAX 215
Area
CCP Ferm B3 FermB
3A/B
R
ecov
ery
3500
COF 3600
Fer
men
tati
on
3505
rtPA 3640
B3
Isol
atio
n
3517 3554 36063510
B3
Fin
al Mexico I
MFP 3651 3659
LSFP/Mexico III
Product
B3 FermCMF Ferm
Area
CCP Ferm
Fer
men
tati
on
3720
3B120
3B110
3810 3700
3B130
AX 215
BTPX 205
B3
Isol
atio
n
3517
BTAX 215
AX 213
TNK
TPA
Nutropin Final
Protropin Final
Protropin Iso
3500
3505
3606
C2B8
Dnase
E25
Her2
Nutropin Iso
B3A
/B
Rec
over
y
3554 3510
3600
MFP 3651 3659
3519 3555 COF
rtPA 3640
B3
Fin
al Mexico I
LSFP/Mexico III
17
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
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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
Today’s Situation at SSF: Challenges
19
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)
20
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 pre-emptive outages.
21
Tightly Coupled vs De-coupled
A B C D E
A B C
A B C D E
C DParallel option
A B D E
Start changeover prior to completing routing
DE
-CO
UP
LE
DC
OU
PL
ED
22
SSF Manufacturing Paradigm
T1T2
T3
Skid is isolated from upstream & downstream vessels; little if any automation, interlocks etcx
x x
Re-configurable skids, product specific—can be changed over in days
System depends on engaged/alert technician to monitor process
23
Technician Engagement
Recruitment and Retention Career path Cross-trained vs silo’d
Wear & Tear issues Transport Parts, tools Automation design for support
Ownership Recognition Mastery
Readiness rituals
24
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
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