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April 18, 2002 Robert Bottome

Flexible Biochemical Manufacturing: Flexible Biochemical Manufacturing: Strategic ConsiderationsStrategic Considerations

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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)

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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

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Generic Process

Large Scale Fermentation (12,000 L)

Packaging

PurificationFilling

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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

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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

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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

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B3A/3B Fermentation

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Portable Skids Used to Purify Growth Hormone

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Top of Buffer Prep

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Bottom of Pool tanks, chrom skid is behind you

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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

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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

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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

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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)

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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.

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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

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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

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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

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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