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Flexible Biochemical Manufacturing: Strategic Considerations April 18, 2002 Robert Bottome 1 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 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 n The strategic value of the SSF Biochemical manufacturing facility à Flexibility • Abstract n The strategic value of the SSF Biochemical manufacturing facility à Flexibility • Ability to rapidly reconfigure shrinks development timelines • Maximizes return on asset à à n Offsets the risk, limitations à à n 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 à Engaged, dedicated cross-trained technicians 3

Generic Process Packaging Filling Large Scale Fermentation (12, 000 L) Purification 4 Generic Process Packaging Filling Large Scale Fermentation (12, 000 L) Purification 4

5 Process Map 5 Process Map

6 Process Map 6 Process Map

Genentech Approx. Theoretical Capacity Tanks ~Revenues CHO 4 x 10 k ~85 0. 7 Genentech Approx. Theoretical Capacity Tanks ~Revenues CHO 4 x 10 k ~85 0. 7 bn CHO 12 x 12 k ~240 2. 4 bn CHO 8 x 12 k ~160 1. 6 bn e. coli 2 x 1 k ~100 clinical 400 -12 k ~20 Porriño Vacaville SSF ~Runs / yr* Filling Pack >0. 3 bn N/a >200 fills > 200 7

B 3 A/3 B Fermentation 8 B 3 A/3 B Fermentation 8

Portable Skids Used to Purify Growth Hormone 9 Portable Skids Used to Purify Growth Hormone 9

Top of Buffer Prep 10 Top of Buffer Prep 10

Bottom of Pool tanks, chrom skid is behind you 11 Bottom of Pool tanks, chrom skid is behind you 11

Today’s Situation at SSF: Challenges n Current LRP says 7 years, à Development Org Today’s Situation at SSF: Challenges n Current LRP says 7 years, à Development Org moved to revise to 9 years as realistic; à PPC and EC held line at 7 years n Development Operating Team Productivity Initiative has set a timeline compression goal à down to 5. 5 years 12

Today’s Situation at SSF: Challenges n Compliance Challenges: à à Simultaneous Multi-product Licensure (“ Today’s Situation at SSF: Challenges n Compliance Challenges: à à 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 n Complex Manufacturing Plant: à Mixture of • Old & New, Traditional & State-of-the-art • Fully automated, Semi-automated and Manual – Manual valves lead to errors à Inconsistencies burden technicians • Controls, automation / HMI’s à Low standardization complicates improvement efforts • Poorly defined labor model, takt times • Not all skids equipped with comparable defenses Footnotes: Slides 52 -53 13

SSF B 3 Complex, “ 4 plants in one” 1: Monoclonal 2 Fermentation 4 SSF B 3 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 n As plant ramped up production volume and variety of products (t. PA Changeover n As plant ramped up production volume and variety of products (t. PA and Pulmozyme to Antibodies) à 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 c 2 b 8 in one day » Eliminate overlap, focus on single shared asset » Pulmozyme uses everything, high overlap » 10 days current max 15

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Lost Product Scenario’s n ‘Cracked’ Manual Valve à Product flowing to drain, masked • Lost Product Scenario’s n ‘Cracked’ Manual Valve à Product flowing to drain, masked • Detected late n Non standard skid design à Buffer made and held, not transferred • Salt collected in dead leg à Pumped onto column through pool filter • Not around through buffer filter n Non standard automation à ‘Acknowledge’ has dwell on some not others • Technician left room, and product pumped to floor n Inconsistent mixing à Variety of vessel sizes, impeller lengths, mixing times 17

Today’s Situation at SSF: Challenges n Optimize fit: Process vs Plant à To what Today’s Situation at SSF: Challenges n Optimize fit: Process vs Plant à 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? à Cost control • Can we learn everything we need at 1000 L vs 12 K? à QC test and validation • Standard tests, uniform turn-around times • Validation philosophy to enable reliable manufacturing 18

Today’s Situation at SSF: Strengths n n n Only site capable of producing all Today’s Situation at SSF: Strengths n n n 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. n Flexible = competitive advantage (e. g. Enbrel) 19

Today’s Situation at SSF: Strengths n CHO processes remarkably similar à à Ferm; Purification Today’s Situation at SSF: Strengths n CHO processes remarkably similar à à Ferm; Purification = 3 chromatographies and 1 formulation Resins and membranes standardized • Long lead times, high expense n Decoupled à Concurrent processing possible • Build buffers to cushion impact of process variability • Changeover begins before routing complete n Redundant à 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 Tightly Coupled vs De-coupled A B C A B A E C D DE-COUPLED Tightly Coupled vs De-coupled A B C A B A E C D E C Parallel option D D B Start changeover prior to completing routing D E 21

SSF Manufacturing Paradigm T 1 T 2 x Re-configurable skids, product specific—can be changed SSF Manufacturing Paradigm T 1 T 2 x Re-configurable skids, product specific—can be changed over in days x Skid is isolated from upstream & downstream vessels; little if any automation, interlocks etc x T 3 System depends on engaged/alert technician to monitor process 22

Technician Engagement n Recruitment and Retention à à n Wear & Tear issues à Technician Engagement n Recruitment and Retention à à n Wear & Tear issues à à à n Transport Parts, tools Automation design for support Ownership à à n Career path Cross-trained vs silo’d Recognition Mastery Readiness rituals 23

Aspects of Flexibility n Product Range à Excellent, able to make all molecules • Aspects of Flexibility n Product Range à Excellent, able to make all molecules • Optimum for Dnase and Activase • Less ideal for others n Mobility à Higher in some areas • Final was designed for flexibility – Central core, ample floor space n Uniformity of Performance à Variable / vulnerable • Utility constraints • Latent errors—automation needs to support operator – Not mask failures 24