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Flexible Biochemical Manufacturing: Strategic Considerations

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.

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Flexible Biochemical Manufacturing: Strategic Considerations

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  1. Flexible Biochemical Manufacturing: Strategic Considerations April 18, 2002 Robert Bottome

  2. (for use with the Nutropin AQ Pen Cartridge) 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

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

  5. Process Map

  6. Process Map

  7. ~Runs / yr* ~Revenues Tanks 4 x 10k ~85 0.7 bn Porriño CHO 12 x 12k ~240 2.4 bn Vacaville CHO 8 x 12k ~160 1.6 bn SSF CHO 2 x 1k ~100 >0.3bn e. coli 400-12k ~20 N/a clinical Filling >200 fills Pack > 200 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. 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

  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

  14. SSF B3 Complex, “4 plants in one” 1: Monoclonal 2 Fermentation 4 Initial Purification 1 Final Purification 2: Lytics 3: Pulmozyme Process Development Raw Materials, Media etc CHO ferm 4: GH E.coli “purification” E.coli & CHO ferm Multi-product purification Utilities

  15. 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

  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 pre-emptive outages.

  20. A A A A B B B B C C C C D D D D E E E Tightly Coupled vs De-coupled COUPLED DE-COUPLED Parallel option Start changeover prior to completing routing

  21. x x x SSF Manufacturing Paradigm Re-configurable skids, product specific—can be changed over in days T2 T1 Skid is isolated from upstream & downstream vessels; little if any automation, interlocks etc System depends on engaged/alert technician to monitor process T3

  22. 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

  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

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