Microbial Services Approach to QbD and Process Characterization Case Study

1. Microbial Services Approach to QbD and Process Characterization Case Study World Vaccine Manufacturing Congress Dr. Axel Erler / Lonza Ltd / 12th April 2012

2. “Quality Can BePlanned.” Joseph M. Juran

3. ProcessKnowledge Generation Lifecycleof a Manufacturing Process Phase 3 Phase 2 Tox Phase 1 Commercial Validation Characterization Development Optimization Knowledge Filing Fixed Process Costly post-approvalchanges

4. Lonza`s New Approach toQbDand ProcessCharacterization in Biomanufacturing A model bioprocess with 10 unit operations • Reduced Cost • and Timeline Step1 Step 2 Step 3 Step 4 Step 5 Step 6 Step 7 Step 8 Step 9 Step 10 # experimental runs for process characterization 43-70 43-70 43-70 43-70 43-70 43-70 43-70 43-70 43-70 43-70

5. Key toKeep ProcessCharacterizationCostlowis ... Efficient Multivariate Experimental Strategies

6. Lonza Expandsit`sDoE ToolboxbytheUseofEfficientMultivariate Designs Process SDM Risk Assessment 1. Main-Effect Screening Study 2. Main-Effect Modeling Study No ProcessCharacterization Capability ? Simulation Statistical Model Yes Yes EffectResolution ? 1. Main-Effect Modeling Study ~25 to 50% fewerruns Confirmatory Run(s) New Approach 2. Augmentation Validation No

7. Lonza`s New Approach ReducestheNumberofRequired Experimental Runs

8. Case Study – Formaldehyde Treatment of a Purified Protein Vaccine

9. Formaldehyde Treatment Reaction Formaldehyde in Water (Paraformaldehyde) Formaldehyde + Protein Crosslinkedside chains (Protein aggregates)

10. ProcessRepresentativeScaleDown Models (SDMs)Can BeasSmall as a 50mL Spinner Flask

11. Input Parameters Output 1 2 3 4 5 6 Protein Quencher Temperature Formaldehyde Aggregate Run Pattern Time (h) pH (g/L) (Lysine-HCl, g/L) (°C) / Protein Ratio Level (%) 1 ----+0 0.1 4 40 7.2 39 2.0 2.9 2 +-+-0- 0.2 4 56 7.2 36 1.5 14.9 3 000000 0.15 5 48 7.4 36 2.0 14.4 4 ++0-++ 0.2 6 48 7.2 39 2.5 27.5 5 000000 0.15 5 48 7.4 36 2.0 14.6 6 0+---- 0.15 6 40 7.2 33 1.5 3.6 7 -++0+- 0.1 6 56 7.4 39 1.5 2.5 8 -+-+0+ 0.1 6 40 7.6 36 2.5 8.5 9 000000 0.15 5 48 7.4 36 2.0 14.1 10 +0-++- 0.2 5 40 7.6 39 1.5 22 11 -0+--+ 0.1 5 56 7.2 33 2.5 4.2 12 000000 0.15 5 48 7.4 36 2.0 14.2 13 --0+-- 0.1 4 48 7.6 33 1.5 2.7 14 000000 0.15 5 48 7.4 36 2.0 15.3 15 0-++++ 0.15 4 56 7.6 39 2.5 28.2 16 ++++-0 0.2 6 56 7.6 33 2.0 30.7 17 +--0-+ 0.2 4 40 7.4 33 2.5 31.9 Lonza ContinuouslyExpandsit’sDoEToolboxbytheUseofEfficientMultivariate Designs • Six input parameters  only 17 experimental runs • Three test levels  covers non-linear effects • Five center points  estimates pure experimental error

12. Parameter EstimatesProvideInsightsintoCorrelationsBetweenInput Parameters and Outputs

13. LeveragePlots oftheStatistical ModelIllustrateActualbyPredictedOutput Values Predictionformula

14. Statistical Models Allow ProcessOutput Simulations Including Input Uncertainties Spec • SD = 20% range on everyinputparameter (worstcase) • Assumption: normal distributionforinputuncertainties • Simulation of 10000 batches • Aggregate levelspecification: <25% • Nosinglebatch out ofspecification.

15. Sound ProcessCharacterizationHasSignificantBenefitsforCompliance and Business • Compliance • Identificationofcriticalprocessparameters • Interactions betweencritical variables • Justificationforoperatingspacesandacceptancecriteria • Reproduciblequalityandyields • Business • Improvedbatchsuccessrates • Yieldimprovements • Minimizenumberofprocessdeviations

16. Lonza`s New Approach on ProcessCharacterizationOffersValuableBenefits

17. CaC2

18. Slough, UK Braine, BE Porriño, SP Portsmouth Nansha Singapore Kouřim, CZ Our Sites Are Able to Handle YourDevelopment and cGMP Manufacturing Needs Houston, TX (USA)Viral-Based U.S. Process R&D Group Mid Scale cGMP(up to 2000L) Kouřim (Czech Republic)Microbial FermentationMid to Large Scale cGMP(75L to 75,000L) Houston Visp, CH Hopkinton Hopkinton, MA (USA)Microbial U.S. Process R&D GroupSmall to Mid Scale cGMP(150L to 2800L) Visp (Switzerland)Microbial European Process R&DSmall to Large Scale cGMP(20L to 15,000L) Key Injectables Oral-grade Headquarter in Basel, Switzerland Employs >11,000 people 45 major production and R&D facilities

20. www.lonzavirtualtours.com

21. Our passion is to deliver sustainablevalue to our customers. ...visitwww.lonza.comandmeetusatbooth 39

22. Backup Slides

23. Lonza’s Interconnected Life-sciencePlatform Comprises Four Divisions Life ScienceIngredients Microbial Control Custom Manufacturing Bioscience Development Services Biological Manufacturing Chemical Manufacturing Nutrition Ingredients Performance Intermediates Hygiene & Preservation Water Treatment Materials Protection Personal Care Wood Treatment Therapeutic Cell Solutions Testing Solutions Research Solutions

24. Market Focus in Biopharmaceuticals Vaccines Microbial Viral Protein Therapeutics mAbs/ Fabs ADCs Recombinant proteins Plasmid DNA Enzymes Cellular Therapeutics Regenerative medicine Tissue engineering Gene therapy Viral vectors

25. Our Microbial Sites OfferProximity ofR&D, Scale-up and GMP Manufacturing Hopkinton, MA (USA) Kouřim (Czech Republic) Visp / Lalden (Switzerland) • Employees: ~350 • 40L to 2x 800L • Employees: ~380 • 15m3, 50m3 and 75m3 • Employees: ~3000 • 20L, 50L, 1000L to 2x 15m3 • Activepharmaceuticalingredients • Biopharmaceuticals • Antibodydrugconjugates (ADC) • Peptides and oligonucleotides • Therapeutics and vaccines for multiple indications such as cancer therapy and infectious diseases • Biotransformation • Secondary metabolites • Recombinant / technical proteins • L-Carnitine (CarnipureTM and CarnikingTM)

26. Houston, TX (USA) • Lonza Houston, Inc., Houston, TX • Employees: 20 • Plant/ process: • Processdevelopment • Scale-up • cGMPproduction • Analytical assays • Regulatorysupport • Products: • Viral-basedtherapeutics (viral vectorgenetherapy, viral vaccineapplications)

27. Our R&D Services Create a Foundation for Successful cGMP Operations Strain development and cell banking Fermentation and recovery development Purification and refold development Analytical development Process validation Support services Lonza Development Services • Economically viable processes • Robust, scaleable, flexible and reliable processes • Broad, full-service offering

28. CategoriesofCustomer Projects High Degree of Process Definition Low Technology Transfer Technology Transfer Technology Transfer Technology Transfer Strain Development Fermentation Development Fermentation Development Process Adaptation Purification Development Purification Development Scale-up Scale-up Scale-up Process Demonstration Process Demonstration Process Demonstration Process Demonstration Process Transfer Process Transfer Process Transfer Process Transfer

29. Optimized for use with PER.C6® cell line Serum-free and chemically defined Reduced COGs and time to market due to high cell density(> 90%) and viability Saves validation time No weaning from serum-containing medium required Minimal lot-to-lot variation Permexcis® Virus Production Medium

30. We Have Expertise in All Types of MicrobiallyDerived Products Broad experience • Novel protein therapeutics • Antibodyfragments • Vaccines (recombinant and attenuated) • Cytokines • Growth factors • Interferons • Polysaccharide-protein conjugates • Recombinant peptides • Plasmid DNA • Fusion proteins • PEGylated products • Products requiring BL2

31. Alignedwith 7 Markets

32. Our Hopkinton, MA (USA) Site Multiple Capacities to Meet Your Clinical Needs Location • 26 miles from Boston History • Founded in 1987 • Biopharma CMO since 1997 • Lonza acquired Feb 2007 Key productions • Ontak®, ATryn® and Increlex® cGMP Capacities (total volumes) • 1 x 150L • 1 x 800L • 1 x 2,000L • 1 x 2,800L (over 500 batches produced since 1998)

33. The Facilities at Our Visp, Switzerland Focus on Clinical and In-market Supply Location • 150 km east of Geneva Key facts • Lonza R&D and production center • World’s largest microbial biopharmaceutical facility dedicated to CMO industry • 25-year history in microbial biotechnology • Producing Cimzia® cGMPcapacities (total volumes) • 1 x 20L • 1 x 50L (new) • 1 x 1,000L • 2 x 15,000L • Additional mid- and large-scale expansion planning under way

34. Milestones Short History of Lonza 1969 1971 1983 1897 1965 Expansion into the US; Foundation of Lonza Inc. Start of the biotechnology research activities in Visp (CH) Lonza founded in Gampel (CH) Verbund and Niacin plant in Visp (CH) Commissioning of the naphtha cracker in Lalden (CH)

35. Milestones Short History of Lonza 1996 1984 2003 1992 First, new multi-purpose plant constructed. Opening of the fine chemicals complex in Visp (CH) Commission of the SSP (small scale plant) in Visp (CH). Expansion of the production capacities with two new 15m3 plants for HAPIs (highly active pharmaceutical ingredients) in Kouřim (CZ) Acquisition of Cell-Tech (Lonza Biologics) Acquisition of the Biotec plant in Kouřim (CZ)

36. Milestones Short History of Lonza 2004 2005 2006 Construction of a second Niacinamide plant in China with a capacity of 6000 tons Acquisition of UCB bio-products peptide business. Braine l’Alleud, (BE) Larch arabinogalactanacquisition, Cohasset, MN (USA) Start up of two further 75 m3 biotechnology plants in Kouřim (CZ) Extension of the cGMP mammalian cell culture capacities with three 20’000 liter fermenters in Portsmouth, NH (USA) Start operation of the BPMSS (biopharmaceutical manufacturing small scale) plant with a 1000 liter fermenter and down stream processing at Visp (CH) Sale of Pasadena site, TX (USA)

37. Milestones Short History of Lonza 2007 2007 2006 Acquisition of Genentech’s mid-scale mammalian biopharmaceutical plant (4 x 10’000 liter) in Porriño (ES) Commence construction of the first large scale mammalian cell culture facility in Singapore (4 x 20’000L) Start-up of large-scale microbial manufacturing in Visp (Cimzia for UCB) Acquisition of the research bioproducts business and the microbial biopharmaceutical business of Cambrex

38. Milestones Short History of Lonza 2010 2008 2009 2009 Acquisition of amaxa, a technology leader in cell discovery. Cologne (Germany) is the new product development site for the Research Solutions business of Lonza Bioscience. Acquisition of Vivante GMP Solutions in Houston, TX (USA) a viral-vaccine and gene therapy company to enter the viral-based manufacturing market. Acquisition of MODA Technology Partners for paperless quality-control solutions to strengthen the rapid testing solutions platform. Acquisition of Algonomics NV (Gent, BE) strengthens Lonza‘s technology offering for biopharmaceutical development. Joint venture between TEVA & Lonza (TL Biopharmaceutical Ltd) to develop, manufacture and market a portfolio of biosimilars.

39. Milestones 2011 2011 2011 Continued growth… Acquisition of Arch Chemicals Inc. to build the world’s leading microbial control business. Secondary listing on the Main Board of the Singapore Exchange Securities Trading Limited (“SGX-ST”)