Recent Developments & Future Directions in the Production of Monoclonal Antibodies. Rob Noel Plasma Product Biotechnology Conference 2009, Menorca

Transcription

1 Recent Developments & Future Directions in the Production of Monoclonal Antibodies Rob Noel Plasma Product Biotechnology Conference 2009, Menorca

2 Forecast sales by molecule type ($m), ,000 Pharmaceuticals (Predicted Sales by Molecule Category) 500, , , , , Vaccine Monoclonal antibody Therapeutic protein Small molecule Datamonitor Monoclonal Antibodies Report 2007

3 Biopharmaceuticals Product Class Products Products Revenue ($million,2006) Recombinant proteins (rdna) ,300 Vaccines ,000 Blood derived Products (human and animal) ,000 Monoclonal antibodies, rdna 30 24,000 Enzymes (excluding rdna) Borderline/grey biopharmaceuticals Interferons (most rdna) 14 7,200 Cancer Monoclonal antibodies, rdna 13 10,700 Factor VIII and IX, rdna 13 4,500 Monoclonal antibodies, non rdna Erythropoietin (EPO) products 11 11,000 Insulin Products (essentially all rdna) 11 8,000 Cultured cells/tissues Enzymes for replacement therapy 7 1,700 Tumor Necrosis Factor antibodies, rdna 4 10,300 Botulinum Toxins 4 1,050 Granulocyte colony Stimulating factors (G CSF) 3 4,300 BioPlan Associates, Fifth Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production, April

4 Biopharmaceutical Pipeline Stage # Investigational Percent of Total New Drugs Pre Clinical/ Discovery 5, % Phase I / IND Filed 1, % Phase II 1, % Phase III % NDA / BLA Filed % Product Launched % Worldwide Pipeline, Large Molecules, by Therapeutic Area, 2008 Source: BioPharm Insight, February

5 Market Variables Effecting Manufacturing Operations Blockbuster Mabs Patient Screening Orphan Drug Biosimilars Emerging Markets Waning targets, competition, benefit/risk ratio too low increase benefit/risk for failed Mab s, improve success rate, open up new targets sub populations?, active development of 300 drugs (7000 indications identified) more rapid than predicted, now inc. CMO s...and manufacturing facilities 5

6 Market Variables Effecting Manufacturing Operations Blockbuster Mabs Patient Screening Orphan Drug Biosimilars Emerging Markets 1000kg/a dedicated facilities will be few 100kg/a multiproduct facilities, flexibility in manufacturing Rapid, low cost development, multiple expression platforms Multiple product facilities, high utilisations, cost efficiencies Transferable manufacturing technologies, cost efficiencies, update design 6

7 Current Manufacturing Trends Cost Economies Yield / Throughput / Facility Fit Increased cell productivities & viability (titre) Reduction in unit operations Use of more rigid, highcapacity adsorbents Disposable unit operations 7

8 Current Manufacturing Trends Cost Economies Process integration Eliminate UF/DF buffer exchange & concentration step, hold tanks. On line dilution replaces buffer preparation Use of Process Analytical Technology Continuous operations 8

9 Current Manufacturing Trends Speed to Market Platform process(es) Transfer ability Greater understanding of the manufacturing process (Quality by Design, Process Analytical Technologies) Faster understanding of the process (Robotics / Data Analysis / Directed Evolutionary Algorithms) 9

10 Cost Efficiencies Modelling Unit Operation Yield Passage 1 100L Seed Passage L Seed 10,000L Production Bioreactor Centrifugation 90% 95% Depth Filtration 90% Affinity Chromatography 95% Virus Inactivation 98% Ion Exchange Chromatograhy 90% 95% Viral Filtration 98% Polishing Chromatography 95% UF/DF#3 95% Sterile Filtration 98% DSP overall yield 59% Fermenter Volume 10,000 L Product Titre 1.00 g/l Annual quantity of 1 MAb product 300 kg/yr Annual number of MAb products 1 #/yr Product changeover time 14 days Cost of Capital 12% % Future Value 10% % Period 8 yrs 10

11 Cost Efficiencies Modelling Throughput # of Bioreactors 5x 10000L bioreactors Batches per campaign 51 #/campaign Product mass per batch 5.9 kg/batch Product mass per campaign 300 kg/campaign Capital Total 118,923,340 $ Per litre of bioreactor 2,378 $/L CoG Cost per batch 851,687 $/batch Cost per gram 145 $/g Water (L/Batch) PW WFI Total % Process 0 25,813 25,813 25% Cleaning 51,389 26,212 77,601 75% Total 51,389 52, , % 11

12 Cost Efficiencies Type Description % of COW Cost ($) Equipment Fixed equipment 20,147,321 Subtotal 100% 20,147,321 Sub contract Installation 38% 7,555,245 Pipework 55% 11,081,027 HVAC 40% 8,058,928 Instrumentation and Control 87% 17,600,924 Electrical Power 25% 5,036,830 Process Utilities 3% 604,420 Building 75% 15,110,491 Fit out 14% 2,896,177 Subtotal 67,944,042 Cost of Works (COW) 100% 88,091,363 Other Validation 15% 13,213,704 Fee 20% 17,618,273 Base Project Total 118,923,340 Annual Annuity Charge $/year 24,906,487 BioPharm Services 12

13 Cost Efficiencies Bioreactor Mab Titre 200 Cost of Goods ($/g), including capital depreciation % centrifugation yield, 95% depth filtration, 45g/L MAbSelect PrA 95% centrifugation yield, 95% depth filtration, 45g/L MAbSelect PrA MAbDirect, 35g/L Titre (g/l), 300kg/annum 13

14 Yield & Throughput & Facility Fit 5 10 kg 10,000L bioreactor, up to 1g/L Downstream Processing 10,000L bioreactor, up to 10g/L Downstream Processing 14

15 Effect of Reducing Number Operational Units Increased yield Simpler PD/ process (facility & operations) Reduced CapEx & OpEx Increased throughput of product / products (facility utilisation) Lower burden of QC/QA 15

16 Mab Downstream Processing Bioreactor (Floculation) Centrifugation Depth Filtration Sterile Filtration Microfiltration UF/DF 1 Protein A Capture Ion exchange Low ph hold & ph adjustment & sterile filtration 2 Ion exchange Hydrophobic / Mixed Mode Ceramic Hydroxyapetite 3 4 Ion exchange Hydrophobic (SEC) Viral Filtration UF/DF Formulation 16

17 Mab Downstream Processing Bioreactor (Floculation) Centrifugation Depth Filtration Sterile Filtration 1 Protein A Capture Low ph hold & ph adjustment & sterile filtration 2 SP Ion exchange 3 Q Ion exchange Viral Filtration UF/DF Formulation 17

18 Downstream Processing Bioreactor (Floculation) Centrifugation Depth Filtration Sterile Filtration 1 Protein A Capture Low ph hold & ph adjustment & sterile filtration 2 Q Ion exchange Viral Filtration UF/DF Formulation 18

19 High Throughput Screening Bioreactor (Floculation) Centrifugation Depth Filtration Sterile Filtration 1 Protein A Capture Low ph hold 2 Q Ion exchange Viral Filtration UF/DF Formulation 19

20 High Throughput Screening/ Data Analysis Process Robustness Quality by Design (QbD) (+ Process Analytical Techniques, PAT) Fast Process Development supported by directed evolution systems 20

21 Manufacturing Cost Efficiencies MAb Manufacturing Cost ($/g) kg/a 50 60% yield 0.5 3g/L cell titre day UPS 4 6 days DSP 1000kg/a 80% yield 3 10g/L cell titre day UPS 2 4 days DSP

22 Direct Capture For Monoclonals Centrifugation or Microfiltration Depth filtration Fine/Sterile filtration Packed bed Protein A 22

23 Bioreactor Titres & Clarification Percivia.com Depth Filtration Sterile Filtration Chromatography +10g/L IgG Large amount of sticky insolubles Clarification results in yield losses (5 10%) 23

24 Direct Capture For Monoclonals Centrifugation or Microfiltration Depth filtration Fine/Sterile filtration Packed bed Protein A 24

25 Direct Capture For Monoclonals 2 nd generation expanded bed adsorption 25

26 CURRENT DISPOSABLE PRODUCTION UNITS Stedim Inc., Hyclone Media Preparation Buffer Preparation Buffer Storage & Handling F F F Fermentation Cell Removal Sterile Filtration Millipore, Sartorius, Pall Chromatographic Step1 (CAPTURE) Chromatographic Step 2 Wave Biotech, Xcellerex Inc. Freeze/Thaw Storage/Shipping Stedim Inc./IBC STERILE LINKS Millipore, Sartorius, Pall Disposable Component Available Not disposable Chromatographic Step 3 Nanofiltration Millipore, Sartorius, Pall 26

27 CURRENT DISPOSABLE PRODUCTION UNITS Stedim Inc., Hyclone Upfront Chromatography GE Healthcare Tarpon Natrix Disposable Component Available Not disposable Media Preparation Buffer Preparation Buffer Storage & Handling F F F Fermentation Cell Removal Sterile Filtration Millipore, Sartorius, Pall Chromatographic Step1 (CAPTURE) Chromatographic Step 2 Chromatographic Step 3 Nanofiltration Wave Biotech, Xcellerex Inc. Freeze/Thaw Storage/Shipping Stedim Inc./IBC STERILE LINKS Millipore, Sartorius, Pall Millipore, Sartorius, Pall GE Healthcare Tarpon Other pre packed 27

28 CURRENT DISPOSABLE PRODUCTION UNITS Single Use... Single Campaign.../...Single Product Cleaning in place Steam in place CIP validation Storage conditions Packing/re packing Set up time 28

29 BioPlan Associates Fifth Annual Report and Survey of Biopharmaceutica l Manufacturing Capacity and Production, April

30 BioPlan Associates Fifth Annual Report and Survey of Biopharmaceutica l Manufacturing Capacity and Production, April

31 BioPlan Associates Fifth Annual Report and Survey of Biopharmaceutica l Manufacturing Capacity and Production, April

32 Future Directions Accelerated Development Pharmaceuticals Programme (DARPA, US Government) From DNA to 3 million doses in 12 weeks <$1/dose subunit vaccine <$10/dose passive immunisation antibody Flexible facilities disposable manufacturing Economics 100% facility utilsation (single product) Development Speed platform USP process (microbial) Common molecular attributes (Fc) Fast process characterisation tools Min. No of unit ops, integrated, maintain low volumes 32

33 THANK YOU FOR YOUR ATTENTION