A CMO s View on Platform Technologies

Transcription

1 Pharma&Biotech A CMO s View on Platform Technologies A3P BioProduction 2013 BioPurification, Lyon, France Louise Elise-marie Ingram/ Seng Lonza /, Basel Biologics / 10. Mai / Jun 13

2 Disclaimer Certain matters discussed in this presentation may constitute forward-looking statements. These statements are based on current expectations and estimates of Lonza Group Ltd, although Lonza Group Ltd can give no assurance that these expectations and estimates will be achieved. The actual results may differ materially in the future from the forward-looking statements included in this presentation due to various factors. Furthermore, Lonza Group Ltd has no obligation to update the statements contained in this presentation. 2

3 Lonza Overview Life sciences driven company Headquartered in Basel (Switzerland) Sales of CHF billion in 2011 Global operations: 45 major production and R&D facilities Employs over 11,000 people Global leader in microbial control and custom manufacturing: Hygiene Water treatment Active pharmaceutical ingredients both chemical and biological Cell therapy Leading positions in product market niches: Endotoxin detection Cell-based research products Nutrition ingredients Performance intermediates 3

4 Our State-of-the-art Slough (UK) Site Is for Pre- and Early Clinical Supply Location 11 miles from Heathrow airport Footprint 105,000 sq. ft. (cgmp) 55,000 sq. ft. (PD) Track record cgmp since 1983 Capacities 2 x 200L (Airlift) 1 x 500L (Stirred) 1 x 800L (Stirred) 1 x 1,000L (Single-use) 2 x 2,000L (Airlift) Associated purification suites Notes Designed for multi-product concurrent manufacturing 4

5 We Have Mammalian Production and Development Sites on 3 Continents Portsmouth, NH (USA) Mammalian cell culture 1,500L to 20,000L cgmp Walkersville Hopkinton Portsmouth Riverside Verviers, BE Slough, UK Braine, BE Porriño, SP Porriño (Spain) Mammalian cell culture 4 x 10,000L cgmp Slough (UK) Mammalian cell culture 200L to 2,000L cgmp Process R&D Services Kouřim, CZ Visp, CH Nansha Singapore Tuas (Singapore) Mammalian cell culture 200L to 20,000L cgmp Process R&D Services 5

6 Presentation Overview 1. Platform Processes 2. Platform Technologies; enable platform processes 10yr evolution 3. Efficiency in Execution Buffer Consumption (L) 50,000 45,000 40,000 35,000 30,000 25,000 20,000 15,000 10,000 5, Fermentation Titre (g/l) 6

7 What Is a Platform Process? 1. Pre-defined sequence of unit operations 2. Requires minimal process development of critical parameters 3. Minimum variation of raw materials and steps into operations Optimization of cost of goods. Stability studies on process intermediates. Full evaluation of polishing steps. Process specific virus validation study is required. 7

8 DSP Platform Evolution, Round 1 Primary goal Eliminate gel filtration Process & technology Cation exchange 8

9 Evolutionary Pressures on DSP Processes Antibody Concentration (mg/l) H11 GS-CHO from CHOK1 host LB01 - GS-CHO from CHOK1SV host CY01 clone of LB H11 orig H11 v1 22H11 v2 LB01 v2 LB01 v3 LB01 v4 LB01 v5 CY01 v Titres of 3-6g/L now routine at clinical phase GMP manufacturing 4x20kL bioreactors in both Portsmouth & Singapore 9

10 Mid 2000 s, the DSP Bottleneck Consider a 5 fold increase in fermentation titre from 1 to 5g/L with no change in Downstream Technology 1. Significant increase in time required for purification Reduced number of batches per annum, inflated COG/g 2. Significant increase in raw materials e.g. Four fold increase in buffer consumption Fermentation Titre (g/l) Time In Purification Target Batch Length Buffer Consumption (L) 50,000 45,000 40,000 35,000 30,000 25,000 20,000 15,000 10,000 5, Fermentation Titre (g/l) 10

11 Limitations of Compressible Media. Reduced processing speed. 11

12 Increasing Titres at low binding capacities, Massive Demand for Buffer 12

13 Impact on Global Manufacturing Base 13

14 DSP Platform Evolution, Round 2 Primary goals Alleviate DSP bottleneck Processing time Buffer demand Increase process safety Process & technology Less compressible matrices Higher binding capacities Faster flowrates Small pore virus filtration 14

15 Chromatography Platform Change (Protein A) 40 (A) (B) 30 MabSelect ProSep 700A Dynamic Binding Capacity (g/l) (C/Co=0.01%) (C) 2.0 g/l 0.5 g/l POROS 50A (D) ProSep 1000A 2.0 g/l 0.5 g/l rmp.proa Hyper D F Immunoglobulin binding domains g/l 0.5 g/l 2.0 g/l 0.5 g/l Ss E D A B C XM Residence Time (min) Gly29Ala mutation MabSelect MabSelect SuRe Z domain 15

16 Impact of Rigid Matrices & VRF changes on DSP Time Rigid matrices across 3 steps rmp Protein A to MabSelect & SuRe Q Sepharose to CaptoQ/HyperD SP Sepharose to CEX/HIC/CHT 16

17 Impact of Rigid Matrices, Higher DBCs on Buffer Demand 2x Reduction 17

18 Traditional Buffer Preparation-GMP Production 18

19 Single Use Buffer Prep Pilot Plant, Non-GMP Existing laboratory space, retrofitted with 4*600kg balances and overhead lightning mixers Volume (L) ph (-) Conductivity ms/cm Time (min) 0 19

20 Traditional vs. Single Use Buffer Prep Stainless Buffer Prep 98 m L/m 2.day-maximum Disposable Buffer Prep 41m L/m 2.day-expandable Pros Near closed system Rapid pressure filling of bags Cons Ageing CIP system Inflexible Tank schedule conflicts 1000L tank most heavily utilized Room dedicated to buffer prep Pros Highly flexible L make-up No single balance over-utilized No CIP, no complicated instructions Rapid tank turnaround Cons Slow bag filling (<20L/min) Open system! Retrofitted room, WFI take-off locations and heights not optimum for prep tanks Not bottom draining 20

21 Disposables Bags Impact of rising titres and process complexity on buffer demand in downstream processing Buffer demand for 12h Protein A recovery operations (2000L batch, 3g/L titre) 1 x 500L 0.1M NaOH 2 x 500L Equil + PLW1 + PLW3 1 x 500L Strip (PEW) 1 x 500L PLW2 2 x 500L Load 1 x 500L Elution buffer 2 x 500L Flowthrough 1 x 500L Elution waste 1 x 500L Levtech Eluate 8 different solutions, 6000L/12h! 21

22 Intermediate Product Storage in Bags 22

23 Batch Length Always Exceeds Purification Time! Discuss Value Added 3kg 3 step process Value added Purification time (h) 25/09/ /09/ /09/ /10/ /10/ /10/ /10/ /10/ /10/ /10/2006 Non value added Setup/Tear down Hold/Wait/Delay Types of Waste Defects Over Production Transportation Movement Waiting Inventory Over Processing One example 19 days to complete 59h purification 13% value added purification work 23

24 Single Use Chromatography Column and Flowpaths (AKTA Ready) Reduced validation No cleaning chemicals No utilities - water Reduced turnaround time (75% per step) Reduced cross contamination risk 24

25 Integrated systems, reducing setup/tear down time Offshelf systems replacing bespoke, one off setups. Increased reliability, standardisation 25

26 DSP Platform Evolution, Round 3 Primary goals Alleviate DSP bottleneck Focus; v.high titre Processing time Hours and days Buffer demand Process & technology Membrane filtration Focused step optimization Binding capacities 26

27 Membrane Chromatography Functional groups are on inner walls of cross-linked cellulose network Open pores and accessible ligands mean that there is negligible diffusion required for binding; convection is the rate limiting factor No need to pack and test a chromatography membrane plug and play Disposable - no post-use cleaning validation of large chrom columns Convection Diffusion a b Ideal for flow through polishing of impurities Reduced buffer consumption Higher flow rates are possible due to larger pores allows much faster processing than packed beds 27

28 Loading Capacity for Q Membranes For some IgG >3,000 mg/ml capacities are possible Load HCP = 952 ng/mg Host Cell Protein (ng/mg) Loading Capacity (mg/ml) 28

29 Membrane Chromatography High Capacity, Small Size! Bed volume 3 ml = 6 g/cycle for 2,000 g/l capacity Bed depth 8 mm15 ml/min (5BV/min) Bed volume 0.08ml Bed depth 4mm 0.4ml/min (5 BV/min) Two 2 units in series 8 mm bed height, 0.16 ml = 320 mg/cycle for 2,000 g/l capacity 29

30 Impact of Membrane Chromatography on DSP Time 30

31 Impact of Membrane Chromatography on Buffer Demand 2x Reduction 2x Reduction 31

32 Platform Processes and Technologies Must Be Fast to develop Capable at scale 32

33 Near Future-refining the platform Next Gen Protein A? Next Gen Virus Filtration 33

34 Conclusions Platform Processes established Well established, maturing Behaves predictably with outliers! Platform Technology adoption is increasing Disposables, bags, filters, columns, membranes Integrated systems; mixing, filtration, UF Execution, competitive advantage Rapid development GMP Production. 34

35 Acknowledgments Lee Allen Jim Davies Abdel Zemmar Samit Patel Mardon McFarlane Lyndsey Morse Lonza Purification Development 35