Application of Disposable Technologies in Biopharmaceutical Manufacturing

Transcription

1 BMD Summit, Disposables for Biopharm Production 13th December 2005 Reston, VA, USA Application of Disposable Technologies in Biopharmaceutical Manufacturing Martin Wrankmore, Continuous Improvement Lead, Lonza Biologics plc., Slough (UK)

2 Presentation Outline Why choose disposables? Traditional process overview Disposables in upstream processing Tank liners Bio-process containers BPCs (bags) Tube welding Disposable bioreactors Disposable harvest systems Disposables in downstream processing BPCs New process overview Benefits & challenges Acknowledgements slide 2

3 What Does Lonza Do? LonzaGroup Swiss based life sciences driven company Custom manufacturer of active chemical ingredients, intermediates and biotechnology solutions to the pharmaceutical and agrochemical industries Lonza Biologics Custom manufacturer of therapeutic monoclonal antibodies and recombinant proteins from mammalian cell cultures making bulk API Operations range from cell line construction and process development to large scale manufacturing and regulatory support Sites in Slough (UK) & Portsmouth (NH, USA) slide 3

4 Why Choose Disposables? Drivers for use Increased flexibility of operations Minimisation of plant validation Ability to change processes quickly Advantages No cleaning requirements No sterilisation procedures needed before use Fast preparation (often none) & ease of use No product carryover/contamination risk Considerations Costs Extractables issues Reliance on external supply chain Connectivity to current systems slide 4

5 Traditional Mammalian Cell GMP Process Flask Flasks Clarification Filters Intermediate Filtration Ampoule Inoculum Fermenter Feeds Holding Mixing Tank Inoculum Fermenter Holding Tank Media Preparation Production Fermenter Concentration Sterile Container 5±3 C Holding Mixing Tank Buffer Preparation Final Filtration Protein A Chromatography Concentration / Dia-filtration 2 nd Stage Chromatography Virus Reduction Filtration Concentration / Dia-filtration 3 rd Stage Chromatography Concentration / Dia-filtration Product Container In Process Filtration In Process Filtration In Process Filtration In Process Filtration In Process Filtration In Process Filtration In Process Filtration 5±3 C slide 5

6 Upstream Processing Traditional Inoculum Fermenter Feeds Holding Mixing Tank Inoculum Fermenter Media Preparation Production Fermenter Steel tanks CIP SIP Steel reactors CIP SIP Steel reactors SIP connections Glass / steel addition vessels slide 6

7 Applications - Tank Liners Replaces medium and buffer preparation tanks Flexible, pre-sterilised bags Mounted into rigid non-contact reusable containers Stirrer assembly, WFI & additions made through top of liner Mixed solution pumped out slide 7

8 Applications - Bio-Process Containers (BPCs) Replaces pre-cleaned steel tanks & filter housings, glass bottles and tubes Flexible, pre-sterilised plastic containers 50mL to 500L scale Used for storing media, feeds, buffers in-process sample collection slide 8

9 Tank Liners & BPCs - Advantages No pre or post use cleaning or sterilising of equipment required Significant reduction in both duration and resource requirements for media / buffer preparations Ability to be much more flexible in volumes prepared Storage of filled BPCs much easier and more flexible than in steel tanks / glass bottles BPCs can be used on weigh scales for monitoring amounts used Has enabled more complex feeding regimes to be used BPCs with integral filters have replaced separate filtration units and multiple stages Reduce time needed to sample reactors and remove need to prepare sampling devices in VLFC slide 9

10 Tank Liners & BPCs Challenges Tank liners can be easily split by impeller Impeller system must be cleaned Different suppliers use different film materials which can cause compatibility problems and additional validation requirements Supply chain issues can cause problems especially if a wide range of BPCs used Incorrect manufacture of bag assemblies (wrong filters, wrong fittings or incorrect tubing sizes) can cause production issues Non-integral BPCs allowing process fluids to leak slide 10

11 Applications - Tube Welding Replaces multiple SIP stainless steel connections Use C-flex tubing Hot blade ( 200 C) used to cut tube Jaws re-align tubes allowing connection to be made Blade removed and tubing anneals to form sterile seal Used in fermentation for manifold & sample bag connections and connections to disposable reactors slide 11

12 Tube Welding Advantages Tube welder has provided considerable time savings Old SIP system took 1 h Tube welder takes 5 min Greater flexibility more connections possible Challenges Ensuring weld quality is good Blades expensive Increased use of non-permanent tubing around plant May increase number of operations slide 12

13 Applications Disposable Bioreactors Replaces two stages of inoculum fermenter hardware Uses disposable bags (each up to 50L operating capacity) Temperature controlled Bag pressurised by 5% CO 2 in air (gives ph & DO control) Mixed by rocking motion of unit Used like a large shake flask slide 13

14 Disposable Bioreactors Comparability 1.0E+7 S200#2 Viable cell concentration (/ml) 1.0E+6 S200#1 S200#4 S200#5 S200#6 Airlift Inoculum 1.0E Elapsed Time (Hours) slide 14

15 Disposable Bioreactors Advantages Preparation times reduced from 3 or 4 days to less than one Can be used as production system with multiple bags in parallel More flexibility in operational volumes Low contamination rate Challenges Multiple bags require additional sampling / additions Additional care required for cell culture transfers Increased CO 2 gas usage Temperature validation slide 15

16 Upstream Processing T r a d it i o n a l Holding Mixing Tank Media Preparation Inoculum Fermenter Inoculum Fermenter Feeds Production Fermenter Materials: steel, glass Cleaning: CIP Sterilisation: SIP Connections: SIP D is p o sa b le Disposable Bioreactor BPC Disposable Bioreactor BPC Feeds Materials: plastic Cleaning: (impeller) Sterilisation: n/a (on-site) Connections: tube weld Media Preparation Production Fermenter slide 16

17 Upstream Processing T r a d it i o n a l D is p o sa b le slide 17

18 Harvest Systems Traditional Clarification Filters Intermediate Filtration Holding Tank Sterile Container Concentration Steel vessels / housings CIP SIP Fitting of filters Plastic containers Autoclaved Connection of filters slide 18

19 Applications - Harvest Systems Replace stainless steel harvest system Uses multiple stage filtration process Filters supplied in disposable capsules Concentration step omitted Used for harvest of fed batch fermentations slide 19

20 Harvest Systems Advantages Removes need for several days of preparation prior to harvest More flexibility in harvest timing Greater capability to increase filter area if unexpected blocking occurs Process can be visually monitored more easily Challenges Diluted purification process stream Consumable costs high slide 20

21 Harvest Systems T r a d it i o n a l Clarification Filters Holding Tank Concentration Intermediate Filtration Sterile Container Materials: steel / plastic Cleaning: CIP Sterilisation: SIP / autoclave On-site prep: fitting filters Harvest Filtration D is p o sa b le BPC Materials: plastic Cleaning: n/a Sterilisation: n/a (on-site) On-site prep: system assembly slide 21

22 Harvest Systems T r a d it i o n a l D is p o sa b le slide 22

23 Downstream Processing Traditional Holding Mixing Tank Holdi Load Tan ng Tank k Mobile Tank Buffer Preparation & Storage Protein A Chromatography Holdi Eluate Tan ng Tank k In Process Filtration Product Containers Steel / glass / plastic vessels & housings CIP SIP Autoclaving slide 23

24 Downstream Processing Advantages Flexibility Product Concentration (mg/l) Reactor Product Concentration Elapsed Time (h) ? Rapid response to increased product concentrations from the cell culture process Larger buffer volumes Larger columns Larger eluates from columns slide 24

25 Summary of Benefits Process simplification opportunities Increased process robustness Significantly reduced on-site preparation work Reduction in reliance on utilities and services More flexibility Minimises risk of product cross contamination slide 25

26 Ongoing Challenges Keeping up with rapid changes in available technologies Lack of industry standardisation Balancing increased consumable costs against potential / realised savings in time and resources Validation issues what can be taken direct from supplier and what needs completion in-house Reliance on suppliers for both delivery and flexibility in design / customisation slide 26

27 Acknowledgements Lonza Biologics: Manufacturing Pilot & Scale-Up Support Documentation QA & QC Continuous Improvement Various disposables suppliers slide 27

28 Thank you for your attention Questions?