A Case Study on the Application of Disposable Technologies in cgmp Manufacturing Processes for a Therapeutic Antibody.

Transcription

1 A Case Study on the Application of Disposable Technologies in cgmp Manufacturing Processes for a Therapeutic Antibody. Jeremy M Tong (presenting), Mark S Kettel, Edward M Perry, David J Pain, David M Valentine, Ashley J Westlake, Martin Wrankmore & Michael Brown Lonza Biologics (UK) ACS 227 th National Meeting 2 nd Apr 2004 Presentation Outline Why disposables? Traditional process overview Applications Liners Bio-Process Containers BPCs (Bags) Tube Welding Disposable Bioreactors Harvest Systems Capsule s with BPCs New process overview Benefits & Challenges Acknowledgements Slide 2

2 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 Why disposables? Drivers for use Increased flexibility of operations for wide range of processes Minimisation of plant validation Reduced unit operation times 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 Slide 4

3 Traditional Mammalian Cell GMP Process Flask Flasks Clarification Filters Intermediate Ampoule Feeds Holding Media Preparation Production Concentration Sterile Nalgene Buffer Preparation Final Protein A 2 nd Stage Virus Reduction 3 rd Stage Product Nalgenes Slide 5 Applications - Liners Flask Flasks Clarification Filters Intermediate Ampoule Feeds Holding Media Preparation Production Concentration Sterile Nalgene Buffer Preparation Final Protein A 2 nd Stage Virus Reduction 3 rd Stage Product Nalgenes Slide 6

4 Applications - Liners Replaces medium and buffer make-up tanks Flexible, pre-sterilised open bags Mounted into rigid noncontact reusable containers WFI, Stirrer assembly & additions made through top of liner Mixed solution pumped out Used currently for cell culture medium and feed preparation planned to extend to buffer preparation Slide 7 Applications - Bio-Process Containers (BPCs) Replaces precleaned steel tanks and glass bottles Flexible, presterilised plastic containers 20 to 500L scale Filled bags stored in re-usable containers Used for medium, feeds, buffers & WFI Slide 8

5 Liners & BPCs - Advantages No pre-use cleaning or sterilising of equipment required nor post-use cleaning Significant reduction in both duration and resource requirements Ability to be much more flexible in volumes prepared BPCs easier to use on balances for monitoring amounts used/delivered Storage of filled BPCs much easier and more flexible Has enabled more complex feeding regimes to be used BPCs with integral filters have replaced separate filtration units and multiple stages Creation of a new or expansion of existing media or buffer preparation facility now easier and quicker Slide 9 Liners & BPCs Challenges liners can be easily split by impeller Impeller system must be cleaned Different films used in BPCs by different suppliers and problems when film changes are made Supply chain issues can cause problems especially if wide range of BPCs used Incorrect manufacture (wrong filters, wrong fittings or in incorrect positions) Care with not letting bag out of container BPCs are quite costly Bag splits never happened so far Slide 10

6 Applications - Tube Welding Flask Flasks Clarification Filters Intermediate Ampoule Feeds Holding Media Preparation Production Concentration Sterile Nalgene Buffer Preparation Final Protein A 2 nd Stage Virus Reduction 3 rd Stage Product Nalgenes Slide 11 Applications - Tube Welding Replaces local SIP stainless steel connections Use C flex tubing Hot blade ( 200 C) used to cut tube Jaws re-align tubes such that appropriate connection is made Blade removed and tubing anneals to form sterile seal Used in fermentation and planned for use in purification Slide 12

7 Tube Welder Advantages Tube welder has provided considerable savings Old SIP system took > 1½ h; generated chart trace that required review Tube welder takes 2 min and generates no data for review Far greater flexibility more connections possible Challenges Ensuring weld is good before proceeding Blades expensive Increased use of non-permanent tubing around plant Slide 13 Applications Disposable Bioreactors Replaces two stages of inoculum fermenter hardware Uses disposable bags (each up to 50L capacity) Temperature controlled Bag pressurised by 5% CO 2 in Air (gives ph & DO control) Mixed by rocking motion of bed Used like a large shake flask Slide 14

8 Disposable Bioreactors Comparability 1.0E+7 S200#2 Viable cell concentration (/ml) 1.0E+6 S200#1 S200#4 S200#5 S200#6 Airlift 1.0E Elapsed Time (Hours) Slide 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 Contamination rate very low Challenges Gas filters wetting out Care over cell culture transfers Increased 5% CO 2 in Air gas usage Temperature validation Slide 16

9 Applications - Harvest Systems Flask Flasks Clarification Filters Intermediate Ampoule Feeds Holding Media Preparation Production Concentration Sterile Nalgene Buffer Preparation Final Protein A 2 nd Stage Virus Reduction 3 rd Stage Product Nalgenes Slide 17 Applications - Harvest Systems Replaces multi stage stainless steel harvest system Uses 5 stage filtration process All filters as disposable capsules Concentration step omitted Used for harvest of 200L fed batch fermentation Slide 18

10 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 19 Applications - Capsule Filters with BPCs Flask Flasks Clarification Filters Intermediate Ampoule Feeds Holding Media Preparation Production Concentration Sterile Nalgene Buffer Preparation Final Protein A 2 nd Stage Virus Reduction 3 rd Stage Product Nalgenes Slide 20

11 Applications - Capsule Filters with BPCs Replaces cartridge elements and stainless steel housings Available in wide range of filter areas and capacities Linked to BPCs Used to perform in-process filtrations of product stream In Purification on each filtration step: reduced three process steps to one saved over 2h duration Slide 21 Process Overview Original Process Flask Flasks Clarification Filters Intermediate Ampoule Feeds Holding Media Preparation Production Concentration Sterile Nalgene Buffer Preparation Final Protein A 2 nd Stage Virus Reduction 3 rd Stage Product Nalgenes Slide 22

12 Process Overview Revised Process Flask Flasks Harvest Wave Bioreactor Ampoule Wave Bioreactor BPC BPC Media Preparation BPC Feeds Production BPC Buffer Preparation Final Virus Reduction 3 rd Stage Product Nalgenes Slide 23 Summary of Benefits Process simplification opportunities Increased process robustness Significantly reduced onsite preparation work Reduction in reliance on utilities and services More flexibility Minimises risk of product cross contamination Extensive use of gamma sterilisation Potential for completely disposable process especially upstream disposable downstream systems catching up rapidly Slide 24

13 Ongoing Challenges Reliance on suppliers for both delivery and flexibility in design / customisation Operating disposables under GMP Keeping up with rapid changes in available technologies Balancing increased consumable costs against potential/realised savings in time and resource costs Validation issues what can be taken direct from supplier and what needs completion in house Slide 25 Acknowledgements Lonza Biologics: Co-authors Manufacturing Continuous Improvement Pilot & Scale-Up Support QA & QC Documentation Various Disposables Suppliers Slide 26

14 Thank you for your attention Questions?