Use of single-use technology in Aseptic processing of vaccines: Application strategy and validation considerations


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Presentation in World Vaccine Congress Asia 2010, Singapore

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Use of single-use technology in Aseptic processing of vaccines: Application strategy and validation considerations

  1. 1. Use of single-use technology in Aseptic processing of vaccines: Application strategy and validation considerations Dr. Priyabrata Pattnaik Technical Manager Biomanufacturing Sciences Network
  2. 2. Vaccine…strong, robust growth in recent years Industry growth CAGR to 2016
  3. 3. How likely would you adopt a completely integrated pre-assembled disposable Solution? For Clinical development Source: Business Intelligence Report, 2010
  4. 4. Disposable Technology in Vaccine Processing: Drivers • New Facility Design • Design, construction, and validation of a GMP biomanufacturing facility – reducing capital expenditures – minimizing the project timeline – increasing operational flexibility – “minimizing operational cost” -Wei Huang, GEN, 2005 Retrofitting Existing Operations – Ease of Use – Flexibility – Reduce Capital expenditure – Changes in process or transfer of new process into facility • New buffer , New media, Process hold volumes increase, etc • Growing spectrum of applications emerge – Mixing, sampling, filtration, bioreactors, transfers, containers etc – In parallel a growing spectrum of components emerge – Engineered solution are evolving from applications and components
  5. 5. Single use technology -Where in Vaccine Process Media Preparation Fermentation/ Cell Culture Cell Harvest/ Clarification Formulation/ Sterile Finish Fill Compounding Filtration Buffer Preparation
  6. 6. Aseptic Applications for Disposable Technologies • Sampling – Aseptic sampling of bioreactors and other sterile vessels • Aseptic product transfer – Transfer of fluids from vessel to vessel • Non sterile to sterile • Sterile to sterile – Transfer of fluids from Class B to Class A filling operations • Sterile Filtration of fluids to and from vessels – Including redundant filtration • Sterile additions to bioreactors or sterile vessels – Antifoam, caustic, innoculum, other small volume additives
  7. 7. Regulatory Point of view -Aseptic processing “The product and all of its contact parts are sterilized separately and brought together under exposed conditions where, if not properly controlled, could result in contamination.” John W. Levchuk, Ph.D CBER, FDA
  8. 8. Regulatory Requirements -Aseptic design “The design of equipment used in aseptic processing should limit the number and complexity of aseptic interventions by personnel…. “ - Avoid manual aseptic connection - Use pre-assembled components - Use pre-sterilized assemblies
  9. 9. What are the challenges -Balancing Product and Operator Operators Product P<0 P>0 Safety Safety Environment Safety Conflicting requirements on Design Closed system Source: M. Borlet, B. Wichert, R. Soikes, Baxter
  10. 10. Finish & Fill – A high risk operation Source: James Oliver, 3D risk assesment model, JVT, Autumn 2008, page 70-76.
  11. 11. Vaccine Formulation & Filling Highest level of product integrity and personnel protection contained Class 10,000 Class 1,000 venting Decontamination contained venting P P P>0 P>0 P Capping Crimping 100% outer washing Air monitoring Inspection Formulation Filling Lyophilization 100% waste decontamination Total wipe down Weighing Avoid aerosols Sampling in closed system Filter inside/outside Control of exposure Vacuum transfer Low pressure transfer isolator PPE SOP for accidental spillage Solution make up Guarded Vents Personnel monitoring Pre-use integrity test Experienced and trained staff Tansfer with canister  port Isolator for filter train
  12. 12. Fixed SS set-up Multiple connections increase risk…. Source: Nigel Bell, GSK, IBC’s Biopharmaceutical Manufacturing & Development Summit, San Francisco, CA, December 2009
  13. 13. Vaccine Formulation & Filling using RABS/Isolator Dr. R Schmidt & H. Schaz ISPE Annual Barrier Isolation Technology Washington D. C. 1-2 June 2009
  14. 14. Sterilizing filtration -Post-sterilisation pre- and post- use IT • Sterilizing filters for air filtration during integrity testing • Flush bags and bags on vent/drain (operator safety) • Gamma-irradiated single-use assembly (efficiency) • Optimized hardware (ease of use)
  15. 15. Filling transfer set to Rab’s/Isolator -Fully closed system for vaccines Closed venting in 2D Sterile holding bag bag Buffers liquid for Test pre-use & accurate filling line Drainage Liquid transfer in Closed filter Class A Integrity test system DPTE bag Inline Closed sterilizing Sampling filtration improves yield Secure Sterile Dosing Connection Loop for peristaltic Lynx S2S pump
  16. 16. La Calhene ported bag
  17. 17. Changing the Paradigm -Single-use Finish & Fill for vaccines Capping Crimping 100% vial washing inspection 100% waste decontamination Total wipe down Weighing Low pressure transfer Sampling in closed system Filter outside isolator Control of exposure PPE Solution make up Guarded Vents SOP for accidental spillage Pre-use integrity test Personnel monitoring Experienced and trained staff
  18. 18. Mixer and Powder Transfer Air filter for venting during heating Solvent addition For filter flushing Isolator for powder Powder bag transfer, Air filter for product blow down Lynx S2S for sterile transfer
  19. 19. Aseptic Alum Mixing Using Mobius Disposable Mixer 100 >48hrs settling 95 Turbidity (NTU) 90 570 rpm 85 80 75 70 0 10 20 30 40 50 60 70 Time (min) 200 rpm 400 rpm Bottom, Run 4 Top, Run 4 Bottom, Run 5 Top, Run 5 Bottom, Run 6 Top, Run 6 Bottom, Run2 Top, Run 2
  20. 20. Design of Single-use Systems • Closed systems (Avoid operator and product exposure) • Limit material handling • Minimise cleaning and decontamination • Optimise product recovery • Assembly designed for operating conditions – Easy-to-use sterile-to-sterile connections – Pre-use integrity testing of filters (post sterilisation) – Tubing fixture – Tubing selection – Closed sampling – DPTE beta-bag integrity and pressure resistance to vacuum/pressure
  21. 21. Validation considerations • Risk assessment and qualification – Chemical compatibility – Extractable and leachable – Impact on vaccine safety and efficacy – Bioburden and endotoxin – Stability studies
  22. 22. Pace of turn around…… Rapid response to pandemics Andrew Sinclair & Miriam Monge BioPharm International, December 2009, pp.34-38
  23. 23. Carbon Footprint Nigel Bell, sterile product lead, GlaxoSmithKline, Barnard Castle, UK BioPharm International, February 2010, pp.20-24
  24. 24. Forward looking….. ……confirms that the benefits seen in bulk API manufacture also are realized in vaccine fill–finish facility, specifically with regard to reduced costs, reduced energy usage, and reduced labor. Based on the outcomes of this case study, the future for disposables use in the final filling arena has significant potential to simplify process operations……. Nigel Bell, GSK, Barnard Castle, UK IBC’s Biopharmaceutical Manufacturing & Development Summit, San Francisco, CA, December 2009
  25. 25. Conclusions • Application of Disposable Technology to Vaccine is Growing Rapidly • Product and operator safety present conflicting facility and equipment design challenges • There is increasing regulatory and occupational safety oversight • Adoption of single-use technologies can help alleviate some of these concerns
  26. 26. Thank You