This document discusses the use of single-use technologies in aseptic processing of vaccines. It notes the growing adoption of these technologies driven by factors like new facility design, retrofitting existing operations, and a growing range of applications. Some key challenges with balancing product and operator safety are discussed. The document also covers regulatory requirements and considerations for validation of these systems. Examples of using single-use technologies for activities like formulation, filling, filtration and powder handling are provided.

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. Vaccine…strong, robust growth in recent years
Industry growth CAGR to 2016

3. How likely would you adopt a completely integrated
pre-assembled disposable Solution?
For Clinical development
Source: Business Intelligence Report, 2010

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. Single use technology
-Where in Vaccine Process
Media
Preparation
Fermentation/
Cell Culture Cell Harvest/
Clarification
Formulation/ Sterile Finish Fill
Compounding Filtration
Buffer Preparation

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. 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. 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. 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. Finish & Fill – A high risk operation
Source: James Oliver, 3D risk assesment model, JVT, Autumn 2008, page 70-76.

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. Fixed SS set-up
Multiple connections increase risk….
Source: Nigel Bell, GSK, IBC’s Biopharmaceutical Manufacturing & Development Summit, San Francisco, CA, December 2009

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. 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. 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. La Calhene ported bag

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. 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. 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. 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. Validation considerations
• Risk assessment and qualification
– Chemical compatibility
– Extractable and leachable
– Impact on vaccine safety and efficacy
– Bioburden and endotoxin
– Stability studies

22. Pace of turn around……
Rapid response to pandemics
Andrew Sinclair & Miriam Monge
BioPharm International, December 2009, pp.34-38

23. Carbon Footprint
Nigel Bell, sterile product lead,
GlaxoSmithKline, Barnard Castle, UK
BioPharm International, February 2010, pp.20-24

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. 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. Thank You