Post on 14-Apr-2017
Use of single-use technology in Aseptic processing of vaccines: Application strategy and validation considerations
Dr. Priyabrata PattnaikTechnical ManagerBiomanufacturing Sciences Network
Vaccine…strong, robust growth in recent years
Industry growth CAGR to 2016
How likely would you adopt a completely integrated pre-assembled disposable Solution?
For Clinical development
Source: Business Intelligence Report, 2010
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
Single use technology -Where in Vaccine Process
Fermentation/Cell Culture Cell Harvest/
Clarification
Finish FillFormulation/Compounding
MediaPreparation
Buffer PreparationSterile
Filtration
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
“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
Regulatory Point of view -Aseptic processing
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
What are the challenges -Balancing Product and Operator
Conflicting requirements on
Design
OperatorsSafety
ProductSafety
EnvironmentSafety
P>0P<0
Closed systemSource: M. Borlet, B. Wichert, R. Soikes, Baxter
Finish & Fill – A high risk operation
Source: James Oliver, 3D risk assesment model, JVT, Autumn 2008, page 70-76.
Vaccine Formulation & Filling Highest level of product integrity and personnel protection
Weighing
Vacuum transfer
Solution make up
Tansfer with canister
port
Avoid aerosols
Low pressure transfer
Guarded Vents
Isolator for filter train
Sampling in closed system
SOP for accidental spillage
Experienced and trained staff
Filter inside/outside isolator
Pre-use integrity test
Control of exposurePPEPersonnel monitoring
P P
Capping
Crimping
100% outer washing
Inspection
Formulation Filling Lyophilization
contained venting
P>0
100% waste decontamination
Total wipe down
P>0
Decontamination
Air monitoring
contained venting
P
Class 10,000 Class 1,000
Fixed SS set-up Multiple connections increase risk….
Source: Nigel Bell, GSK, IBC’s Biopharmaceutical Manufacturing & Development Summit, San Francisco, CA, December 2009
Dr. R Schmidt & H. SchazISPE Annual Barrier Isolation Technology Washington D. C. 1-2 June 2009
Vaccine Formulation & Filling using RABS/Isolator
• 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)
Sterilizing filtration -Post-sterilisation pre- and post- use IT
Filling transfer set to Rab’s/Isolator -Fully closed system for vaccines
Secure Sterile Connection Lynx S2S
Inline sterilizing filtration
improves yield
Closed venting in 2D
bag
Closed filter Integrity test
system
Sterile holding bag
Buffers liquid for accurate filling
Dosing Loop for peristaltic
pump
Test pre-use & line Drainage Liquid
transfer in Class A
DPTE bag
Closed Sampling
La Calhene ported bag
Changing the Paradigm -Single-use Finish & Fill for vaccines
Capping
Crimping
100% vial washing
inspection
Weighing
Solution make up
Low pressure transfer
Guarded Vents
Sampling in closed system
SOP for accidental spillage
Experienced and trained staff
Filter outside isolator
Pre-use integrity test
Control of exposurePPEPersonnel monitoring
100% waste decontamination
Total wipe down
Mixer and Powder Transfer
Air filter for product blow down
Lynx S2S for sterile transfer
For filter flushing
Solvent addition
Air filter for venting during heating
Powder bagIsolator for powder transfer,
70
75
80
85
90
95
100
0 10 20 30 40 50 60 70Time (min)
Turb
idity
(NTU
)
Bottom, Run 4 Top, Run 4 Bottom, Run 5 Top, Run 5Bottom, Run 6 Top, Run 6 Bottom, Run2 Top, Run 2
>48hrs settling
400 rpm200 rpm
570 rpm
Aseptic Alum Mixing Using Mobius Disposable Mixer
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
Validation considerations
• Risk assessment and qualification
– Chemical compatibility– Extractable and leachable– Impact on vaccine safety and efficacy– Bioburden and endotoxin– Stability studies
Pace of turn around…… Rapid response to pandemics
Andrew Sinclair & Miriam MongeBioPharm International, December 2009, pp.34-38
Carbon Footprint
Nigel Bell, sterile product lead,GlaxoSmithKline, Barnard Castle, UK
BioPharm International, February 2010, pp.20-24
Forward looking…..
Nigel Bell, GSK, Barnard Castle, UKIBC’s Biopharmaceutical Manufacturing & Development Summit, San Francisco, CA, December 2009
……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…….
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
Thank You