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Cell culture based vaccine production :Engineering Bottlenecks
Etienne Malhaize,
Director of Technical Service – Process Biotech.
Cell culture based vaccine production :Engineering Bottlenecks
Etienne Malhaize,
Director of Technical Service – Process Biotech.
NAE/IOMConference April 10 th , Vaccine production : Potential Engineering Approach to a Pandemic
AgendaAgenda
GSK Biologicals Flu approach Introduction to vaccine manufacturing process
Engineering approach to a pandemic : – The request :
• « Please, build a 100 MM dose/y Flu Pandemic facility… »
– The context : • Cell culture technologies • GMP and Biosafety Level 3 (BL3)• Qualification
– The standard timing for a new vaccine facility
– The opportunities to reduce timing
Product streams
• Classical flu vaccine: egg derived
• Classical flu vaccine: adjuvanted formulation
• Tissue Culture
• Pandemic
Flu approach in GSK BiologicalFlu approach in GSK Biological
Hamilton
Rixensart
Shanghai
Singapore
Dresden
Egypt
Gödöllö Moscow
St. Amand les Eaux
Nashik
Brazil
Marietta
(Asia Pac)
Wavre
Alliances
JV’s
Affiliates
QuebecMontreal
GSK BiologicalsGSK Biologicals
Global Industrial Operations NetworkGlobal Industrial Operations Network
Improved Flu Vaccine for elderly
using adjuvant
Build egg-based critical mass: • Dresden (60 m doses) • ID Biomedical (75 m doses)
Introducing a new cell-culture based
production (~2010)
GSK Positioned to be a Flu Vaccine LeaderGSK Positioned to be a Flu Vaccine Leader
Extensive preparationsfor pandemic flu
Developing new delivery systems
IntroductionIntroduction
Typical vaccine production process :Typical vaccine production process :
PACKAGING
FORMULATIONBULK
Antigen 1
Antigen 2
Antigen 3
Adjuvant
FILLING
The request The request
« Please, build a 100 MM dose/y facility for Flu-pandemic »« Please, build a 100 MM dose/y facility for Flu-pandemic »
Question 1 – What does a « dose » mean ? – Is it 100 µg , 10µg, 1 µg…?
Nobody knows…and unfortunately, first clinical trials on H5N1 demonstrate poor immune response compared with classical seasonal Flu-vaccine.
Question 2– How Engineering can help ?
Design and build Flu facilities as « flexible » as possible for both
Antigen and Adjuvant Bulk production.
– modular design approach
Learning 1 :Learning 1 : We need to buildbefore clinical results are completed
Risk : Potential impact: -Capacities-Budget-Timing
µ-carriers Cells are anchorage dependent
and are growing on µ -beads
High antigen yields (Y=5) Typical size : 1.000 L
Majors challenges– Shear stress and mixing– Sub passages – Continuous fresh culture
media perfusion (often 3 days)
Free cell suspension Cells are growing on a free suspension
Low antigen yields (Y=1) Typical size : 5.000 L
Major challenges– Bigger volumes – Longer cell culture lead time.
The context : The context :
Cell culture : µ-carriers or free suspension ? Cell culture : µ-carriers or free suspension ?
Question 3 : « What will be the impact of cell culture technology on design ?»
The context : The context :
Impact of cell culture on equipment and facility design Impact of cell culture on equipment and facility design
µ-carriers cell culture Free cell suspension culture
Tank(CIP/SIP)1x 3000L
MediaTank(in use)1x 3000L
Footprint unit in Media Prep. Area
Fermented1x1000L
Fermented1x1000L
Fermented=Harvest tank1x5000L
Harvest tank1x3000L
Footprint unit in Cell Culture room
MediaTank(in use or in SIP/CIP)1x 1000L
MediaTank(in use or in SIP/CIP)1x 5000L
µ-carriers Free cell suspension
6Footprint (in unit for one train) 4
6
6
~4mCeiling height(in meters)
~3m
~6m
~6m
Learning 2 :Learning 2 : Depending on the cell culture technology , the equipment and facility design can dramatically change…then, build very flexible !
The context :The context :
Impact of cell culture on equipment and facility designImpact of cell culture on equipment and facility design
Media Prep. Area
Cell Culture room
2 x 3000LMedia tank (by train)Fermented (by train)Harvest tank (by train)
1 x 1000L1x1000L + 1x5000L1x1000L + 1x5000L
1 x 3000L NA
µ-carriers Free cell suspension
From design…
Fermenters(1000L)
10 months
Fermenters(5000L)
10 to 14 (*) months
(*) Special facility construction
design if >5000 L
...to Delivery
The context :The context : Impact of cell culture on equipment and facility designImpact of cell culture on equipment and facility design
Learning 3 :Learning 3 :
Anticipate purchasing of long lead items (strong specifications and long term partnership with critical suppliers required…)
Learning 4:Learning 4:
Introduce new technologies (e.g. disposables)
The context : The context :
GMP and Biosafety in BL3GMP and Biosafety in BL3
Personnel Flow
Clean Equipment/Material FlowWaste Flow
Process Flow
MALIN
MALOUT
PAL1
PAL3
PAL2
Typical BSL 3 process viral contained area
Sterilecorridor
Wastecorridor
- 45
- 45- 30
+15
+15
+30
- 45Room pressure (Pa)
Connection to Biokill
GEP Control (Engineering steps)GMP Control (Qualification steps)Process Validation & Continuous Validation
User Requirement Brief Basic Design
Specification Phase
System Build
System Level Impact Assessment
Validation Master Plan
Design QualificationStartStart
Detailed Design
URS
Design Phase
Construction Phase
ProductionContinuous Validation
(Maintenance)
Process Validation
Post-Commissioning
Installation Qualification
Operational Qualification
Performance Qualification
Installation &Operational Phases
Performance Phase
Design QualificationCompleteComplete
Pre-Commissioning
Commissioning
GSOPBIO VAL-1204-30001
The context :The context : ““Never compromise with Quality…”Never compromise with Quality…”
Standard timing for «Greenfield » project Standard timing for «Greenfield » project
The opportunities :The opportunities : System Level Impact AssessmentSystem Level Impact Assessment
The opportunities: The opportunities:
Parallel Commissioning Parallel Commissioning
Learning 5:Learning 5: A strong and rational qualification approach helps to reduce timing
The opportunities : The opportunities :
Renovation of existing facilitiesRenovation of existing facilities
Why is renovation a nightmare ?
Existing facilities are usually BSL 2 , which is much less stringent in Biosafety
Unexpected « bad surprises » can delay timing (when « as build » is unfortunately not « as found »)
Commercial scale must comply with all GMP and BSL 3all GMP and BSL 3 requirements (GSK never compromises with Quality and Safety).
When renovation remains attractive ?
If footprint area remains unchanged, permitting procedure with township is much more rapid. Civil work and Permitting are on critical path.
For development and clinical trial (phase I,II,III) facilities at a smaller scale (10 L – 80L – 600L…)
ConclusionsConclusions
How engineering can help to a pandemic approach ?
1/ Build before completion of clinical trials
2/ Always build flexible (especially if process is still under development)
6/ When possible, chose renovation to speed small scales units.
3/ Anticipate purchasing of long lead equipments
4/ Use new innovative technologies
5/ Have a strong and rationale validation approach
Thank you for your attention.
Etienne Malhaize,
Director of Technical Service – Process Biotech.
Thank you for your attention.
Etienne Malhaize,
Director of Technical Service – Process Biotech.
NAE/IOMConference April 10 th , Vaccine production : Potential Engineering Approach to a Pandemic