robert morenweiser - dechema · the world vaccine market 93% 7% pharma vaccines 53% 47% 2006 data...
TRANSCRIPT
Vaccine ManufacturingChallenges & Strategies
Robert Morenweiser
Fast Trak Services Europe
GE Healthcare
2Dechema Vaccine Workshop_Oct 2010
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Outline
• Challenges in Vaccine Production
• Current Trends & Correspondings Strategies
• Summary
3Dechema Vaccine Workshop_Oct 2010
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The world vaccine market
93%
7%
Pharma Vaccines
53%
47%
2006 Data
Pharma market: 241 Bn $
Vaccine market: 18 Bn $
89%
11%
non USA USA
Industrialized countries
Developing countries
Ref. Human Vaccines 2007 Reportwww.strategyR.com
4Dechema Vaccine Workshop_Oct 2010
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Why this enormous interest in Vaccines?
Vaccine environment
No 1 solutionto global health issues
New technologies
Greater knowledge ofDiseases & immune system
New emerging markets
Need to cut Healthcare spending
Pandemic threat /Bioterrorism
5Dechema Vaccine Workshop_Oct 2010
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Challenges in Vaccine Production
6Dechema Vaccine Workshop_Oct 2010
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Manufacturing ChallengesGeneral
• Paradigm = Product defined by Process (live/bacterial vaccines)
• Complex range of vaccine products & sessional variation
• Very diverse production and purification platforms
• Majority of vaccines still produced “traditionally”
• Higher regulatory demands
• Cost for entry is very high
• Risk management
Practical & Technical • Limited number of vaccine CMOs
• Manufacturing: capacity, speed, economy, response
• Capacities not equally distributed worldwide
• Technology knowledge owned by few major accounts
• Analytical assays with low throughput
• Complex impact of process on product
• Time to clinic/approval: PD and clinical material
Picture courtesy of Greg Knobloch
7Dechema Vaccine Workshop_Oct 2010
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Trends and Strategies
8Dechema Vaccine Workshop_Oct 2010
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Trends in the Vaccine Market
• New virus based application: immune stimulation, cancer treatment
• ”Old diseases” in formerly ”safe” regions” : Dengue fever, West-Nile virus, Malaria
• Currently many small/mid-size biotech companies pursuing new vaccines
• Differences in regional vaccine & vaccine quality requirements
• Time to market and process economy becoming vital
• New vaccine platform technology: VLP, plants, DNA
9Dechema Vaccine Workshop_Oct 2010
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Generations of Vaccines
•Killed/ Inactivated
• Subunit
• Toxoid
• Conjugate
• Live-attenuated Viruses
• Adjuvants
• Virus-Like Particles
• Recombinant Antigens
• DNA
• Recombinant vectors
• Novel routes of administration
ImprovedState-of-the-Art Novel
10Dechema Vaccine Workshop_Oct 2010
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The vaccine landscape is changinge.g. influenza vaccine
System
Lead time
Maturity
Vaccine
Eggs Mammaliancells
Insectcells
No cells
6-9 months ~6 months ~3 months Days ?
On marketNew on market
In 2-4 yearstime
?
All – whole virus, split etc
Molecularapproaches
?
Cell freeEgg based Cell culture based
All – whole virus, split etc
11Dechema Vaccine Workshop_Oct 2010
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Novel approaches
Pseudomonas fluorescens is a nonpathogenic (BSL-1), Gram-negative, obligately aerobic, bacterium
VaxInnate's fusion vaccine can be efficiently and economically manufactured in E.coli
Tobacco plant-based Proficia™ technologyand its Virus-Like Particles (VLPs).
Virus-like particles expressed in Baculovirus expression system
12Dechema Vaccine Workshop_Oct 2010
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Efficient Process Development
13Dechema Vaccine Workshop_Oct 2010
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FDA’s - Guidance for Industry
Process Design:
…Design of Experiment (DoE) studies can help develop process knowledge by revealing relationships, including multifactorial Interactions, between
the variable inputs (e.g., component characteristics or processing parameters) and the resulting outputs (e.g., in-process material, intermediates, or the final product). …
Source: www.fda.gov
14Dechema Vaccine Workshop_Oct 2010
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Optimize
Plan Predict
PerformOptimize
Evaluate
DoE & HTPD
X2
X1X3-1
1
-1
1-11
Analyze
15Dechema Vaccine Workshop_Oct 2010
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Screening for hcDNA removalPreDictor™ plates /Capto™ ViralQ
A/Wisconsin/67/2005 (H3N2)A/Solomon Islands/3/2006 (H1N1)
16Dechema Vaccine Workshop_Oct 2010
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Capto™ ViralQDNA scavenging
0
1000
2000
3000
4000
mAU
0
50
100
150
200
250
mS/cm
0.0 5.0 10.0 15.0 20.0 25.0 30.0 ml
Column: Capto™ ViralQ (CV=1ml)Sample: Influenza A/PR/8/34 (H1N1), produced in MDCK cells
UV_280nm
Cond
DNA level (PicoGreen)
UV_260nm – UV_280nm
Flowthrough=Virus fraction
"Eluate" CIPMDCK DNA levels per dose (45µg HA)
1
10
100
1000
10000
100000
Clarified Harvest UF/DF retentate Capto Q virusfraction
Sucrose grad centr
Purification intermediate
DN
A le
vel (
ng/d
ose)
A/PR/8/34 (inact)A/PR/8/34 A/SI/3/06A/W/67/05
17Dechema Vaccine Workshop_Oct 2010
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Analytics
18Dechema Vaccine Workshop_Oct 2010
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Analytical tools - The bottleneck
Typical analytical challenges during viral vector development and production
• 100s of tests per run in both development and production
• Few minutes to hours/days to complete test, particularly lengthy for in-vivo testing
• Varying uncertainty in test accuracy
19Dechema Vaccine Workshop_Oct 2010
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Analytical methodse.g. in influenza vaccine production
Haemagglutinin (HA) SRID,Dot Blot, HA ELISA (H1N1), HPLC, Western Blot, Hemagglutination assay,
genomic dsDNA qPCR, Molecular Probes PicoGreen™
host cell proteins (HCP) BCA & Bradford protein assay, anti-HCP serum for western blotting, HCP ELISA, 1D-DIGE
virus infectivity TCID50, Fluorescent Focus Assay
quantification
20Dechema Vaccine Workshop_Oct 2010
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BIACORE assay setup & principle
[Virus standard]( µg/ml)
0
400
800
1200
0 200 400 600
0
0.5
1.0
2.0
4.08.0
x
x
x
xx
x
[ ]( µ
0
400
800
1200
0 200 400 600
0
0.5
1.0
2.0
4.08.0
x
x
x
xx
x
[ ]( µ
Seru
m r
espo
nse
(RU
)
Time (s)
0
400
800
1200
0 200 400 600
0
0.5
1.0
2.0
4.08.0
x
xx
x
xx
x
Sensorgram
21Dechema Vaccine Workshop_Oct 2010
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HA-assayBIACORE vs. SRID
BIACORE™ SRIDdynamic range
(µg HA/mL) 0.5-10 8-30
sensitivityLOD (µg HA/mL) 0.3 6
LOQ (µg HA/mL) 0.8 13
precision#samples CV < 5%
(%) 97 18
22Dechema Vaccine Workshop_Oct 2010
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Increasing Productivity
23Dechema Vaccine Workshop_Oct 2010
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Pandemic PlanningCapacity Time
0
500
1000
1500
2000
2500
mill
ion
dose
s
2006 PandemicPlanning
WHOgoal
• There is a huge gap between the expected demand and the current capacity
• Most countries are looking for in-country domestic solutions
• WHO is driving local capacity build up
20102004
• Need of faster supply – less than 3 months production time
• Currently the manufacturing time is ~6-9 months
• Difficult and time consuming to scale up with old technology
24Dechema Vaccine Workshop_Oct 2010
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Disposables in vaccine productionProduce faster, safer, and cheaper
Higher project throughput• Shorter setup times• Shorter process times• Less validation efforts/time
Safer operations• Reduced cross-contamination• No re-use, closed system
Reduced costs• Lower capex• Lower start up costs• No cleaning procedures
25Dechema Vaccine Workshop_Oct 2010
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Vaccine manufacturing solutionsGeneric
TechnologySpecific
SolutionsManufacturing
PlatformsCompleteSolution
Cell harvestingHollow fiber ultrafiltrationNMWC 750kDa, 1 mm lumen
Fermentation
Alkaline lysis
ClarificationNormal flow depth filtration20, 5 and 0.5 µm
ConcentrationHollow fiber ultrafiltrationNMWC 100 or 300kDa
RNA removalGroup separationSepharose 6 Fast Flow
Supercoiled plasmid DNA captureThiophilicaromatic chromatographyPlasmidSelect Xtra
Plasmid DNA polishingAnion exchange chromatographySOURCE 30Q
Concentration/formulationHollow fiber ultra/diafiltrationNMWC 100 or 300kDaSterilizationNormal flow filtration0.2µm
Fill and finish
Cell harvestingHollow fiber ultrafiltrationNMWC 750kDa, 1 mm lumen
Fermentation
Alkaline lysis
ClarificationNormal flow depth filtration20, 5 and 0.5 µm
ConcentrationHollow fiber ultrafiltrationNMWC 100 or 300kDa
RNA removalGroup separationSepharose 6 Fast Flow
Supercoiled plasmid DNA captureThiophilicaromatic chromatographyPlasmidSelect Xtra
Plasmid DNA polishingAnion exchange chromatographySOURCE 30Q
Concentration/formulationHollow fiber ultra/diafiltrationNMWC 100 or 300kDaSterilizationNormal flow filtration0.2µm
Fill and finish
Cell harvestingHollow fiber ultrafiltrationNMWC 750kDa, 1 mm lumen
Fermentation
Alkaline lysis
ClarificationNormal flow depth filtration20, 5 and 0.5 µm
ConcentrationHollow fiber ultrafiltrationNMWC 100 or 300kDa
RNA removalGroup separationSepharose 6 Fast Flow
Supercoiled plasmid DNA captureThiophilicaromatic chromatographyPlasmidSelect Xtra
Plasmid DNA polishingAnion exchange chromatographySOURCE 30Q
Concentration/formulationHollow fiber ultra/diafiltrationNMWC 100 or 300kDaSterilizationNormal flow filtration0.2µm
Fill and finish
Aseptic Processing
Virus Affinity Media
Chromatography
Filtration
Cell Culture, Bacteria, Plants
Flexible
Conventional
Developing WorldPandemic Solutions
26Dechema Vaccine Workshop_Oct 2010
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Summary
• DoE or HTPD support PD and optimization (up/downstream) even in a more and more diverse vaccine world
• Technologies like RTP and single-use products can minimize time to market
Variety of existing and future vaccine and virus based applications will put an enormous pressure on vaccine produces, suppliers and academia to work closer together
27Dechema Vaccine Workshop_Oct 2010
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Thank you
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