process economy for vaccines - dcvmn
TRANSCRIPT
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Process economy for vaccines
DCVMN 10 March 2017
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Outline
Vaccine production today and tomorrow
Process economy for vaccines
Strategy for process economy calculations
Case study 1
• Single-use strategy for microbial fermentation
Case study 2
• Evaluation of productivity for modernizing a vaccine process with a different purification technique
Conclusions
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Background vaccine production
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Need for updated vaccine processing and process optimization for global access
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Processes developed decades ago Processes difficult to scale up
Old cell substrates or eggs
Limited purification
Significant expertise required
Unfavorable process economyIncreased regulatory requirements
Vaccine production today
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Centrifugation
Fixed installations
Roller bottles
Low yields
Long process times
Labor-intense processes
Dedicated facilities
Open handling
Batch variability
Serum supplementation
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Processes developed decades ago Processes difficult to scale up
Old cell substrates or eggs
Limited purification
Significant expertise required
Unfavorable process economyIncreased regulatory requirements
Vaccine production tomorrow
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Centrifugation
Fixed installations
Roller bottles
Low yields
Long process times
Labor-intense processes
Dedicated facilities
Open handling
Batch variability
Serum supplementation
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Platform cell lines
Efficient purification
Scalable technologies enabled by, e.g., single-use technologies
Efficient and rational process design
Flexible facilites
Closed handling
QbD
Chemically defined cell culture media
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Process economy considerations for vaccines
Low productivity
Technology change
Low yield
Purity issues
Robustness issues
Market size
Cost structure
Expected profit
Process re-designs New vaccine introduction
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Will the vaccine be profitable?
Market analysis
Business drivers
• Market size• Market share/competition• Market growth• Profitability• Uncertainty
Business case
Detailed process economy
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• Facility construction
• Facility utilization
• Cost structure contributions: USP, DSP, QA, QC, logistics, etc.
• Product titers
• Raw materials
What will affect the process economy for a vaccine product?
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USP = upstream production DSP= downstream production
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Process design will effect process economy
Yield
Robustness
Number or process steps
Unit operations
Automation/smart engineering
Chromatography resins
Raw materials/chemicals
Platform processes
Disposables vs stainless steel
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Examples of software
• BioSolve™
• SuperPro Designer
• SchedulePro
• Microsoft® Excel®
Process economy calculation tools
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Process economy outcome...
...will never be better than the input data to simulation model
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Strategy for process economy calculations
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Proposed workflow for process economy calculations
Scope/objectives
Collect input data—identify differences and similarities
Make assumptions
Identify cost categories to investigate
Calculations
Analyze outcome
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1. Scope/objectives2. Collect data—
identify differences and similarities
3. Make assumptions4. Identify cost categories to investigate
5. Calculations 6. Analyze outcome
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Case study:comparing single-use to stainless steel strategies for microbial fermentation
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Objectives
Estimation of batch production cost
Stainless steel or single-use equipment
Equipment choice
Effects on the production capacity of the facility
Comparing facility types
Single-product to multi-product facility
Equipment strategy
How does it affect the total annual cost at different facility utilization scenarios?
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1. Scope/objectives2. Collect data—
identify differences and similarities
3. Make assumptions4. Identify cost categories to investigate
5. Calculations 6. Analyze outcome
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Differences between systems
• Fixed piping
• Valves, steam traps
• Mechanical seals
• SIP and CIP cycles
• Maintenance
• Limited adaptability
• Flexible tubing
• Integrated filters
• No mechanical seals
• Fast turnaround
• Adaptable
Stainless steel system Single-use system
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SIP = sanitization in place CIP = cleaning in place
1. Scope/objectives2. Collect data—
identify differences and similarities
3. Make assumptions4. Identify cost categories to investigate
5. Calculations 6. Analyze outcome
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Media preparation: example of differences between systems
In stainless steel equipment
• Sterilize-in-place, addition of heat sensitive components aseptically
In single-use equipment
• Option 1: sterile filter
• Option 2: autoclave in separate vessel, add to fermentor aseptically
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1. Scope/objectives2. Collect data—
identify differences and similarities
3. Make assumptions4. Identify cost categories to investigate
5. Calculations 6. Analyze outcome
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Growth comparison using optical density
• Comparable growth results from single-use fermentor for same process in 20 L stainless steel fermentor*
Optical density in single-use and stainless steel fermentor
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— Single-use — Reference stainless steel
1. Scope/objectives2. Collect data—
identify differences and similarities
3. Make assumptions4. Identify cost categories to investigate
5. Calculations 6. Analyze outcome
* B. Braun Biotech GmbH, Germany (historical data)
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Comparison of dAb expression
• Linear expression after induction • Titer comparable with reference
• Some variability, but within expected range
dab expression level immediately post induction in single-use fermentor
dab expression in single-use fermentor and stainless steel fermentor
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Reference Single-usestainless steel
1. Scope/objectives2. Collect data—
identify differences and similarities
3. Make assumptions4. Identify cost categories to investigate
5. Calculations 6. Analyze outcome
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General assumptions
• 300 fermentation days/year available
• Cost of labor: 100 USD/man hour
• Labor performed in two shifts
• Batch failure rate: zero
• Capital investments (including 10% interest) and qualification costs will be spread over the number of batches that can be produced over the depreciation time (10 years) for the equipment
• For multi-product, each product is produced in campaigns of five batches
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1. Scope/objectives2. Collect data—
identify differences and similarities
3. Make assumptions4. Identify cost categories to investigate
5. Calculations 6. Analyze outcome
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Unit operations with identical needs excluded from the model
Examples
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• Seed train procedure in shaker flasks
• Type and amount of medium components
• Minor hardware such as scales and tube welders
• Minor disposables such as C-Flex® tubing, pump tubing, syringe filters, vials, and similar
1. Scope/objectives2. Collect data—
identify differences and similarities
3. Make assumptions4. Identify cost categories to investigate
5. Calculations 6. Analyze outcome
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Cost categories
• Capital investments
• Installation and operation qualifications (IQ/OQ), performance qualification (PQ), and cleaning validation
• Production related costs:
– Preparations prior to fermentation
– Fermentation process in the production facility
• Disposables, chemicals, water for injection (WFI), steam, and similar
• Annual requalification and maintenance
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1. Scope/objectives2. Collect data—
identify differences and similarities
3. Make assumptions4. Identify cost categories to investigate
5. Calculations 6. Analyze outcome
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Harvest days (five batches per production campaign) CIP and required analysis
Carry-over calculations, reporting, and quality assurance (QA) approval Maintenance
Production schedules for multi-product facility
Stainless steel equipment Single-use equipment
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• 135 batches/year• 27 full campaigns/year
• 67 batches/year• 13 full campaigns/year
1. Scope/objectives2. Collect data—
identify differences and similarities
3. Make assumptions4. Identify cost categories to investigate
5. Calculations 6. Analyze outcome
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Production capacity
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Single-use equipment enables higher throughput in both types of facilities
Doubled production capacity enabled in multi-product facilities with single-use equipment
1. Scope/objectives2. Collect data—
identify differences and similarities
3. Make assumptions4. Identify cost categories to investigate
5. Calculations 6. Analyze outcome
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Cost per batch: multi-product facility
• Stainless steel cost is higher for– Capital investment
– Qualifications
– Annual maintenance and requalification
• Equal cost for– Production (preparations and fermentation)
• Single-use cost is higher for– Consumables (disposables, facility media, chemicals, etc.)
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1. Scope/objectives2. Collect data—
identify differences and similarities
3. Make assumptions4. Identify cost categories to investigate
5. Calculations 6. Analyze outcome
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Annual production cost in microbial fermentation
• Single-use equipment is advantageous:
– if facility utilization rate is low or
– when a high production capacity is needed
• Stainless steel equipment is advantageous:
– at mid-facility utilization rates and when capacity is not a limiting factor
Total annual production cost Comparison stainless steel and single-use equipment
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1. Scope/objectives2. Collect data—
identify differences and similarities
3. Make assumptions4. Identify cost categories to investigate
5. Calculations 6. Analyze outcome
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Evaluation of productivity for modernizing a vaccine process with a different purification technique
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Study objectives
Evaluate the effect on productivity by replacing a size exclusion chromatography (SEC) step with a core bead chromatography step in a vaccine process in different production scales
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1. Scope/objectives2. Collect data—
identify differences and similarities
3. Make assumptions4. Identify cost categories to investigate
5. Calculations 6. Analyze outcome
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Size exclusion chromatography (SEC)
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Exluded from pores
Enter a fraction of the pores
Enter all pores
Absorbance
Sample injection
High molecular
weight
Intermediate
molecular weightLow
molecular weight
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Core bead chromatography: host cell proteins and DNA fragments bind to the core and viruses stay in the void
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Data collection for comparison of SEC and core bead chromatography: lab-scale experiments with influenza virus
Val1 3001:10_UV1_280nm Val1 3001:10_UV2_260nm Val1 3001:10_Cond Val1 3001:10_Inject
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 ml
Gelfiltrering001:10_UV1_280nm Gelfiltrering001:10_UV2_260nm Gelfiltrering001:10_Cond Gelfiltrering001:10_Inject
0
500
1000
1500
mAU
0
50
100
150
200
250
mS/cm
0.0 10.0 20.0 30.0 40.0 50.0 ml
Core bead chromatography
CV (mL) 1
Load (CV) 10
HA yield (%) 85
HCP removal (%) 32
SEC
CV (mL) 47
Load (CV) 0.1
HA yield (%) 86
HCP removal (%) 31
1. Scope/objectives2. Collect data—
identify differences and similarities
3. Make assumptions4. Identify cost categories to investigate
5. Calculations 6. Analyze outcome
CV = column volumeHA = hemagglutinin
HCP = host cell protein
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Assumptions for comparison of SEC and core bead chromatography
Included Not included
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• Facility-related costs
• QA/QC costs
• System validating costs
• Cost for ex-class facility for Capto™ Core 700
Operational cost (€)/batch
Hardware cost (€)/ batch
Chromatography system
Column
Buffer totes
Buffer cost (€)/ batch
Labor cost (€)/batch
System set-up
Buffer prep
Processing
Cleaning
Column packing
Waste cost (€)/batch
Disposables
Organic solvent
Cosumables (€)/ batch
Buffer and product hold
Chromatography resin and single-use columns
1. Scope/objectives2. Collect data—
identify differences and similarities
3. Make assumptions4. Identify cost categories to investigate
5. Calculations 6. Analyze outcome
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Productivity for SEC and core bead chromatography
0
100
200
300
400
500
600
700
800
Core bead chromatography,SS column
Core bead chromatography,SU column
Size exclusionchromatography, SS column
Influ
en
za a
nti
ge
n (H
A m
g) /
tim
e (h
)
0
100
200
300
400
500
600
700
800
Core bead chromatography,SS column
Core bead chromatography,SU column
Size exclusionchromatography, SS column
Influ
en
za a
nti
ge
n (H
A m
g) /
tim
e (h
)
200-L scale 2000-L scale
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1. Scope/objectives2. Collect data—
identify differences and similarities
3. Make assumptions4. Identify cost categories to investigate
5. Calculations 6. Analyze outcome
HA = hemagglutinin, SS = stainless steel, SU = single-use
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Confidential. Not to be copied, distributed, or reproduced without prior approval.
Cost comparison stainlesss steel versus single-use technologies
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Confidential. Not to be copied, distributed, or reproduced without prior approval.
Single Use vs Stainless Steel savings
User reports – compiled data from publications and conference presentations
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Confidential. Not to be copied, distributed, or reproduced without prior approval.
Users reports – last 5 yearsSavings with Single Use versus Stainless Steel
Company Consumables
Facility Cost
Facilityfootprint
Labor Time to build
Turnover time
Water /Energy
Capacity increase
COGs
Large Vaccine
+200% -40% -50% -70% /-45%
-40%
Small Vaccine
-75%
Large pharma
+120% -50% -25% -48% -70% +30% -57%
Large Pharma
-60% -50% -25%
Large biotech
-75% -75% -50% -80% / -80%
-67%
Large Biotech
-25% -35% -25% -85% / -25%
Small biotech
+250% -45% -25% -25%
CMO +50% -50% -10% -50% -25% -30%
Substancial savings by using SUT despite increased consumables cost
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Confidential. Not to be copied, distributed, or reproduced without prior approval.
Single Use $ savings - reports from users 5 years
• Facility cost savings, footprint reduction• Facility build-out time savings• Equipment cost savings• Labor cost savings • Cycle turnover time savings• Water, chemicals and energy savings
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Confidential. Not to be copied, distributed, or reproduced without prior approval.
Benefits of single-use technology
• Less handling can reduce the required FTEs, leading to lower labor cost.
• Lower capital investment as some equipment can be omitted.
• If the production process is not limited by the equipment, more batches can be produced.
• Eliminate cleaning requirements and time consuming QA/QC, for faster campaign turnaround time.
• Excluding of some equipment allows for smaller facility, reducing capital investment.
• Less chemical consumption and waste.
QA/QC = quality assurance/quality control
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Conclusions
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Conclusions
Paradigm shift for vaccine production—from lab bench process to rational design
Start early with process economy in process development
Integrate process economy as a part of process development
Use a strategy for process economy calculations
Productivity can be increased by rational process design
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