Description of process optimization opportunities and approaches

1. Optimizing Biopharmaceutical Processing
by Value - Added Services
Optimization – Two Prong Approach
1. during development & process scaling
Discovery Pre Clinical Phase I Phase II Phase III Commerical
2. of an existing process step & chain
Upstream Fermentation | Purification Form | Fill
Cell culture tech.
Media Bioreactors Cell harvesting Concentration Target Virus removal Sterile filtration
-Filtration Contaminant purification
-Media bags removal Buffer prep | Filtration
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2. 1. Optimization Potential in the Development & Scaling Phase
Discovery Pre Clinical Phase I Phase II Phase III Commerical
Sequence Route Process Process Pilot
Selection Development Development Scaleup Batches Commerical
mg g 1-10 kg 10-50 kg 100-300 kg
IND BLA/NDA
Prerequisites:
Up & down scalability
Identical design & configuration of either equipment or process
Defined & repeatable & documented test methodologies/results
Constant material composition in all scales
Proper time frame definition & hand-over to next phase
Scale- Up/Down Opportunities
Equipment: Examples of adequate scalability:
Pumps
Fermentation
Centrifugation
Purification
Filtration
Valves
Concentration
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3. Why is Scalability Needed ?
Smooth scale-up from development phase, down from process
scale
Ease of validation, due to the utilization of existing development
phase results
Optimization of processes and improved equipment choice
Performance evaluation of comparable process equipment
Reduction of product losses during testing
Scale-Up/Down – Important Factors
Equipment requires linear scaling (performance predictions)
Equipment design criteria requires to be similar or equal
(reproducible results)
Material and components within equipment should not change
with scaling (validation & extractable issues)
Process parameters need to be kept (minimum variability)
Process design should stay constant (reproducibility &
comparability)
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4. Involvement of Value – Added Services - Examples
Quality system design
Training
Equipment design & testing
Discovery Pre Clinical Phase I Phase II Phase III Commerical
New innovative Filing support Validation services
technologies
Process design support
Process step integration
Example Filtration – Equipment design & testing
Important Factor:
Flow per cm² has
to be constant
Flow per filter cm²
Flow per filter element
Filtration area (cm2)
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5. Development Phase Optimization – Potential Savings
Biopharmaceutical equipment development focus on small scales:
$ Reduction of multiple validation steps/studies – cost reduction,
faster time-to-market
$ Opportunity for process optimization - yield enhancement
$ Reduction of product losses during development – cost reduction,
enhanced test numbers
$ Excelleration of regulatory compliance/filing – faster time-to-
market
2. Optimization Potential of an Existing Process Step or Chain
Upstream Fermentation | Purification Form | Fill
Cell culture tech.
Media Bioreactors Cell harvesting Concentration Target Virus removal Sterile filtration
-Filtration Contaminant purification
-Media bags removal Buffer prep | Filtration
Prerequisites:
Open minded approach to new technologies and improvements
Up & down scalability
Appropriate test procedures which reflect large scale results
Possibilities of process equipment integration
Validation support & services
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6. Examples of Technology Changes
Time Frame – a Drug Development Cycle
3 x higher flow
2-3 x higher throughput
much less leachables
reliably integrity testable
higher thermal strength
higher flow rates
wider retention rating
higher thermal strength
easy, faster cleaning
full automation
higher sensitivity
no user interference
high user friendliness
full automation
reliable data logging
Examples – Savings by Process Optimization of Sterilizing Filter
140
120
Flow Rate (l/min)
100
Sizing/Dead-Volumes 80
(flow rate/throughput enhancements 60
reduce the required equipment size, 40
i.e. flush volumes, dead-volumes etc. 20
annual potential savings and/or 0
revenue enhancement of $ mil) 0.5 1 1.5 2 2.5
Differential Pressure (bar)
1. Generation 2. Generation 3. Generation
IgF Adsorption Different Membrane Materials
90
Adsorptivity 80
70
(difference between 85 % down to 25 %
IgF Recovery (%)
60
per 10“ filter cartridge; depending on 50
the drug product: 40
losses of $ 30 to > $ 65.000 30
per filtration run) 20
10
0
CA PVDF PES1 PES2 PES3 PES4
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7. Examples – Savings by Process Optimization of Tanks/Mixing
Disposable Bags
(low or no capital investment, low storage space needs,
no cleaning, i.e. no down-time, higher capacity utilization,
multi-product use posibilities, less man hours, less cleaning
solution costs - one tank cleaning can take up to 6 hours
and costs up to $ 10,000 per tank total)
Disposable Mixing
(lower capital investment and storage needs due to the
elimination of multiple sets of tanks (one for use, one in
cleaning), no cleaning , i.e. no down-time, higher capacity
utilization, multi-product use posibilities, less man hours, less
cleaning solution costs – one more batch per week due to
higher capacity utilization adds tens of millions of revenue)
Validation Support – Example – Extractable Testing
Any polymeric system requires
leachable/extractable testing
with the actual product or a Gamma-Bag Extraction with DI-Water at 50°C
model solvent under process 22
Acetic Acid
22
TOC [mg/l] / Conductivity [µS/cm ]
20 20
conditions
TOC
18 18
pH
pH / Acetic Acid [mg/ l]
16 16
Conductivity
14 14
12 12
10 10
8 8
6 6
4 4
2 2
Value-Added Service 0
Blank 24h 50°C 48h 50°C 120h 50°C
0
Extraction Time and Temperature
CONFIDENCE®
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8. Downstream Systems Integration
From Fermentation to Clarification to Concentration to Purification
Source: Sartorius
Source: Sartorius
Source: Kendro/Carr
Source: Sartorius
Source: Sartorius
Examples - Downstream Integration
From Fermentation to Clarification to Concentration to Purification
Source: Sartorius
Source: Bayer AG
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9. Involvement of Value – Added Services - Examples
Process integration Optimization services
Upstream Fermentation | Purification Form | Fill
Cell culture tech.
Media Bioreactors Cell harvesting Concentration Target Virus removal Sterile filtration
-Filtration Contaminant purification
-Media bags removal Buffer prep | Filtration
Filing support
Validation services
Training
Conclusion
Optimization is a two prong approach starting in the development
phases and continuing in existing processes
Optimization requires appropriate equipment scalability to perform
multiple trials at low product losses and requirements
Optimization trials require to be defined to be able to determine the
realistic needs; e.g. a 47 mm disc trial can only be used as an indicator
trial and has to be verified and assured
Optimization properly performed can create not only savings, but
especially additional revenue; real world example – 1 batch more per
week means $ 1.2 bio/year
Optimization tasks & projects can and should be supported by the
value-added service of the vendor
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