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![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®
7](https://image.slidesharecdn.com/pdavirtualtrainingoptimizingprocesses032006-12861949430317-phpapp02/85/PDA-Virtual-Training-Optimizing-Processes-03-2006-7-320.jpg)
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PDA Virtual Training Optimizing Processes 03 2006
- 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 1
- 2. 1. Optimization Potentialin 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 2
- 3. Why is ScalabilityNeeded ? 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) 3
- 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) 4
- 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 5
- 6. Examples of TechnologyChanges 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 6
- 7. Examples – Savingsby 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® 7
- 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 8
- 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 9