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1、Bringing a Process to ScaleEach product creates its own unique challenges for process development:oDeveloping a Biofuels process to the 300,000L scale faces different challenges than developing a Pharmaceutical production process to the 100L-25,000L scale.oDeveloping a Pharmaceutical production proc
2、ess in a microbial host faces different challenges than would be faced in a mammalian process.Despite the wide range of differences,most process development efforts require the same basic steps and these steps are a result of shared end goals.第1页/共29页What is the Goal?.To run a multi-million(billion)
3、dollar production facility at full capacity producing end products worth millions(billions)of dollars.第2页/共29页How is this Goal Achieved?At the heart of the process is a stable,reliable cell line and culture approach which has been well characterized at a smaller and more manageable scale.Create Cell
4、 LineSelect in Well-PlatesAdvance to Flasks,Select Further.Expand Cell LineDevelop the ProcessScale the ProcessIdentify ProductR&DLarge Scale Process第3页/共29页Identify ProductR&DSelection StepsDevelopment StepsBecause these steps provide very little information to the researcher,“Selection”is possible
5、,but true process development is difficult.The data recorded at each step during process development is what allows the researcher to control and therefore scale the process.Information Available at Different Stages.第4页/共29页Identify ProductR&DEarly,High-throughput stages provide little information.R
6、esearchers are often limited to Cell Counts and Titers.Process Development stages track and control many parameters:pH,DO,pCO2,OTR,Osmolarity,Nutrient Feeds,Cell Viability,Cell CountSelection StepsDevelopment StepsScaling a Process Requires Information.第5页/共29页Scaling Steps Require Control.Selection
7、 Steps,Approach:1.Nutrients,keep media the same and hope for the best.2.Oxygen Transfer Rate,keep mixing the same and hope for the best.3.pH,use buffers to control the process you get the idea.4.Temperature.Process Development Steps,Approach:1.Nutrients,keep constant-control media composition,feed t
8、iming and rates.2.Oxygen Transfer Rate,keep OTR the same,control agitator speeds and sparge gas compositions.3.pH,dual sided pH controller,use the same acid or base at each scale.4.Temperature,closed loop control over temperature.5.pCO2,Osmolarity,Cell Counts and Viabilities monitored,controls may b
9、e adjusted to match performance of previous scales.Selection Steps must be predictive of the first controlled scale.Development Steps constrain the culture to achieve reproducible results.第6页/共29页Well plates,Shake Flasks,STBRsLarge Flasks/SpinnersTraditional Process FlowUpstream process development
10、steps typically rely on antiquated technologies.These technologies have questionable scalability.?第7页/共29页Better Tools,Better Decisions,Earlier-FlasksSensored -FlasksSTBRsImproved consistency,monitoring and control permit better quality experiments.Improved experiment quality upstream of STBRs allow
11、s better decisions.-Flasks,SDR,SFR,AFS and The RAM make your existing work more predictive.AFM,The RAM第8页/共29页u-FlaskThe RAMu-Flask+SDR,SFRAFS(Alcohol Fermentation System)ConsistencyMonitoringControl(limited)Consistency,Monitoring and Control第9页/共29页-Flasks 第10页/共29页Test Tubes,Shake flasks.Increased
12、 aeration.Reduced evaporative loss.Solid support,Re-useable/Autoclavable.May be used with the SensorDish Reader.-Flasks are Shake Flasks第11页/共29页-Flasks Scale to Shake Flasks第12页/共29页-Flask ConfigurationsFrom 100ul to 4.0ml第13页/共29页Applikon Small-ScaleA big STEP AHEAD with a small footprint.-FlasksT
13、he SDR and SFR第14页/共29页Predictive Results,Earlier-Flask:Replaces well plate lids,test tubes and shake flasksWorks with all shaker-incubatorsSensorDish Reader+SensorFlask ReaderAdd Sensors to well plates and Shake FlasksCompatible with-flask closuresCollect data from hundreds of parallel cultures第15页
14、/共29页SensorDish Reader,SDR第16页/共29页SensorDish Reader,SDR1.Non-invasive,online.2.pH or Dissolved Oxygen.3.No Calibration Required.6-well24-well第17页/共29页ExpandableAdditional SDRs link into the Basic Set.Up to 10 SDRs on one Laptop.No additional software required for expansion.第18页/共29页SDRs Integrate w
15、ith -Flasks-Flasks Integrate with the SensorDishReader1.Eliminate Well-plate inconsistency.2.Reduce and equalize evaporative losses across well-plates.3.Obtain online pH or dissolved oxygen data for all wells.第19页/共29页DO profiles(all 24 for each well-plate)Polystyreneu-Flask第20页/共29页SensorFlaskReade
16、r,SFR第21页/共29页The SensorFlask Reader,SFRShaker-mounting blue-tooth sensor platform.Shake Flasks with DO and pH sensors.(also single DO or pH if desired)Multiple volumes(125/250/500/1000 ml).Up to 9 flasks on the platform at one time.第22页/共29页Microbial and Mammalian ApplicationsMicrobial Applications
17、:Monitor pH and DO levels.Ensure aerobic growth.Follow carbon source utilization and exhaustion.Adjust orbiter speeds to maintain DO levels for better scalability.Mammalian Applications:Accurately monitor pH/pCO2 levels.Adjust bicarbonate levels more accurately.Monitor DO levels,adjust orbiter speed
18、s for better scalability.第23页/共29页Software第24页/共29页Individual Flask Calibration第25页/共29页Complete HardwareHardware Includes:Platform.Batteries.Bluetooth adapter.Software.Clamps.Bluetooth range of 15ft.Battery life 3 months on a single charge.(platform can operate on single battery)第26页/共29页Predictive Results,Earlier-Flask:Replaces well plate lids,test tubes and shake flasksWorks with all shaker-incubatorsSensorDish Reader+SensorFlask ReaderAdd Sensors to well plates and Shake FlasksCompatible with-flask closuresCollect data from hundreds of parallel cultures第27页/共29页Questions?第28页/共29页