pmt222 tups vortrag continuous improvement and process monitoring tools 01
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Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 2;
Continuous Improvement and Process Monitoring Tools
Presentation Preview:
� FDA Guidance for Industry PAT
� Online Analytics
� Online Spectroscopy and SpectroBAY ®
�Drying
�Granulation
�Tableting
� Advanced Process Control and Online Analytics
� Performance Monitoring PerMonDO ®
� Six Sigma Projects
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 3;
D. Christopher Watts, Ph.D.D. Christopher Watts, Ph.D.Office of Pharmaceutical Science, CDER, FDAOffice of Pharmaceutical Science, CDER, FDA
Science Seminar Series for the Office of CommissionerScience Seminar Series for the Office of Commissioner
April 9, 2004April 9, 2004
Process Analytical TechnologyProcess Analytical Technology(PAT):(PAT):
What’s in a name?What’s in a name?
http://www.fda.gov/cder/guidance/6419fnl.pdf
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 4;
PATPAT = Process Understanding = Process Understanding
• A process is well understood when:
– all critical sources of variability are identified andexplained
– variability is managed by the process
– product quality attributes can be accurately andreliably predicted
• Accurate and Reliable predictions reflectprocess understanding
• Process Understanding inversely proportionalto risk
Ref.: C. Watts, FDA CDER http://www.fda.gov/ cder/OPS/PATCommissionerSem2004.ppt
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 5;
PATPAT Approach: Quality by DesignApproach: Quality by Design
Focus on Process Understanding (= PAT)
• What parameters are critical to ProductQuality?– Experimental Design
• How do we monitor and analyze theseparameters?
– Appropriate Instrumentation and Visualization
• How do we control these parametersthroughout the process?
Ref.: C. Watts, FDA CDER http://www.fda.gov/ cder/OPS/PATCommissionerSem2004.ppt
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 6;
Continuous Improvement and Process Monitoring Tools
BTS view: Opportunities for using PAT
[2] Test order
[3] Order
ProcessProcess
DCSDCS
EBRSEBRS
ArchiveArchive PDBPDB
InterfaceInterface
LIMSLIMS
AnalyticsAnalytics
[4] Device-
data
[5] MeasuredDatapoints
[6] Datapoints,References
[7]Datapoints,Test orders
[10] Datapoints, Test orders
[8] Analysis, References
Index
[9] Datapoints
,Analysis
[1] In Process
Testing
Proben-etikett
Proben-etikett
Legend:LIMS Lab Informat. Manag. SystemEBRS Electronic Batch RecordingPDB Production Database DCS Distributed Control SystemAPC Advanced Process ControlOnline
Analytics
APC
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 7;
Traditional Analytics – Offline
Sampling Sample transport Lab analyser
� High costs for lab analysers and personnel
� Large delay of analytical information
� Not suitable for process automation
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 8;
Innovative Analytics – Online
Example:ProcessChromatography withintegrated samplepreparation
� High costs forequipment andmaintenance
☺ Continuous analyticalprocess information
☺ Suitable for processautomation
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 9;
Innovative Analytics – Inline
Examples:NIR-, UV-, VIS-,Raman-Spectroscopy
� Moderate costs forequipment andmaintenance
☺ Nearly real time data(~ 1 min),multiplexing
☺ Suitable for processautomation
NIR probe NIR-SpectrometerSpectroBAY ®
Light fiber
Field Analyzerhouse
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 10;
Online Analytics – Online Spectroscopy
Several technologies have the capability for online applications.
200 400 800 1000 2500 20000 Wavelength [nm]
UV VIS NIR MIRUV VIS NIR MIR
Transitions: Electronic Ove rtone-Vibrational Fundamental Vibrat ional
Absorptionstrength: strong weak strong
Groups: Aromates, Chromophores CH/OH/NH-Bondings A norganics, Organics
Spectroscopic Inline / Online - Methods:
– Diode Laser- Spectroscopy– Raman- Spectroscopy– UV/VIS- Spectroscopy– Near infrared- Spectroscopy (NIR)– Mid infrared- Spectroscopy (MIR)
Spectroscopic Inline / Online - Methods:
– Diode Laser- Spectroscopy– Raman- Spectroscopy– UV/VIS- Spectroscopy– Near infrared- Spectroscopy (NIR)– Mid infrared- Spectroscopy (MIR)
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 11;
Inline Monitoring of Moisture with NIR during Drying
Goal• Monitoring of moisture during drying
processes with NIR
Scope• Developing and validating quantitative
NIR-Applications for moisture content• Installing NIR-system at a dryer in a
pilot plant• Quantitative Inline Monitoring of drying
processes with NIR-Spectroscopy
Benefits• Provide real time information• Basis for process control• Ensuring endpoint concentration
Fast dryingSlow drying
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 12;
Inline NIR-Spectroscopy – Polymorphic Transition
Mod 1 and SolventMod 2 and SolventMod 2
Goal• Monitoring of polymorphic transitions
during drying processes with NIR
Scope• Developing and validating quantitative
NIR-Applications for polymorphicspecies and solvent content
• Installing NIR-system at a dryer in apharma plant
• Quantitative Inline Monitoring of dryingprocesses with NIR-Spectroscopy
Benefits• Provide real time information• Achieve increased capacities
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 13;
Inline NIR-Spectroscopy – Fluidized Bed GranulationGoal • Monitoring of moisture during Flui-
dized Bed Granulation with NIRScope • Developing and validating quanti-
tative NIR-Application for moisture• Installing NIR-system at a Fluidized
Bed Granulator in a pharma plant• Quantitative Inline Monitoring of
drying processes with NIR-Spectroscopy
Benefits • Provide real time information• Achieve increased capacities
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Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 14;
Atline NIR-Spectroscopy – API-Content in tablets (IPC)
Goal • Atline monitoring of API-content and
optional of moisture in tablets with NIR-Spectroscopy as a IPC method during tableting
Scope• Developing and validating quantitative
NIR-application for “API”-content in tablets
• Integrating NIR-Spectroscopy using a SpectroBAY system in the tablet quality control system RQ 100 of IMA Kilian
• Feasibility study with “mock” tablets
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 15;
Atline NIR-Spectroscopy – API-Content in tablets (IPC)
Further Results • During method development we found
a density dependence within our tablets• For the density also a multivariate
model could be built • Predictions of the density could be
made with high accuracyBenefits• Non invasive• Non destructive• Improved statistics• Provide real time information• “Continuous content uniformity test”
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 16;
PAT-Application: Microreaction Technology
Microreaction technology opensup a new outlook for novel andinnovative reaction processes.Ehrfeld Mikrotechnik BTS GmbHoffers a portfolio of modularmicroreaction technology
components:
� several types ofcontinuous micro reactors
� ultra-fast mixer,
� highly effective heat exchanger
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 17;
PAT-Application: Microreaction Technology
in collaboration with partnersEhrfeld Mikrotechnik BTS GmbHoffers also analytical micro sensordevices for PAT-applicationsduring micro reaction processes:
� micro NIR flow cell
� ATR probe
� micro pH-probe
� conductivity sensor*
* under development
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 18;
SpectroBAY ® - a modern online spectroscopy system
From our perspective the benefitsof Online-Spectroscopy are:
• real time information
• multiplexer for several measuring points
• simultaneous monitoring of several components at each measuring point
• direct analysis of chemical compositions
• basis for process control
NIR-spectra of a batch polymerisation
KPI # 1KPI # 2
KP
I # 2 mg / g
KP
I # 1
m
g / g
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 19;
SpectroBAY ® - a modern online spectroscopy system
Suitable for many applications:
� analysing a whole production area (raw materials,
reaction, separation, final products)
� concentration monitoring in organic solutions
� online reaction monitoring of polymerizations
� moisture measuring in liquids, powders, granulates,
active ingredients and tablets
� online reaction monitoring of API synthesis
� online monitoring in several unit operations (drying,
mixing, agglomeration, ...) during a drug production
decreasing water content
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 20;
SpectroBAY ® - a modern online spectroscopy system
SpectroBAY is a modern online spectroscopy
system with the following features:
� a proved spectroscopic system
� robust process spectrometer
(e.g. MATRIX-F, Bruker Optics)
� Multiplexer for 6, 13 or 20 fiber-coupled
measuring cells or probes
� Industrial standard PC and PLC
� Analyser Result Transfer Software (ARTS)
� Several DCS-interfaces available (current loop,
bus protocols, profiNet, file transfer to server)
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 21;
Continuous Improvement and Process Monitoring Tools
BTS view: Opportunities for using PAT
[2] Test order
[3] Order
ProcessProcess
DCSDCS
EBRSEBRS
ArchiveArchive PDBPDB
InterfaceInterface
LIMSLIMS
AnalyticsAnalytics
[4] Device-
data
[5] MeasuredDatapoints
[6] Datapoints,References
[7]Datapoints,Test orders
[10] Datapoints, Test orders
[8] Analysis, References
Index
[9] Datapoints
,Analysis
[1] In Process
Testing
Proben-etikett
Proben-etikett
Legend:LIMS Lab Informat. Manag. SystemEBRS Electronic Batch RecordingPDB Production Database DCS Distributed Control SystemAPC Advanced Process ControlOnline
Analytics
APC
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 22;
26
Manufacturingprocess
Control function
On-line monitoringof critical process
parameters
Process control
Process feedProcessoutput
Closed loop control(process
parameters only)
TemperatureTime
Pressureetc.
Future control philosophyFuture control philosophy
Ref.: D. Rudd, GlaxoSmithKline
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 23;
Advanced Process Control
� Conceptual design of control structure and advanced process control concepts
� Controller performance optimization
� Dynamic optimization and control of unit operations (reactors, separation units, ...)
� Control of coupled units and complete production plants
� Optimization and automation of plant start-up, load change, and grade change procedures
X
XTIC002
FIC003
FIC007
FIC004
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 24;
Controller
Advanced Process Control and Online Analytics
Online data of chemical composition are essential for an integrated automation of chemical and pharmaceutical production processes.
Examples:
� Quality control for reactors and separation steps (e.g. distillation, crystallization, drying).
� Exact determination of reaction end points.
� Specific characterization of end products.
Controller
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 25;
combinationshybrid modelshybrid models
Performance Monitoring – Methods and Tools
monitoring toolsmonitoring tools KPIsprocess data laboratory data
based on first principles (heat / mass transfer etc.)
rigorous modelsrigorous models heuristic modelsheuristic models
PCA, neural nets (NN), data mining tools, SPC
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 26;
Performance Monitoring
EquipmentEfficiency
EquipmentAvailability
ControllerPerformance
EnergyUsage
ProductQuality
PlantCapacity� Calculation and visualization of process
KPI (energy, yield, ....)
� Calculation and visualization of asset KPI (heat exchangers, controllers, ....)
� Data reconciliation (e.g. for material accounting)
� Soft sensoring (fouling, plugging, selectivity, conversion, ....)
� Sensor checking, trend detection
� Prediction of equipment lifetime
� Optimization of process conditions, predictive maintenance
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 27;
Capacity Yield Energy Environment Quality Reliability
Potential Assessment(a quantitative “reality check”)
Improvements
PLUS
Monitoring
D e f i n e
M e a s u r e
A n a l y s e
I m p r o v e
C o n t r o l
BU
/ B
TS
Par
tner
s hip
A step-by-step way to realize efficient production:
assess, improve and monitor
Six Sigma Projects
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 28;
Six Sigma Projects - Project Execution
Phase IDefine
Measure
• Identify customer’s needs• Identify relevant KPIs and control objectives• Perform “reality check”• Estimate economic benefit
� Milestone 1: Project proposal• Analyse system in detail• Identify performance impacting parameters• Design and customize methods and tools
� Milestone 2: Working plan• Implement monitoring and control functions• Train plant personnel• Integrate into workflow• Monitor and sustain improvement
Phase IIAnalyse
Phase IIIImproveControl
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 29;
PAT-Application: Plugging Detection
Monitoring ScreenMonitoring Screenflow rates
valve position
remaining „life time“
pluggingindicator
• Early detection of mixer plugging to avoid shut down
• Continuously calculate „plugging index“ based on flow rates / valve positions
• Predict remaining „life time“• Set alarm when necessary
• Avoid shut down by timely cleaning
• Increase plant availability
Goal
Benefit
Scope
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 30;
PAT-Application: Reaction Monitoring
QIQI
QIQI
EDnBA
CBA
+→+→+
measurement errormeasured
concentrations
Reconciledconcentrations
• Achieve precise reactor control
• Minimize measurement errors by data reconciliation based on rigorous process model
• Visualize reconciled values online• Control reactor based on
reconciled concentrations
• Increased selectivity due to optimal conditions
• Identify faulty measurements
Goal
Benefit
Scope
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 31;
PAT-Application : Batch Monitoring - Yield
Goal
• Reduce batch to batch yield variations
Benefit
Scope• Evaluate data from electronic
batch recording system• Apply multivariate statistics to
identify yield related KPI• Define and implement „Golden
Batch“ rules for KPI
• Establish cause-effect relationship• Improve operating conditions• Achieve consistent yield
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 32;
Continuous Improvement and Process Monitoring Tools
Conclusion:With online analytics and process automation we enhance
theperformance of our chemical and pharmaceutical productionprocesses and contribute to the PAT-Initiative of FDA
� Increasing plant capacities and production yields
� Reproducible product quality within specification limits
� Reducing operational costs
� Reducing offline analytics in the laboratories
� Contribute to operational and environmental safeties
Continuous Improvement and Process Monitoring ToolsDr. H. Tups2007-03-11, page 33;
Continuous Improvement and Process Monitoring Tools
„If you can‘t measure it,
you cannot improve it !“
[email protected]: +49 175 [email protected]