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© Siemens AG 2010. All Rights Reserved.
The potential of Continuous Processing in secondary manufactuirng
Ivo BackxSiemens, Industry automationVertical Market Management Pharma
© Siemens AG 2010. All Rights Reserved.Industry SectorPage 2 Oct 6st, 2010 Ivo Backx
Today’s Pharmaceutical World…
low efficiency example: secondary manufacturing
large batch equipment, inefficiently used
low equipment utilisation (30% - 40% avg)
low product yields
long production lead time (intermediate QCs)
individually controlled equipment
high inventory volumes & cost
space consumption & add-on utilities
scrap & rework
labour intensive
improvement perceived limited by regulatory
© Siemens AG 2010. All Rights Reserved.Industry SectorPage 3 Oct 6st, 2010 Ivo Backx
Oral Solid Dosage manufacturing today
Granulator
Dryer
Coating
Delay Delay Delay
High inventory including “work in progress”, long changeovers, disconnected processes, high process losses, off line analysis, low asset utilization, …
1 to 2 months to
release
Blender
Raw Material
Tablet press
Delay
Blender
© Siemens AG 2010. All Rights Reserved.Industry SectorPage 4 Oct 6st, 2010 Ivo Backx
PAT: Key Enabler for Continuous Manufacturing and Real Time Product Release
Raw Material
Dryer
Granulator Tablet press
Blender
Qualitycheck
SIPATSIPAT
Coating
Right First Time
Real time release
In/At line check
© Siemens AG 2010. All Rights Reserved.Industry SectorPage 5 Oct 6st, 2010 Ivo Backx
Hol
d /
rele
ase
LabLabTemp., Speed,
Liquid addition,
Compression Force, …
Process output
LIMSLIMS
Sample
Classic controlClassic control
Process Analyzer
monitoringmonitoringprocessprocess datadata
monitoringmonitoringproduct product qualityquality
PATPAT
mathematicalmathematicaltranslationtranslation
RealReal--TimeTimeReleaseRelease
Advanced Advanced ControlControl
Quality built in by design
Right First Time
PAT Basics – Holistic Approach
Closed loopClosed loopcontrolcontrol
© Siemens AG 2010. All Rights Reserved.Industry SectorPage 6 Oct 6st, 2010 Ivo Backx
ConsiGma™ Continuous Tabletting Line example
© Siemens AG 2010. All Rights Reserved.Industry SectorPage 7 Oct 6st, 2010 Ivo Backx
ConsiGma™ Continuous Tabletting Line example
7 Insert text with “Insert Header & Footer”
Materials Handling
Feeding
Blending
Milling
Extra Granular additions
Granulating
Drying
LubricationCompression
Coating
© Siemens AG 2010. All Rights Reserved.Industry SectorPage 8 Oct 6st, 2010 Ivo Backx
PAT/QBD in solid dosage
•
Drying
control
Process
parameters
Blending /
Lubrication
control
Process
parameters
Compression
control
Process
parameters
Coating
control
Process
parameters
Dispense
& Blend
control
Process
parameters
Api
Excipients
Wet
Granulation
control
Process
parameters
Liquid addition
Lubricant excipient
Coating solution
Loss On Drying
Bulk Physical
Defects
Test against
specifications
Bulk Physical
Defects
Content
Uniformity
Packaging
control
Process
parameters
Particle size
Sampling &
Off-line analysis
© Siemens AG 2010. All Rights Reserved.Industry SectorPage 9 Oct 6st, 2010 Ivo Backx
Quality predictions
•
Lubricant excipient
Drying
control
Process
parameters
Blending /
Lubrication
control
Process
parameters
Compression
control
Process
parameters
Coating
control
Process
parametersApi
Excipients
Dispense
& Blend
control
Process
parameters
Liquid addition
Wet
Granulation
control
Process
parameters
Coating solution
Loss On Drying
(NIR)
Assay
Dissolution/disintegration
(NIR)
Packaging
control
Process
parameters
Particle size
(Malvern)Weight
Hardness
Thickness
Input material
characteristics
Visual
Inspection
Coating
thickness
Content
Uniformity
© Siemens AG 2010. All Rights Reserved.Industry SectorPage 10 Oct 6st, 2010 Ivo Backx
SIPAT Data Flow principlefocus on-line data acquisition and processing
Data alignment
Contextualization
Rules separating non-representativedata
Statistical RT Modelse.g. PLS, PCA
Chemometrics(Umetrics, Matlab,…) engine embedded in SIPAT
CQA
Aggregation of CQA over process context
- Average,
- Standard deviation
On line Monitoring
Out of control detection
Deviation tracking
AP
CR
TR
SIPAT
Raw Material
Characteristics
LIMS
Process
+
Context data
SCA
DA
Analytical
Data
NIR, PSD
Analyzer
Critical to QualtyAttribute
/sec.
© Siemens AG 2010. All Rights Reserved.Industry SectorPage 11 Oct 6st, 2010 Ivo Backx
MES LIMS
SCADA
PLC / Motion Control
PROCESS
ANALYZERS
SIPAT
Line
SITE
(2)
(5)
(1) (3)
(4)
(6)
High Level System Architecture
Control Analyzers
Multivariate Data handling
On-line monitoring of the Critical to Quality Attributes (CQA)
Deviation Tracking CQA
Out of Control Detection & input to APC
Supervisory & Control
Alarm handling
Line Recipe handling
Trending Univariate Data
Deviation Tracking Critical Process Parameters
Real Time Releasereporting
© Siemens AG 2010. All Rights Reserved.Industry SectorPage 12 Oct 6st, 2010 Ivo Backx12
Data Driven Manufacturing
• SIPAT allows to measure inline the CQA’s, real time
• Increased number of measurementsTest case of 50hrs run @25kg/hr=1250kg material
- Moisture measured 960 times
- Particles size distribution measurements: 960 times
- Content uniformity: 100 times
- Tablet weight: each tablet (1,8 Mio)
- Enhanced product security
- Data correlation across units
© Siemens AG 2010. All Rights Reserved.Industry SectorPage 13 Oct 6st, 2010 Ivo Backx
Lot 1 Lot 2
Lot 1 Lot 2
Lot 1 Lot 2
F1C1 F1C2 F1C3 F1C4 F1C5 F1C6 F2C1 F2C2 F2C3 F2C4 F2C5 F2C6 F3C1 F3C2 F3C3 F3C4 F3C5 F3C6 F4C1 F4C2 F4C3 F4C4 F4C5
F1C1 F1C2 F1C3 F1C4 F1C5 F1C6 F2C1 F2C2 F2C3 F2C4 F2C5 F2C6 F3C1 F3C2 F3C3 F3C4 F3C5 F3C6 F4C1 F4C2 F4C3 F4C4
F1C1 F1C2 F1C3 F1C4 F1C5 F1C6 F2C1 F2C2 F2C3 F2C4 F2C5 F2C6 F3C1 F3C2 F3C3 F3C4 F3C5 F3C6 F4C1 F4C2 F4C3
F1C1 F1C2 F1C3 F1C4 F1C5 F1C6 F2C1 F2C2 F2C3 F2C4 F2C5 F2C6 F3C1 F3C2 F3C3 F3C4 F3C5 F3C6 F4C1 F4C2
API
Excipient 1
Excipient 2
Granulation
Ingredients
Drum 1 Drum 2 Drum 3Output
Time
Drying
Millling/Blending
Compression
Coating
Material Residence Time distribution Product Plug tracking
© Siemens AG 2010. All Rights Reserved.Industry SectorPage 14 Oct 6st, 2010 Ivo Backx
Lot 1 Lot 2
Lot 1 Lot 2
Lot 1 Lot 2
F1C1 F1C2 F1C3 F1C4 F1C5 F1C6 F2C1 F2C2 F2C3 F2C4 F2C5 F2C6 F3C1 F3C2 F3C3 F3C4 F3C5 F3C6 F4C1 F4C2 F4C3 F4C4 F4C5
F1C1 F1C2 F1C3 F1C4 F1C5 F1C6 F2C1 F2C2 F2C3 F2C4 F2C5 F2C6 F3C1 F3C2 F3C3 F3C4 F3C5 F3C6 F4C1 F4C2 F4C3 F4C4
F1C1 F1C2 F1C3 F1C4 F1C5 F1C6 F2C1 F2C2 F2C3 F2C4 F2C5 F2C6 F3C1 F3C2 F3C3 F3C4 F3C5 F3C6 F4C1 F4C2 F4C3
F1C1 F1C2 F1C3 F1C4 F1C5 F1C6 F2C1 F2C2 F2C3 F2C4 F2C5 F2C6 F3C1 F3C2 F3C3 F3C4 F3C5 F3C6 F4C1 F4C2
API
Excipient 1
Excipient 2
Granulation
Ingredients
Drum 1 Drum 2 Drum 3Output
Time
Drying
Millling/Blending
Compression
Coating
Material Residence Time distribution Real Time Release floating window
Release window
© Siemens AG 2010. All Rights Reserved.Industry SectorPage 15 Oct 6st, 2010 Ivo Backx
10 m
7 m
7 m
1 2
Granulation/Drying/Milling Equipment Comparison
Batch Processroom requirements
70 m2
490 m3
Legend:1.= granulator2.= dryer
2,5 m
3,6 m
2,5 m
12
Continuous Processroom requirements
6.25 m2
22.5 m3
© Siemens AG 2010. All Rights Reserved.Industry SectorPage 16 Oct 6st, 2010 Ivo Backx
Cleaning philosophy
Granulation unit: Wash in place - Wash off lineDrying unit: Wash in place - Wash off lineGranule conditioning unit: Cleaning in place
© Siemens AG 2010. All Rights Reserved.Industry SectorPage 17 Oct 6st, 2010 Ivo Backx
Investment & Running Cost: Case StudyCommercial manufacture of compound X in plant Y, using base case 1.5 bn tablets/yr
Conventional Batch Approach (all inclusive) 42 mio euroContinuous (all inclusive) 17 mio euro
A continuous line requires 30% of manufacturing space (70 m² vs. 18,75m² )
Cost of direct labour for conventional plant 3,471,000 euroCost of indirect labour for conventional plant 1,066,000 euro40% saving on labour costs expected
Material saved via raised yield @ ½ % of 450 ton/yr = 2,250 kg material2,250 kg @ 900 euro/kg = 2,025,000 euro/yr Reduced space requirement reduces HVAC costs, smaller surface areacontact parts reduces cleaning utility requirements, this is estimated to be worth 115,000 euro/yr
© Siemens AG 2010. All Rights Reserved.Industry SectorPage 18 Oct 6st, 2010 Ivo Backx
Why Continuous Manufacturing?
© Siemens AG 2010. All Rights Reserved.Industry SectorPage 19 Oct 6st, 2010 Ivo Backx
Benefits to late stage process development
Equipment scale
development=manufacturing
Faster process understanding and
optimization through Automation and
integrated data management
PAT/ Controls developed simultaneously
Faster to market
Faster to Market
© Siemens AG 2010. All Rights Reserved.Industry SectorPage 20 Oct 6st, 2010 Ivo Backx
Good Collaboration makes this happen
OEMProcess Know-HowSupply specific equipment + instrumentation to handle a specific production operationFocus on equipment specific optimization Equipment automation specification (PLC, HMI, drive, instrumentation, ...)Equipment validationEquipment specific 21 CFR Part 11 functionalityWorldwide Packaged Unit Support
SiemensIndustry know HowStandard platformScalable solutionsEasy integrationGMP supporting functionsCost effective solutionsLong term Support (investment protection)Worldwide Product Support
End-UserProduct Know-HowSpecify required machinery to fulfill a specific production operationEquipment must comply with the own specific norms and standardsFocus on the optimized functioning of the complete production lineEasy integration of the control level into Plant-IT
End-user
Supplier
OEM
© Siemens AG 2010. All Rights Reserved.
Ivo BackxSenior Consultant drug manufacturingI IA VMM Pharma
Nieuwe Weg 1B-2170 Zwijndrecht, Belgium
Phone: +32 2 536 98 41 Cellular: +32 477 69 93 31
E-Mail: [email protected]
Thank you for your attention!