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SPAES @ Goa 2011
Emerging Technologies in Pharma IndustryUse of Automation & IT for quality & manufacturing excellence..
SRAES @ Goa 2011Industry Sector2011-08-10/11
External Changes having direct impacts on the pharmaceutical manufacturing needs
Technology changeTechnology change
Industrial ITIndustrial IT
Advanced Advanced controlcontrol
IntegratedIntegratedsolutionsolution
Social changeSocial change
DemographicDemographic
Life styleLife style
PatientsPatients
Economical pressureEconomical pressure
Low pipe lineLow pipe line
ManufacturingManufacturing
Supply ChainSupply Chain
Market changeMarket change
New therapiesNew therapies
Delivery formDelivery form
PersonalizePersonalize
Pharmaceutical Pharmaceutical IndustryIndustry
driven by;Cost
Patient safety
SRAES @ Goa 2011Industry Sector2011-08-10/11
Changes leading to new requirements / challenges
The situation for Pharma production changes Resulting requirements on
Technology changeTechnology change
Industrial ITIndustrial IT
Advanced Advanced controlcontrol
IntegratedIntegratedsolutionsolution
Social changeSocial change
DemographicDemographic
Life styleLife style
PatientsPatients
Economical pressureEconomical pressure
Low pipe lineLow pipe line
ManufacturingManufacturing
Supply ChainSupply Chain
Market changeMarket change
New therapiesNew therapies
Delivery formDelivery form
PersonalizePersonalize
Pharmaceutical Pharmaceutical IndustryIndustry
driven by;Cost
Patient safety
RegulationsRegulations
Manufacturing performanceFirst Time RightIncrease product throughputRecipe driven flexible manufacturing
Supply chainTracing & tracking / E-PedigreeDemand driven
Asset utilizationOverall Equipment Effectiveness / Efficiency (OEE)
Time to marketPaperless manufacturingProcess Analytical Technology (PAT)
EnvironmentEnergy managementWaste reductionHigh potent drugs
Integrated manufacturing based on Automation & IT is the key !
SRAES @ Goa 2011Industry Sector2011-08-10/11
Large scope for improving quality / quality consistencyDrug makers can save significant cost by getting it right first time
Research driven companies 31%
Generic Manufacturers 51%
Contract Manufacturers 62%
Cost of manufacturing –Pharmaceutical Industry
Cost of Quality as % of cost of manufacturing, Pharma versus Semiconductor
How to reduce cost of
Quality?
‘Getting it right the first time’ is the key
Reduce existing inefficiencies in manufacturing
- Reduce re-work
- Reduce scrap / WIP (Work In Progress)
- Increase equipment efficiency / utilization
SRAES @ Goa 2011Industry Sector2011-08-10/11
How to get the product ‘first time right’ ?Shift from traditional ‘Quality by Inspection’ to ‘QbD’ approach
Variable input Inconsistent qualityFrom Quality by
Control/Inspection& strict compliance
To Quality By Design, risk & science based
product development
Fixed process
Variable input Consistent qualityVariable process
PAT/QbDenabled
Traditional manufacturing
The key lies in understanding the CQPs of the product, understanding process parameters which determine CQPs & controlling such parameters in such a way that the product quality as well as process end point can be exactly predicted on line !
Process understanding is critical to achieving desired quality !
SRAES @ Goa 2011Industry Sector2011-08-10/11
PAT ensures desired product quality without scrap / re-work (right first time) and also enables online product release !
Process feed
Hol
d /
rele
ase
LabProcess data (Temp,
Pressure, …)Closed loopClosed loopcontrolcontrol
Process output
LIMSLIMS
Sample
Classic control
Process Analyzer
monitoringmonitoringanalyzeranalyzer datadata
monitoringmonitoringproduct product qualityquality
PATPAT
mathematicalmathematicaltranslationtranslation
RealReal--timetimereleaserelease
Advanced Advanced ControlControl
Quality build in by design
Right first time
PAT (Process Analytical Technology) is the enabler for QbD
SRAES @ Goa 2011Industry Sector2011-08-10/11
PAT = understanding + controlling mfg. process..better the understanding, lesser the risk..
PAT is a system for controlling manufacturing processes based on Online & timely measurements of critical Quality & performance attributes with the goal of ensuring final product Quality
Focus of PAT is process understanding, better the understanding, lesser the (quality related) risk
A process is well understood when:
- All critical sources of variability are identified & explained
- Such variability is managed by process control
- Product quality attributes can be accurately & reliably predicted
Process data collected during development phase helps in understanding process, hence development & manufacturing to be integrated from PAT perspective
Process Analyzer
DataMultivariate modeling
Information
1
2
3
4
Improved process understanding !
5
SRAES @ Goa 2011Industry Sector2011-08-10/11
US FDA has taken initiatives to facilitate application of new technologies like PAT for Pharma manufacturing
US FDA has released guidance for PAT in Sep’04, & various other white papers on application of PAT for Pharma manufacturing & new risk based approach, with an objective to:
- Improve manufacturing quality
- Accelerate drug development
- Reduce regulatory burden
US FDA’s future focus #:
- Integration of R&D and manufacturing
- Development of ‘quality surrogates’ for clinical performance (link CPAs to clinical outcome)
- Rigorous, mechanistically based & statistically controlled processes
(# Keynote address at IFPAC February 2007, by FDA's Chief Medical Officer, Dr. Janet Woodcock)
By US FDA in September 2004
SRAES @ Goa 2011Industry Sector2011-08-10/11
Analyzers (for gathering data) and PAT software (for processing data) are THE key components of PAT solution..
SRAES @ Goa 2011Industry Sector2011-08-10/11
Raw Material
Dryer
Granulator Tablet press
Blender
Qualitycheck
Coating
Delay 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
PAT has the potential to ‘change the clock speed of drug manufacturing’
Raw Material
Dryer
Granulator Tablet press
Blender
Qualitycheck
SIPATSIPAT
Coating
In/At line check
Cycle time can come down from typical 1-2 months to 2 days !
Right First Time
Real time release
SRAES @ Goa 2011Industry Sector2011-08-10/11
Business drivers for PAT go much beyond quality..
Company Image
Reduced risk via technology platform, anti-counterfeitingImproved product trackingReverse poor imageImproved quality system throught auditsReduced risk fo recall, warning letter, consent decree
Validation Optimization
Validation needs understandinIntegral part of projectBuilt validation into process
Improve Existing Process
Gain new process understandingProcess optimizationReduced cost of qualityRaw material specificationsKnow product availability + yieldReal Time Release
New Product Development
Real Time Release (RTR)Fast time to marketFast scale-upClinical batchesProcess optimizationReduced cost of quality
End of life-cycle
Transferability of processScale down
Site to Site transfer
Accelerate transferReduce validation effortReduce project timeMitigate transfer riskMove manufacturing to mosteffective site
PAT/QbD
SRAES @ Goa 2011Industry Sector2011-08-10/11
Siemens plays key role in developing concepts & solutions for continuous manufacturing based on PAT
The project ‘SPRINT’ (Secondary Processes INTensification)
- project launched in UK by technology strategy board (backed by UK Govt.)
- objective is to provide proof of feasibility for continuous manufacturing using PAT
Partners: from all fields of expertise
- GlaxoSmithKline as End User
- GEA as supplier for process technology and machinery
- Siemens as solution provider for process automation & information technology
Results are encouraging !
PoF completed in record 4 month time
Approval from regulatory authorities underway
To be followed by implementation in production unit!
SRAES @ Goa 2011Industry Sector2011-08-10/11
Expected results of ‘SPRINT’ project answer our question !
Expected results after implementing the concept for a production unit:
85% reduction in waste / scrap
60% lower capital cost
65% less building volume
60% less manpower
Reduction in WIP,
Increased equipment efficiency
Reduced cost of Quality!
By increased process understanding & control
through PAT !
SRAES @ Goa 2011Industry Sector2011-08-10/11
Counterfeit medicines – a growing global concern....has serious implications on society & drug manufacturers
European commission observed sharp increase in seized counterfeit drugs in 2007, +51% wrt 2006
Counterfeits account for 10% of medicines worldwide, (up to 50% in some countries) as per WHO
India and China accounted for 64% counterfeitproducts seized in year 2009
The result is twofold:
- Deaths of thousands of people (more compared to car accident deaths!)
- Loss of revenue due to counterfeiting (est. €35 billion in 2007) & due to non traceability related write offs (€ 2 to 6 billion) (est.)
SRAES @ Goa 2011Industry Sector2011-08-10/11
Counterfeit medicines – a growing global concernThe evidence is chilling
SRAES @ Goa 2011Industry Sector2011-08-10/11
Mass serialization & e-PedigreePermanent solution to counterfeits !
Mass serialization involves assigning unique identification number to each package, case & pallet of drug & then using that number to record all transactions involving the product, thus giving information about drug pedigree
As defined by US FDA, a drug pedigree is a statement of origin that identifies each prior sale, purchase or trade of a drug including dates of those transactions & the names & addresses of the parties involved in them..
e-Pedigree (electronic pedigree) for medicines is simply capturing & recording drug pedigree data in an electronic format, enabling use of IT
Manufacturer Before W/S Wholesale Pharmacy Patient
Global pedigree Database
SRAES @ Goa 2011Industry Sector2011-08-10/11
The world has taken serious note of the issue,Guidelines are being put in place..
In March 2010, US FDA released a guidance for standardized numeric identifier (code)
Most of the states in US have already law in place (red) / law being drafted (green) for drug pedigree & tracking
e.g. Californian law mandates e-Pedigree for drug makers by Jan 2015 & for drug wholesalers & retailers July 2016..
Most of the countries have adopted some standard for serialization & coding of drugs (though not uniform)
EFPIA (European Federation of Pharmaceutical Industries & Associations) is running a project to standardize the same
France (by December 2010) Belgium & Italy are mandating serial number for each saleable pack
Brazil announced law no. 11903 on 14th Jan 2009 making tracking of all drugs mandatory within 3 years
Korea to mandate tracking of drugs by 2012, China contemplating on similar lines
SRAES @ Goa 2011Industry Sector2011-08-10/11
Serialization & tracking – Global architecture
Man
ufac
ture
r inf
rast
ruct
ure Track & Trace
Databases
Tracing and Object Data
Verify, Update Status information
Verify, Update Status, Store tracing information
Verify, Update Status, Store tracing information
7 8 9
Verify, Update Status, Store tracing information
Verify, Update Status, Store tracing information
Verify, Update Status information
Receiving Delivery Receiving Delivery Receiving Sell
Distributor WholesalerDrugManufacturer
Rea
l Wor
ld Packaging DeliveryDrug
Production
ERPLocal
AutoIDService
Initiate production / packaging
Confirm Serial#
3
5
Provide serial #’s to suppliers
Initiate serial# generation to packaging supplier
12 Confirm serial#
4
Confirm Serial#6 Generate
Point-of-Sale
Legend: Manufacturer – Serialization LogisticPoint-Of-Sales Track & Trace Databases
CentralSerialization
Service
Track & TraceDatabases
SRAES @ Goa 2011Industry Sector2011-08-10/11
Serialization & e-pedigreeApplication as per Brazilian law
Brazil
China
Blank labels From Brazilian1
Serialization & aggregation on packaging line
Serialized, aggregated products with: GTIN, IUM, Medicine Registration #, Product Lot # , Expiration Date
2
Electronic notification of item IUM Numbers to the Brazilian
National Tracking System3
Law no. 11903 on 14th Jan 2009 making tracking of all drugs to be sold in Brazil mandatory within 3 years: Drug makers to start serializing items in 1st year, data to be integrated to public database in 2nd year, retail stores to be integrated in 3rd year (2012)
Every saleable unit will carry a 2D Data Matrix printed on security label, provided & distributed by Brazilian authority (label size 19mmx25mm, DM code size 9mmx9mm)
The label to contain information like GTIN (product identifier), IUM (medical Unique Identifier as per GS1 standard for serialization), medicine registration no., batch number and expiry date
SRAES @ Goa 2011Industry Sector2011-08-10/11
Automation & IT is THE backbone for any serialization / tracing tracking & e-Pedigree solution
Global Logistic
chain
Leve
l 4Le
vel 5
ERP
Leve
l 3Le
vel 2
Leve
l 1
Site Manager
Control- / Acquisition
level
Device level
Enterprise-wide connection for Event dataAuthentication Services
Auto ID Devices like DMC Printer, Cameras, RFID Reader/Writer, Barcode Scanner
Device-ManagementData acquisitionProcess support at the packaging line
Track&Trace Enterprise database
Serial number handlingAcquisition/Reports/Monitoring/Alarm messagesAcquisition and summary of EventsBatch & User management
SRAES @ Goa 2011Industry Sector2011-08-10/11
Siemens plays key role in developing concepts & solutions for e-Pedigree – in IT as well as Automation
EFPIA has launched a pilot project for feasibility study of e-Pedigree solution
Siemens to provide IT solution along with SAP & HP
25 pharmacies in Sweden with 180 dispensing points selected
Involves tracking 25 products with 110,000 packs from 14 companies
Solution based on Siemens-SAP architecture
To be recommended as standard solution by EFPIA after success
Data Matrix Code identification mandatory by Dec’10 in France
Germany based ‘pester pack’ chose Siemens as partner for automation & IT for implementing serialization solution for its end of the line packaging machines
Coding unit including controls integrated in packaging line, code via manual input from HMI or via MES / ERP
Machines now fully compliant with French coding requirement
SRAES @ Goa 2011Industry Sector2011-08-10/11
PAT & e-Pedigree ensure & enhance for end to end quality in Pharmaceutical Industry !
Summary PAT Summary e-Pedigree
The need for ensuring drug pedigree is well understood by all agencies & is beyond question
Concepts / policies & laws are currently being put in place to ensure drug pedigree
Need for harmony / standardization between various existing concepts / standards
PAT has the potential to transform quality as well as manufacturing scenario for Pharmaceutical Industry
US FDA has already released guidance for PAT and made PAT as part of its long term strategy
Need for stakeholders (analyzer, automation & IT vendors & users) to work together (PAT is a solution)
Automation & IT is the key for ‘end to end’ quality for Pharmaceutical Industry !
SRAES @ Goa 2011Industry Sector2011-08-10/11
Typical ‘liquids’ process consists of four broad steps
- Weighing- Dispensing- Assembly
- Active ingredients- Non active ingredients
- Weighing & dispensing- Balance verification
Preparation
In process testing & SamplingClean room monitoring
Formulation
- Dose WFI- Solution prep- Mixing- Filtration
-Utilities: WFI, PW, ...- Filters
- Adding Raw Material- Dosing- Sampling
Finishing
- Wash/sterilize- Filling/stopping- Lyo-philization- Capping- Inspection
- Vials- Bottles- Capsules- Caps- Stoppers
- Line clearance- Sampling- Reconciliation
Packaging
- Primary packaging- Endpackaging- Labeling
- Inserts- Cartons- Labels
- Line clearance- Reconciliation
Ass
embl
y/Ve
hicl
e
Sem
i fin
ishe
d go
ods
Fini
shed
goo
ds
Clean room
SRAES @ Goa 2011Industry Sector2011-08-10/11
Using high voltage, pressure, vacuum, laser, camera etc.
7. Leak testing
Put into trays for intermediate storage
8. Traying
Typical steps / equipments used in ‘finishing’ of liquids
Containers washed with WFI
1. Washing
Containers sterilized with dry heat @ 300 °C
2. Sterilizing tunnel
Around 400-600 containers per minute
3. Filling
Frozen to powder at -70 °C to increase shelf life
4. Freeze drying
Apply aluminum caps to guarantee sterility
5. Capping
Manual or camera, particles, cosmetic / functional defects
6. Inspection
SRAES @ Goa 2011Industry Sector2011-08-10/11
In today’s scenario, there are ‘automation islands’throughout the manufacturing line..
A AA
CCC
A A
B BBB
????M1 M3M2
MES / ERP
SRAES @ Goa 2011Industry Sector2011-08-10/11
..making integration almost impossible if not impossible
DataInterface 2
Machine 1 from OEM x Machine 2 from OEM y Machine n from OEM z
PLCHMI
I/O I/O
Drives
Motors
LV Sensors
Net
wor
k
Net
wor
kMotionControl
PLCHMI
I/O
Drives
Motors
LV LV Sensors
PLC PLC
I/O
Motors
Drives
LV Sensors
DataInterface n
Line Overview HMI
MIS/MES
????????
No DataInterface
Diversity
Complexity
Difficult integration
Difficult Diagnosis
High Asset Costs
Many plants are currently made up of different products, systems and interfaces from different suppliers thus creating high diversity & complexityMissing standardized network structure and machine data interfacespreventing simple integration of the Machines and higher level systems
SRAES @ Goa 2011Industry Sector2011-08-10/11
‘Initial investment cost’ governs decision for machine automation, leading to high lifecycle costs
Initial investment
Spares MaintenanceService
Downtimes
UpgradesTraining
Invest
Capital
Energy
Personal
Space
Support
Extension
Additional operating costoccurred by:
poor integration
complex service
increased spare part purchase / storage
elevated training costs
non-optimized energy consumption
SRAES @ Goa 2011Industry Sector2011-08-10/11
Option 1: Easy integration with ‘cba’ approach (component based automation)
Same open communication standardDefined machine interfacesNo additional programming for Intercommunication
Machine – Machine, Line ControlLine Monitoring, Data acquisition
Ethernet TCP/IP
ERP
verticalIntegration
horizontal Integration
Cleaning Conveyor Filling Conveyor Packaging
Cleaning(Vendor A)
Conveyor 2(Vendor B)
Filling(Vendor C)
Packaging(Vendor D)
Conveyor 1(Vendor B)
Fieldbus X Fieldbus Y Parallel Wiring Fieldbus Y Fieldbus Z
MES
SRAES @ Goa 2011Industry Sector2011-08-10/11
cbA - Each machine is represented as a software component
Mechanicalcomponents
Controlsoftware
Intelligent field device
HMI block
ResultComponents withdefined Data interface
The machine interface contains all data for the intercommunication, visualization and data acquisition
Filling product 1reset operatesenable finishedstop enable
faultstart
SRAES @ Goa 2011Industry Sector2011-08-10/11
Creating the component
The manufacturer/vendor of the machinePrograms the machine control as he is used to, application specificDefines and maps the relevant machine data to a bi-directional interface from a technological viewEncapsulates the functionality of the machine control and interface description in a SW componentautomatically generated by programming tool
Vendor BFilling Filling product 1
reset operatesenable finishedstop enable
faultstart
Filling product 2reset operatesenable finishedstop enable
faultstart
Filling product 3reset operatesenable finishedstop enable
faultstart
XML
SRAES @ Goa 2011Industry Sector2011-08-10/11
Easy integration at site with ‘cbA’ enabled machines
Maschine 1ON STARTINGSTART READYSTOP
Lifestate
RUNNINGHELD
Maschine 2ON STARTINGSTART READYSTOP
Lifestate
RUNNINGHELD
Maschine 3ON STARTINGSTART READYSTOP
Lifestate
RUNNINGHELD
Maschine 4ON STARTINGSTART READYSTOP
Lifestate
RUNNINGHELD
3rd Step
SIMATICWinCC
Plant Owner
2nd Step
SIMATICiMap
Integrator
STEP7shadow projectand download
1st Step
Machine A
Machine AMachine B
Machine AMachine C
OEMs
XML-file interface definition
SRAES @ Goa 2011Industry Sector2011-08-10/11
Option 2: Project specific standardization in close collaboration with OEMs & automation supplier
Machine 1 from OEM x Machine 2 from OEM y Machine n from OEM z
Standard DataInterface
Net
wor
k
MotionControl
PLCHMI
I/O
Drives
Motors
LV
Standard DataInterface
Line Overview HMI
Standard Data Interface
Net
wor
k
HMI
I/O
Drives
Motors
LV
Net
wor
kPLCHMI
I/O
Drives
Motors
LV
MotionControl
MIS/MES
IntegrationLevel 5Overview visualizationCommunicationsDiagnosisBackUp&Recovery
Level 1:HardwareSoftware
Level 4:Data-Interfaces
Level 3:Architecture
Level 2:Specification
User & automation supplier define specificationsUser, automation supplier & OEM work closely to implement the laid down specifications, to achieve integration
SRAES @ Goa 2011Industry Sector2011-08-10/11
Close collaboration is necessary among User, OEM & automation supplier, for integrated manufacturing line
ResponsibilitiesDelivers specific machine
to handle a specific production operation
Focus on machine specific optimization
ResponsibilitiesStandard & scalable platformEasy integrationGMP supporting functionsCost effective solutionsLong term worldwide Support (investment protection)Industry know How
ResponsibilitiesSpecify required machinery to fulfill
a specific production operationMachine must comply with the own
specific norms and standardsFocus on the optimized
functioning of the complete production line
Easy integration of the control level to the system structure
End-user
Supplier
OEM
SRAES @ Goa 2011Industry Sector2011-08-10/11
Typical architecture of an integrated manufacturing line
Process network Ethernet
Production network Ethernet
Local HMI
Full local equipment controlLocal Equipment HMIObject orientedUniform look & feel by usingobject libraries
ERP
S7-315 PN/DP
SIMOTION DS7-414-2 +CP 443-1 Advanced
Panel PC MP 370 Inox
Central SCADAView Line statusVisualize Batch progressProduction Data Acquisitionfrom PU’sCritical alarms
MESProduct definitionProduction capabilityProd. scheduleProd. performance
WinCCflexible
Multi Panel
WinCCflexible RT
Equipment 2 Vendor BEquipment 1 Vendor A Equipment 3 Vendor C
WinCC ServerWinCC Clients
MP 277 Inox10“
WinCCflexible
MP
SRAES @ Goa 2011Industry Sector2011-08-10/11
Integrated central recipe management
Process network Ethernet
Production network Ethernet
Local HMI
WinCC flexible + options:
AuditRecipes
Central SCADA
WinCC V6.0 + options:
SIMATIC LogonPM-CONTROL
WinCC Clients
WinCC server
Parameters EQ1Par1, Par2…..
Batch idProduct idQuantity…..
Parameters EQ2Par1, Par2…..
Batch idProduct idQuantity…..
SIMATIC IT
Recipe xyz V2.1Batch idProduct idQuantity…..
Parameters EQ3Par1, Par2…..
Parameters EQ2Par1, Par2…..
Parameters EQ1Par1, Par2…..
ERP
ERP
SIMATIC IT
PDefMPOM
PM
HistorianProd SuiteOEE/DTM
DIS (B2MML)
SAP
MES
MP 370 Inox
Parameters EQ3Par1, Par2…..
Batch idProduct idQuantity…..
SRAES @ Goa 2011Industry Sector2011-08-10/11
Central archive depository & electronic batch records
SIMATIC IT
Process network Ethernet
Production network Ethernet
Local HMILocal EquipmentHMI WinCC flexibleAlarm & EventsEquipment RecipedownloadLocal data collection for EBRLocal archivesLocal audit trail
ERP
Machine 1 Machine 2
S7-315 PN/DP
SIMOTION D
S7-414-2 +CP 443-1 Advanced
Machine 3
Panel PC MP 370 Inox
Central SCADACentral archivedepository foralarms, audit trails& process dataData Mining
MESOverall EquipmentEfficiencyDowntime MngtBatch reporting
WinCC Clients
WinCC server
PDefM
POMPM
HistorianProdSuite
OEE/DTM
PM Open Import
SIMOTION D
MP 370 Inox
SRAES @ Goa 2011Industry Sector2011-08-10/11
Line integration helps you achieve demands / needs due to new business drivers !
Manufacturing performance improvement
- Improved performance with flexible recipe driven manufacturing
Supply Chain optimization
- Tracing & tracking possible at central location / e-pedigree
Better asset utilization
- By downtime analysis & reduction
Reduced time to market
- By electronic batch records & paperless manufacturing
SRAES @ Goa 2011Industry Sector2011-08-10/11
Siemens has all the necessary ingredients to deliver the solution
Know-how
Resources
SolutionPlatforms
Integration
Industry specific: regulations (validation, GMP, ...)Process specific (from molecule to production)Engineering specificSystem specific - Batch / DCS / PLC / IT
Products / SystemsSystem Add-On’s
Local & regional resourcesProject ManagementEngineering Validation / QA
Experience in integration technologiesOne-stop shopping
SPAES @ Goa 2011
We wish you a successful meeting!
Abhijit TambatProject Management, Engineering & CommissioningI IA AS DLS
Kalwa WorksThane Belapur RoadPhone: +91 (022) 2764-5707Fax: +91 (022) 2764-5627Cellular: +91 9820265282
E-Mail: [email protected]