PAT Initiative – Pilot Project API Production Gerhard Korb...
Transcript of PAT Initiative – Pilot Project API Production Gerhard Korb...
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Gerhard Korb
Sanofi-Aventis Deutschland GmbH
Process Development Chemistry
Chemical & Particle Engineering
Frankfurt
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Summary
• Tools - Definition
• Example
• Additional PAT Elements
• Resources/Infrastructure
• Cooperation with the FDA (POV)
• PAT Comparability Protocol
• Learning experience
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Sanofi-Aventis PAT Tools
Sensors
Data
Analysis
Design for Quality
ProcessControl
Inferential•pH, pressure, tempDirect•NIR, Raman, NMR
•Feed-Forward•Feedback•Multivariate Control•Continuous Processes
•DOE•FMEA•Qualification•Validation
•Univariate•Multivariate•Real-Time•On Location
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Overview – Definition: PAT System
Current Test• off-line
Alternate Test*• at-line• same specs• same sample size• near real-time
control• backed-up by lab
test• etc.
PAT PAT MeasurementMeasurement System*System*•• onon--line or inline or in--lineline•• differentdifferent acceptance criteriaacceptance criteria•• differentdifferent sample sizesample size•• realreal--time releasetime release•• feed back / forwardfeed back / forward•• increased increased 'knowledge''knowledge'•• PAT submissionPAT submission•• etc.etc.PA
T-Ap
proa
ch
like-for-likeapproach
PAT SystemApproach
Like-for-like can mean: using modern sensor technology not integrated in a PAT system.
PAT SystemApproach
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Options to implement PAT
A. Currently marketed “robust” products. PAT to improve efficiency (minimalimprovement in quality assurance)*
B. Currently marketed products that needimprovement. Step-wise PAT approach -First improve quality and then improveefficiency
C. New products. PAT utilized throughoutdevelopment and scale-up. Lab basedtests to ensure shelf-life and/or forestablishing “public standards”.
IO Pilot
R & D
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Project overview – API production and DP manufacturing
DP1
Wet Granulationacitve
Excipients
DP2
Drying
CompendialTesting
processparameters
Control
process parameters
Control
LOD
DP4
Blending/Lubrication
processparameters
Control
Powder Fineness
DP5
Compression
processparameters
Control
WeightHardnessThickness
DP6
Film Coating
processparameters
Final Product
Avg Tablet WeightBulk Physical Defects
Control
Bulk Physical DefectsFriability
Spec TestingID
AssayWaterCU
DegradentsDissolution
PAC
PAC
PAC PAC
PAC
proposedPAT System
IP 6
API Hydrate
API
API (milled)
NIR (reagentcontent)
NIR (Processcontrol)
Laser Diffraction(Process Control)
RM IP 1
IP 3
IP 2
SM IP 5
IP 4NIR
NIR(distillation)
NIR(turnover)
NIR
GC (off-line)GC (off-line)
IR (off-line)
HPLC (off-line)
Base titration (off-line)
Water contentKarl Fischer (off-line)
Particle Size andSSA (off-line)
Current Analytical Method
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Projekt API production - Overview
proposedPAT System
IP 6
API Hydrate
API
API (milled)
NIR (reagentcontent)
NIR (Processcontrol)Laser Diffraction
(Process Control)
RM IP 1
IP 3
IP 2
SM IP 5
IP 4NIR
NIR(distillation)
NIR(turnover)
NIR
GC (off-line)GC (off-line)
IR (off-line)HPLC (off-line)
Base titration (off-line)
Water contentKarl Fischer (off-line)
Particle Size andSSA (off-line)
Current Analytical Method
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Example – Intermediate: Overview ReactionSide reaction
A + B CA + D E
100%
Example
50%
5%0%
Sampling
Conversion
ContentA
Reaction90 – 120 °C/3 bar
In-line NIR
On-lineReaction timeOff-line sampling(HPLC)
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Example – Intermediate: Situation without PAT
Parameter-Nitrogen flow-Heating-Dosage B Off-line Test
-Main product-Hydrolysis by product
IntermediatePre step Next step
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Example – Intermediate: PAT Approach
IP 6
API Hydrate
API
API (milled)
RM IP 1
IP 3
IP 2
SM IP 5
IP 4
Optimal conversionAvoiding hydrolysis
Minimaziationdecomposition
Reduction of variability ofRelated substance
Minimaziation E
Minimaziation F
Minimaziation G
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Example – Intermediate: PAT Approach
NIR In-line-Content Water
-Content A-Nitrogen flow-Heating-Dosage B
IntermediatePre step Post step
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Example – Intermediate: Information from NIR spectra
Water content
Content A
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Example – Intermediate: Scale Up/Scale Down
Dosage B
NIR
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Example – Intermediate: Scale Down/Scale Up
NIR Sensor
Nitrogenflow Hydrodynamic!
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Example – Intermediate: Implementation
To PCS Non Ex Zone Ex Zone
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Generell Procedure for implementation of PAT tools
Scale Down
Feasibility
Model Validation
Implementation
Laboratoryconditions
Conditions inProduction plant
T, p, ..... constant T, p, .....variabel
Process Monitoring
Process Control
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
0
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8.20
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Content Water ppm (NIR)Content p-CPKE coarse modelTemperature reactorHCl mass (kg)Content p-CPKE release modelpressure (bar)
Water (NIR)
Content A Release model (NIR, Model validated
Mass B
Content A Coarse model (NIR)
Temperature
Pressure
Example – Intermediate: Data integration
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Example – Intermediate: Variability Content A Control chart: batches produced in 2004 (without PAT)
HP
LC: c
onte
nt p
-CP
KE
(%)
CTR = 0,76UCL = 2,31
LCL = -0,78D
0692
D07
03
D07
14
D07
25
D07
36
D07
47
D07
58
D07
69
D07
80
-0,8
0,2
1,2
2,2
3,2
4,2
Control chart: batches produced in 2004 (with PAT)
HP
LC: c
onte
nt p
-CP
KE
(%)
CTR = 0,46UCL = 1,09
LCL = -0,16
D 0
790
D 0
801
D 0
812
D 0
823
-0,8
0,2
1,2
2,2
3,2
4,2
Control chart: batches produced in 2004 (with PAT)
NIR
: con
tent
p-C
PK
E (%
)
CTR = 0,49UCL = 1,11
LCL = -0,13
D 0
790
D 0
801
D 0
812
D 0
824
-0,8
0,2
1,2
2,2
3,2
4,2
Batches 2004 without NIR
Monitoring Final ImplementationHPLC NIR
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Example – Intermediate: Variability G in API
Fexofenadin gemahlen (Gehalt Isopropyl-Analog)
Geh
alt (
%)
CTR = 0,01
UCL = 0,02
LCL = 0,01
Spezifikation: <= 0,15 %L7
32L7
53L7
74L7
95L8
16L8
37L8
58L8
79L9
00L9
21L9
42D
963
D98
4D
007
D02
8D
049
D07
0D
091
00,010,020,030,040,050,060,070,080,09
0,10,110,120,130,140,15
Content related substance in API
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Example – Intermediate: Results
• Measurement of differnet substances
(Water + A) with one sensor Reduction von Investitment
• Optimal reaction conditions Yield improvement
• Monitoring of Water and conversion Minimaziation of by products
• Batch release by operators Cycle time reduction
• Reduction of variability Quality improvement/Risk minimaziation
• Avoiding of sampling Improvement of operators safety
Return On Investment? Payback
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Additional PAT Elements: System Performance (NIR)SPEKTROMETER COMPUTER EXTERNE SYSTEME
Control Module
Start / StopMeasurement
4 ... 20 mA,
ProfiBus
Industry-PCOPUS-Software-Modules
Data
SENSOR
FO
Conection box
Light source Spectra
File Server
PCS
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Additional PAT Elements: Model generation/Validation NIR
Model generation and Model validation
Sensor calibration
System CalibrationMethod Transfer/Monitoring
Long term satability
NIR-Water content-Content A
Method PAT Laboratory Plant
Spectral Information Model Chemometry Test/Validation
Documentation
Transfer
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Additional elements: Risik analysis
Measurement
PeopleMachine
Variability (Water, pCPKE) NIR
Method
Automation
Material
Piping
P-CPKE
Sensor design/location
Length
NIR
Humidity (Heptan)
Reactor
Agitator
Temperature/Pressure settings
Volumetric rate
Material of construction
Calibration
Maintenance
Performance
Operatop‘s error
No Training
Carelessness
No process understanding
Nitrogen blowing
Nitrogen volumetric rate
Calibration/Maintenance
Controler settings HCl cylinder
Agitator speed
Toluene
Sampling System
Process/System p-CKE Area Affected: p-CKE production IC14 Prepared ByPAT TeamResponsible Team: PAT Team Product: Fexofenadine HCl FMEA Date (20. Aug 04
Other Areas InvoProduction, Engineering, Quality Quality Control NA FMEA Date (Draft; 26. Aug. 2004
PROCESS FUNCTION
POTENTIAL FAILURE
MODE
POTENTIAL FAILURE EFFECT
POTENTIAL FAILURE CAUSE
Current Controls in
Place
Current Detection Method
Recommended
Action(s)
Area/Individual
Responsible for Action
and
Action Results
Action(s) Taken
SEV
OC
C
QQQQQ
QQQ
Potential Failure Mode and Effects Analysis
Effect Severity
Occurence of C
ause
Detectability
RPN
Effect Type Q S B
Gehalt A
• Fishbone• FMEA• FTA• ...........
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Resources for PAT Project:• Programmer
• Database Expert
• Material Characterization Scientist
• Statistician
• Manufacturing Leader
• Operators
• Regulatory specialist
• PAT Project Leader
• Analytical Development Scientist
• Chemometrician
• Spectroscopist
• Process Engineer
• Process Control Engineer
• Quality Leader
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Infrastructure for PAT Project
Dioden Array NIR
Dioden Array UV/VIS
Turbitidy
Reactor control
Computer FT-NIR
FT-NIR withMultiplexer
Sensor
10 l HC4 Reactor
PCS
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Cooperation with the FDA: Chronologie
• Mai 2003 Presentation of the project (Rockville, MD)
• Nov 2003 – Juli 2004 Discussion of CP drafts with PATRIOT
• Aug 2004 FDA Pre Operational Visits (KC, FFM)
• Okt 2004 PAT CP (Comparability Protocol) Submission
• Dez 2004 PAT CP Approval
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Cooperation with the FDA: Pre Operational Visits (POV)
DP manufacturing and API production
•Technologies und scientific approach-Measurement systems, Data models, Development reports.......
•Industrialisation-Vendor selection, Data architecture.......
•Process-Prozess understanding, Risik analysis........
•Methodology-Calibration, Qualification, Documentation, Training.........
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Learning experience from PAT Pilot Project
• Use of New Technologies in lab and production
• Generation of Models for Prediction of properties, .......
• Data Analysing/Risk Analysis
• Calibration/Qualification/Validation of In-/On-line measurements
• Transfer of Analytical Methods from Laboratory to Plant
• Working in Multidisciplinary Teams
• To cooperate with regulatory bodies like FDA
PAT Initiative – Pilot Project API Production
G. Korb Sanofi-Aventis Deutschland GmbHPDC/C&PE Frankfurt
Take Home Message:Multidisciplinary Team Approach necessary
to have success