pat and uplc round table introducing patrol systems biopharma_uplc fo… · pat and uplc round...
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©2012 Waters Corporation 1
PAT and UPLC Round Table
Introducing PATROL Systems
David Lascoux
Jean-Michel Plankeele
Biopharma LC Meeting
Eschborn, October 17th
©2012 Waters Corporation 2
What Is PAT? What Are the PATROL Systems For?
PAT, PATROL: Process Analytical Technology
– ICH Guideline Q8(R2) and ICH Q9 & Q10 :
o A system for designing, analyzing, and controlling
manufacturing through timely measurements (i.e., during
processing) of critical quality and performance attributes of raw
and in-process materials and processes with the goal of ensuring
final product quality
All tools (techniques) for measuring/controlling the quality of
any (chemical/production) process
What is the Purpose of PAT?
– Improve knowledge (about a process) & reduce variability
– Improve the process
– Implementation of a QbD approach with real time data
©2012 Waters Corporation 3
Sensor Technology Utilized for PAT Applications Today
Probes (Temp, pH)
Dissolved Gas (02, CO2)
Total Organic Carbon (TOC)
Near-Infrared (NIR)
Infrared (IR)
Raman
UV-visible
Fourier Transform Infrared (FTIR)
X-Ray Powder Diffraction (XRPD)
…
Real time, simple, non destructive, fast response
But not quantitative, not specific, lack of resolution
©2012 Waters Corporation 4
Liquid Chromatography Lab Analysis Reference Standard
HPLC is a major analytical technique in every QC lab
– Too slow to get a “real-time” answer
– But it is not a major tool for Online/At-line analysis
UPLC overcomes limitations of HPLC
– Performance improvements
– Richer information
– Increased speed times of 10x or faster
End of Process
0 3 6 9 12 15 18 21 24 27 30 33 36 39
UPLC
HPLC
Minutes
©2012 Waters Corporation 5
Waters’ answer and solutions PATROL System
UPLC power
– « UPLC Inside » systems
– Speed, resolution, sensitive
Specially designed autosampler : PSM
– At-line and On-line sampling
– Automated dilutions
Rugged configurations for unattended use
Three configurations meeting lab/pilot and production scales
– Patrol UPLC Laboratory Analyzer
– Patrol UPLC Pilot system
– Patrol UPLC Process Analyzer (in the manufacturing area)
Connections with lab/plant environment
– Fluidics (eg sterile sampling)
– Informatics : DCS and Data management
©2012 Waters Corporation 6
PATROL UPLC Process Analyzer Three Configurations
Stainless steel cabinet Solvent & containers
Corporate network
UPLC BSM
UPLC Process Sample Manager
UPLC CM
PATROL Flex cart ELSD or SQD or TQD
PATROL Lab PC
Empower PATmanager
Laboratory/Pilot System Process System
PDA / TUV
©2012 Waters Corporation 7
Biopharmaceutical Process LC Dependant Large Molecule Applications
DOWNSTREAM UPSTREAM
©2012 Waters Corporation 8
On-Line Reaction Monitoring As the reaction progresses you
map the formation of the API and
the consumption of the starting
material
Additionally because of the high
linear range of the detector, you
can also monitor the formation of
any low level impurities
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Minutes
0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00
Injection #1
Injection #14
Injection #37
Injection #60
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Pe
ak A
rea
%
Injection #
API Starting Material Process Impurity 1 Process Impurity 2 Process Impurity 3 Process Impurity 4
©2012 Waters Corporation 9
Downstream Processing off-line, HPLC control of fractions
0 12 hours
Main Peak widths are measured in Hours
40 minute analysis
A minimum of 160L
requires reprocessing
Initial process
recovery yield 40%
Final recovery yield
after reprocessing
58%
COLLECT WASTE REPROCESS
©2012 Waters Corporation 10
Downstream Processing on-line, UPLC control of fractions
0 12 hours
Main Peak widths are measured in Hours
3.5 minute analysis
No fractions need
to be reworked
Total initial process
recovery yield
of 87% (40%/58%)
6 month ROI (1 of 4
steps)
COLLECT WASTE
©2012 Waters Corporation 11
UPLC Analysis
3.5 minute chromatography
Total initial process recovery:
87%
No reprocessing required
6 month ROI
Downstream Process Biopharmaceutical Purity Analysis
HPLC Analysis
40 minute chromatography
Initial process recovery - 40%
160L reprocessed at minimum
Final recovery after reprocessing:
58%
©2012 Waters Corporation 12
Biopharmaceutical Process LC Based Application Opportunities
Cleaning validation Additional process steps
Waste water testing
Waste Stream
©2012 Waters Corporation 13
Opening Questions
Would direct transfer method & process be beneficial?
– Improve handshake between development and production?
– Minimize scale up risk?
– Enable broader use of scientific information?
How does “real time” monitoring & control benefit your process?
– Enable improved yields & cycle times while reducing offline testing?
– Create fewer operator, dilution or equipment variability errors?
– What is the commercial value of this impact?
Can technology effectively extend the life of your product?
Time to Market (12-14 yrs)
Patent Protection (20 yrs)
Sales/Profits (10-12 yrs)
©2012 Waters Corporation 14
Technical Overview
©2012 Waters Corporation 15
Waters’ answer and solutions
UPLC power
– « UPLC Inside » systems
Specially designed autosampler : PSM
– Automated dilutions
– At-line and On-line sampling
Rugged configurations for unattended use
Two configurations meeting lab/pilot and production scales
– Patrol UPLC Laboratory Analyzer
– Patrol UPLC Process Analyzer
Connections with lab/plant environment
– Fluidics (eg sterile sampling)
– Informatics : DCS and Data management
©2012 Waters Corporation 16
Online Process Sample Manager Fluidic Components
Process Pump
Process Valve
Sample Pump Inject Valve
Diluent Pump
Priming Valve
Sampling Valve
Courtesy of Bob Tacconi
©2012 Waters Corporation 17
Atline Dilution Capabilities Linearity (n = 6)
R2 = 0.99994 1/x Weighting Excellent linearity across the entire
dilution range Aqueous rProtein sample diluted with 6M urea
Undiluted 2x Dilution 4x Dilution 10x Dilution 20x Dilution 100x Dilution
Dilution %RSD
Undiluted 0.11
2x 0.48
4x 0.70
10x 0.49
20x 0.59
100x 0.66
©2012 Waters Corporation 18
Online Injections
R2 = 0.99977
©2012 Waters Corporation 19
Technical Overview
©2012 Waters Corporation 20
Waters’ answer and solutions
UPLC power
– « UPLC Inside » systems
Specially designed autosampler : PSM
– Automated dilutions
– At-line and On-line sampling
Rugged configurations for unattended use
Two configurations meeting lab/pilot and production scales
– Patrol UPLC Laboratory Analyzer
– Patrol UPLC Process Analyzer
Connections with lab/plant environment
– Fluidics (eg sterile sampling)
– Informatics : DCS and Data management
©2012 Waters Corporation 21
Online Process Sample Manager Fluidic Components
Process Pump
Process Valve
Sample Pump Inject Valve
Diluent Pump
Priming Valve
Sampling Valve
Courtesy of Bob Tacconi
©2012 Waters Corporation 22
Sample Work Flow Comparison ACQUITY & PATROL Atline
LOAD
VIAL
VERIFY
VIAL
READ
BARCODE
VALIDATE
SAMPLE
ASPIRATE
SAMPLE
DILUTE
SAMPLE
INJECT
SAMPLE
ACQUITY
SAMPLE
MANAGER
LOAD
VIAL
ASPIRATE
SAMPLE
INJECT
SAMPLE
PATROL
PROCESS
SAMPLE
MANAGER
©2012 Waters Corporation 23
Process Sample Manager
Sample Introduction Access Door (open position)
Sample/Standard Insertion Slide (open with vial partially inserted)
©2012 Waters Corporation 24
The Process Sample Manager
can be included in UPLC (BSM)
and H-Class (H-Class Bio)
systems
This is another sample
manager for UPLC (SM-FL, SM-
FTN, 2777, OSM and PSM)
Empower control
On-line and At-line
32 sample position
Bar code reader
Sample dilution
PATROL Laboratory System
©2012 Waters Corporation 25
Patrol UPLC Laboratory Analyzer
Designed for Lab & Pilot use
Easy connection with small size reactors
Flexibility of detection around PSM
– TUV
– PDA
– FLR
– DEDL
©2012 Waters Corporation 26
PATROL Process System PATROL Laboratory System
UPLC based analyzer for the online /atline analysis of inprocess samples
Online UPLC analyzes reaction progress
– Measures concentration of starting material, intermediate, impurities, and final product
– Reaction stopped when residual starting material target achieved or impurities reach a threshold value
Two configurations:
– Patrol Process System (explosion proof cabinet)
– Patrol Laboratory System (benchtop or flex cart)
Automatic or manual transfer
On line dilution of samples
©2012 Waters Corporation 27
UPLC Module Access and Maintenance
©2012 Waters Corporation 28