PAT and UPLC Round Table Introducing PATROL Systems David Lascoux Jean-Michel Plankeele Biopharma LC Meeting Eschborn, October 17th 2012 Waters Corporation 1
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 2
Sensor Technology Utilized for PAT Applications Today Probes (Temp, ph) Dissolved Gas (0 2, CO 2 ) 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 3
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 UPLC HPLC End of Process 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Minutes 2012 Waters Corporation 4
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 5
PATROL UPLC Process Analyzer Three Configurations Laboratory/Pilot System Process System Empower PATmanager PDA / TUV UPLC CM UPLC Process Sample Manager UPLC BSM PATROL Flex cart ELSD or SQD or TQD PATROL Lab PC Stainless steel cabinet Solvent & containers Corporate network 2012 Waters Corporation 6
Biopharmaceutical Process LC Dependant Large Molecule Applications UPSTREAM DOWNSTREAM 2012 Waters Corporation 7
AU Process Impurity 1 Process Impurity 2 Process Impurity 3 Starting Material API Process Impurity 4 Process Impurity 1 Process Impurity 2 Process Impurity 3 Starting Material API Process Impurity 4 Peak Area % AU AU Process Impurity 2 Process Impurity 3 Starting Material API API AU Starting Materia On-Line Reaction Monitoring 1.40 0.70 Injection #1 As the reaction progresses you map the formation of the API and the consumption of the starting material 0.00 1.40 0.70 Injection #14 Additionally because of the high linear range of the detector, you can also monitor the formation of any low level impurities 0.00 100 1.40 Injection #37 90 80 0.70 70 60 0.00 50 1.40 Injection #60 40 30 20 0.70 10 0 0.00 0 10 20 30 40 50 60 0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 Injection # Minutes 2012 Waters Corporation API Starting Material Process Impurity 1 Process Impurity 2 Process Impurity 3 Process Impurity 4 8
Downstream Processing off-line, HPLC control of fractions 40 minute analysis A minimum of 160L requires reprocessing Initial process recovery yield 40% Final recovery yield after reprocessing 58% 0 12 hours Main Peak widths are measured in Hours COLLECT REPROCESS WASTE 2012 Waters Corporation 9
Downstream Processing on-line, UPLC control of fractions 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) 0 12 hours Main Peak widths are measured in Hours COLLECT WASTE 2012 Waters Corporation 10
Downstream Process Biopharmaceutical Purity Analysis HPLC Analysis 40 minute chromatography Initial process recovery - 40% 160L reprocessed at minimum Final recovery after reprocessing: 58% UPLC Analysis 3.5 minute chromatography Total initial process recovery: 87% No reprocessing required 6 month ROI 2012 Waters Corporation 11
Biopharmaceutical Process LC Based Application Opportunities Cleaning validation Additional process steps Waste Stream Waste water testing 2012 Waters Corporation 12
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) Sales/Profits (10-12 yrs) Patent Protection (20 yrs) 2012 Waters Corporation 13
Technical Overview 2012 Waters Corporation 14
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 15
Online Process Sample Manager Fluidic Components Process Pump Sampling Valve Sample Pump Inject Valve Diluent Pump Priming Valve Process Valve Courtesy of Bob Tacconi 2012 Waters Corporation 16
Atline Dilution Capabilities Linearity (n = 6) Excellent linearity across the entire dilution range R 2 = 0.99994 1/x Weighting 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 17
Online Injections R 2 = 0.99977 2012 Waters Corporation 18
Technical Overview 2012 Waters Corporation 19
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 20
Online Process Sample Manager Fluidic Components Process Pump Sampling Valve Sample Pump Inject Valve Diluent Pump Priming Valve Process Valve Courtesy of Bob Tacconi 2012 Waters Corporation 21
Sample Work Flow Comparison ACQUITY & PATROL Atline LOAD VIAL ASPIRATE SAMPLE INJECT SAMPLE ACQUITY SAMPLE MANAGER LOAD VIAL VERIFY VIAL READ BARCODE VALIDATE SAMPLE ASPIRATE SAMPLE DILUTE SAMPLE INJECT SAMPLE PATROL PROCESS SAMPLE MANAGER 2012 Waters Corporation 22
Process Sample Manager Sample/Standard Insertion Slide (open with vial partially inserted) Sample Introduction Access Door (open position) 2012 Waters Corporation 23
PATROL Laboratory System 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 2012 Waters Corporation 24
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 25
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 26
UPLC Module Access and Maintenance 2012 Waters Corporation 27
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