PAT Initiative Pilot Project API Production. Gerhard Korb. Sanofi-Aventis Deutschland GmbH. Process Development Chemistry

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Gerard Hensley
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1 Gerhard Korb Sanofi-Aventis Deutschland GmbH Process Development Chemistry Chemical & Particle Engineering Frankfurt

2 Summary PAT Initiative Pilot Project API Production Tools - Definition Example Additional PAT Elements Resources/Infrastructure Cooperation with the FDA (POV) PAT Comparability Protocol Learning experience

3 Sanofi-Aventis PAT Tools DOE FMEA Qualification Validation Sensors Inferential ph, pressure, temp Direct NIR, Raman, NMR Design for Quality Univariate Multivariate Real-Time On Location Data Analysis Process Control Feed-Forward Feedback Multivariate Control Continuous Processes

4 Overview Definition: PAT System PAT-Approach PAT System Approach like-for-like approach Current Test off-line PAT System Approach Alternate Test* at-line same specs same sample size near real-time control backed-up by lab test etc. PAT Measurement System* on-line or in-line different acceptance criteria different sample size real-time release feed back / forward increased 'knowledge' PAT submission etc. Like-for-like can mean: using modern sensor technology not integrated in a PAT system.

5 Options to implement PAT A. Currently marketed robust products. PAT to improve efficiency (minimal improvement in quality assurance)* IO Pilot B. Currently marketed products that need improvement. Step-wise PAT approach - First improve quality and then improve efficiency R & D C. New products. PAT utilized throughout development and scale-up. Lab based tests to ensure shelf-life and/or for establishing public standards.

6 Project overview API production and DP manufacturing RM IP 1 NIR GC (off-line) IP 2 IP 3 NIR (distillation) GC (off-line) IR (off-line) NIR HPLC (off-line) NIR (turnover) IP 4 SM IP 5 IP 6 API Hydrate NIR (reagent content) Base titration (off-line) Laser Diffraction (Process Control) Particle Size and SSA (off-line) API API (milled) NIR (Process control) Water content Karl Fischer (off-line) proposed PAT System Current Analytical Method PAC Compendial PAC Testing Excipients acitve Control process parameters Wet Granulation DP1 Control process parameters LOD PAC Drying DP2 Control process parameters Blending/ Lubrication PAC Powder Fineness DP4 Control process parameters Compression DP5 Bulk Physical Defects Friability Weight Hardness Thickness PAC Control process parameters Film Coating Avg Tablet Weight Bulk Physical Defects Spec Testing ID Assay Water CU Degradents Dissolution Final Product DP6

7 Projekt API production - Overview RM IP 1 NIR GC (off-line) IP 2 IP 3 NIR (distillation) GC (off-line) IR (off-line) NIR HPLC (off-line) NIR (turnover) IP 4 SM IP 5 IP 6 API Hydrate NIR (reagent content) Base titration (off-line) Laser Diffraction (Process Control) Particle Size and SSA (off-line) API API (milled) NIR (Process control) Water content Karl Fischer (off-line) proposed PAT System Current Analytical Method

8 Example Intermediate: Overview Reaction Side reaction A + B C A + D E Conversion Content A 100% 50% Example Reaction C/3 bar Sampling 5% 0% In-line NIR Reaction time On-line Off-line sampling (HPLC)

9 Example Intermediate: Situation without PAT Parameter -Nitrogen flow -Heating -Dosage B Off-line Test -Main product -Hydrolysis by product Pre step Intermediate Next step

10 Example Intermediate: PAT Approach RM IP 1 IP 2 IP 3 IP 4 Optimal conversion Avoiding hydrolysis Minimaziation E SM IP 5 IP 6 API Hydrate Minimaziation decomposition Minimaziation F API API (milled) Reduction of variability of Related substance Minimaziation G

11 Example Intermediate: PAT Approach NIR In-line -Content Water -Content A -Nitrogen flow -Heating -Dosage B Pre step Intermediate Post step

12 Example Intermediate: Information from NIR spectra Water content Content A

13 Example Intermediate: Scale Up/Scale Down NIR Dosage B

14 Example Intermediate: Scale Down/Scale Up Nitrogen flow NIR Sensor Hydrodynamic!

15 Example Intermediate: Implementation To PCS Non Ex Zone Ex Zone

16 Generell Procedure for implementation of PAT tools Laboratory Conditions in conditions Production plant T, p,... constant T, p,...variabel Feasibility Scale Down Model Validation Implementation Process Monitoring Process Control

17 Example Intermediate: Data integration Mass B Temperature Content A Coarse model (NIR) Content A Release model (NIR, Model validated Content Water ppm (NIR) Content p-cpke coarse model Temperature reactor HCl mass (kg) Content p-cpke release model pressure (bar) Water 20 (NIR) Pressure :00: :38: :16: :54: :33: :11: :49: :27: :06: :44: :22: :00: :39: :17: :55: :33: :12: :50: :28: :06: :45: :23: :01: :39: :18: :56: :34: :12: :51: :29:15

18 Example Intermediate: Variability Content A Control chart: batches produced in 2004 (without PAT) HPLC: content p-cpke (%) 4,2 3,2 2,2 1,2 0,2-0,8 D0692 D0703 D0714 D0725 D0736 D0747 D0758 HPLC D0769 D0780 UCL = 2,31 CTR = 0,76 LCL = -0,78 Batches 2004 without NIR NIR Monitoring Final Implementation Control chart: batches produced in 2004 (with PAT) Control chart: batches produced in 2004 (with PAT) HPLC: content p-cpke (%) 4,2 3,2 2,2 1,2 0,2-0,8 D 0790 D 0801 D 0812 D 0823 UCL = 1,09 CTR = 0,46 LCL = -0,16 NIR: content p-cpke (%) 4,2 3,2 2,2 1,2 0,2-0,8 D 0790 D 0801 D 0812 D 0824 UCL = 1,11 CTR = 0,49 LCL = -0,13

19 Example Intermediate: Variability G in API Gehalt (%) Fexofenadin Content gemahlen related (Gehalt substance Isopropyl-Analog) in API Spezifikation: <= 0,15 % 0,15 0,14 UCL = 0,02 0,13 0,12 CTR = 0,01 0,11 0,1 LCL = 0,01 0,09 0,08 0,07 0,06 0,05 0,04 0,03 0,02 0,01 0 L732 L753 L774 L795 L816 L837 L858 L879 L900 L921 L942 D963 D984 D007 D028 D049 D070 D091

20 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

21 Additional PAT Elements: System Performance (NIR) SPEKTROMETER COMPUTER EXTERNE SYSTEME Light source Spectra Industry-PC OPUS-Software-Modules File Server Conection box FO SENSOR Data ma, ProfiBus Start / Stop Measurement Control Module PCS

22 Additional PAT Elements: Model generation/validation NIR Transfer Method PAT Laboratory Plant NIR -Water content -Content A Model generation and Model validation Sensor calibration System Calibration Method Transfer/Monitoring Long term satability Spectral Information Model Chemometry Test/Validation Documentation

23 Additional elements: Risik analysis Automation Reactor Machine People Operatop s error Controler settings Piping Agitator HCl cylinder Sampling System P-CPKE Length Sensor design/location No Training Carelessness No process understanding Variability (Water, Gehalt pcpke) ANIR Temperature/Pressure settings Fishbone FMEA FTA... Humidity (Heptan) Material of construction NIR Toluene Calibration Maintenance Nitrogen blowing Volumetric rate Material Measurement Nitrogen volumetric rate Performance Calibration/Maintenance Method Agitator speed Potential Failure Mode and Effects Analysis Process/System p-cke Area Affected: p-cke production IC14 Prepared ByPAT Team Responsible Team: PAT Team Product: Fexofenadine HCl FMEA Date (20. Aug 04 Other Areas InvoProduction, Engineering, Quality Quality Control NA FMEA Date (Draft; 26. Aug PROCESS FUNCTION POTENTIAL FAILURE MODE POTENTIAL FAILURE EFFECT Effect Type Q S B Effect Severity POTENTIAL FAILURE CAUSE Current Controls in Place Occurence of Cause Current Detection Method Detectability RPN Area/Indivi dual Recomm Responsi ended ble for Action(s) Action and Action(s) Taken Action Results OCC SEV Q Q Q Q Q Q Q Q

24 Resources for PAT Project: PAT Project Leader Analytical Development Scientist Chemometrician Spectroscopist Process Engineer Process Control Engineer Quality Leader Programmer Database Expert Material Characterization Scientist Statistician Manufacturing Leader Operators Regulatory specialist

25 Infrastructure for PAT Project 10 l HC4 Reactor Dioden Array NIR Dioden Array UV/VIS Turbitidy Reactor control Computer FT-NIR Sensor PCS FT-NIR with Multiplexer

26 Cooperation with the FDA: Chronologie Mai 2003 Nov 2003 Juli 2004 Aug 2004 Okt 2004 Dez 2004 Presentation of the project (Rockville, MD) Discussion of CP drafts with PATRIOT FDA Pre Operational Visits (KC, FFM) PAT CP (Comparability Protocol) Submission PAT CP Approval

27 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...

28 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

29 Take Home Message: Multidisciplinary Team Approach necessary to have success

Application of PAT for Tablet Analysis. Case examples from Novartis Lorenz Liesum, Lead PAT Hamburg, 19 th of April 2013

Application of PAT for Tablet Analysis Case examples from Novartis Lorenz Liesum, Lead PAT Hamburg, 19 th of April 2013 Agenda PAT@Novartis Organization Business Drivers and Cases NIR Spectroscopy for