The Development of an Integrated Control Strategy for a Continuous Primary Pharmaceutical Process

Transcription

1 The Development of an Integrated Control Strategy for a Continuous Primary Pharmaceutical Process Hannah Robinson GlaxoSmithKine 2 nd International Symposium on Continuous Manufacturing of Pharmaceuticals, th Sept 2016 Cambridge, MA

2 Agenda 1. Introduction Process overview 2. Implementation of a flow process control strategy Chemistry and equipment control Material control Traceability Batch definition Parameter control Controlled state Disturbance handling Process monitoring and trending 3. Summary Process performance over time Data trending and sampling rate

3 Introduction

4 Process Overview Stripping Column Reagent 3 Reagent 4 Holding tank Starting Material Reagent 1 Reagent 2 Reagent 5 Reagent 6 Buffer Pot Stage 1 Reactor DTW Intermediate Feed Stage 2 Reactor Stage 3 Reactor 1 Stage 3 Reactor 2 DTW Crystalliser

5 Implementation of a Flow Process

6 Viscosity (cp) Process profile (see legend) Process Profile (concentration) Process Understanding Chemical control Kinetics Calorimetry Physical property behaviour of streams Mixing sensitivity Viscosity of reaction solution 10 8 ST V Lab-scale targe t conditions Reaction 1 By-product Reagent 2 Reaction Product 1 Intermediate 1 Product Temperature o C Time (min) Residence time (min) 6

7 Equipment Specification and Characterisation Equipment control Stripping Column Reagent 3 Reagent 4 Holding tank Starting Material Reagent 1 Reagent 2 Reagent 5 Reagent 6 Buffer Pot Stage 1 Reactor DTW Intermediate Feed Stage 2 Reactor Stage 3 Reactor 1 Stage 3 Reactor 2 DTW Crystalliser Mixing intensity and Re Reactor volumes and surface area Heat transfer capability Residence time distribution Residence Time Distribution 7

8 Material control 8

9 Material control System dynamics Stripping Column Reagent 3 Reagent 4 Holding tank Starting Material Reagent 1 Reagent 2 Reagent 5 Reagent 6 Buffer Pot Stage 1 Reactor DTW Intermediate Feed Stage 2 Reactor Stage 3 Reactor 1 Stage 3 Reactor 2 DTW Crystalliser Plug flow CSTR Plug flow CSTR Divert to waste point 9

10 Material control Material boundaries Start of equipment End of equipment Stripping Column Reagent 3 t Reagent 4 Holding tank Starting Material Reagent 1 Reagent 2 Reagent 5 Reagent 6 Buffer Pot Stage 1 Reactor DTW Intermediate Feed Stage 2 Reactor Stage 3 Reactor 1 Stage 3 Reactor 2 DTW Crystalliser Residence Time Distribution 10

11 Parameter Control 11

12 Parameter control State of control DS higher range (where applicable) CPP / PP SP DS lower range Time Parameter has entered the design space (1), converging on its set point (2) and remains inside the design space for the duration of the reactor (3)

13 Parameter control Control system infrastructure Quality Traffic Light Quality alarms activated depending on sequence phase Quality met? Yes / No Collect / Divert To Waste (DTW) Ratio control Active during controlled state To maintain stoichiometry To allow co-ordinated step up step down of each section of the process Alarms, trips and interlocks Sequence Phases Safety system active throughout Sequence phases drive allowable activities CM EM Individual control loops maintain SP PAT and MVA process monitoring Trending of tags, to detect system drift operational controls Operational prompt to look at control system to identify need for manual action Data gathering for process understanding System Characterisation RTD Providing timings for start-up, shutdown, alarm settings and DTW actions

14 Parameter control Disturbance handling CPP / PP SP Warning alarm Parameter limit Time DCS offers tiered approach to parameter control: Control loop logic return to set point Alarm system alerts operator to disturbance Warning Interlock system allows automatic DTW if a parameter limit is exceeded

15 Process Monitoring and Trending 15

16 Flow and Pressure Flow rate (g/min) Process monitoring and trending Control trends Start-up Sequence Controlled state Control Box 5 Flow Controller 1 g-min Control Box 5 Flow Controller 2 g-min Control Box 5 Flow Controller 3 SP g-min Reactor 1 Pump 1 Flow g-min Reactor 1 Pump 3 Flow g-min Reactor 2 Pump 1 Flow g-min Reactor 2 Pump 2 Flow g-min Reactor 2 Pump 3 Flow g-min Conductivity Probe 3 us Conductivity Probe 6 us Time Control Failure Control Blip Control Box 5 Flow Controller 1 g-min Control Box 5 Pressure Controller barg Reactor 1 Pump 1 Flow g-min Reactor 1 Pump 4 Flow g-min Control Box 5 Flow Controller 3 g-min Time 16

17 Process monitoring and trending MVA Monitoring Process drift RCA Pump alarm and pump switch Multivariate alarm Multivariate alarm: 12:48 Univariate alarm: 13:52 Action: pump switch at 13:52 DTW and/or shutdown prevented Operational Space Pump alarm and pump switch Univariate trend Flow rate (ok) 17

18 Peak Area % PAR Process monitoring and trending PAT data for process monitoring Process utilises online HPLC Sample taken every 20 mins Indication of process stability 72 Chromatogram overlay Starting material recharge Sample number 18

19 Conductivity (us) Process monitoring and trending PAT data for process monitoring Process utilises online HPLC Sample taken every 20 mins Indication of process stability Conductivity /03/ :30 22/03/ :00 22/03/ :30 22/03/ :00 Date (dd/mm/yy), Time (hh:mm) Stage 1a Stage 1b Stage 2a Stage 2b Stage 3ai Stage 3aii 24/03/ :12 24/03/ :42 24/03/ :12 Date (dd/mm/yy), Time (hh:mm) Stage 1a Stage 1b Stage 2a Stage 2b Stage 3ai Stage 3aii 19

20 Summary

21 Summary Use of continuous technology processes within the Pharma industry requires a change in batch operation mindset Some additional quality levers Some additional challenges Continuous processes offer many opportunities for utilisation of combined process and equipment understanding Predictive modelling Scaling capability Operational controls Continuous processes offer a wealth of data which can be used pro-actively to manage the process and equipment Data display Use of MVA Need to use data wisely at an appropriate scale of scrutiny

22 Acknowledgements Malcolm Berry Peter Shapland Mark Hughes Matt John Gill Turner Irene Areri Peter Hamilton Melanie Dumarey Yahyah Yahyah Neil Hodnett Augustine Ochen Sabri Ukuser Andrew Richards Andrew Rutter Gareth Alford Dave Johns Rob Wadley Heather Todd Peter Clements Chris McKay Ben Hagger Mathew Callaghan-Till Clarence Wong Lesley Wong Wei-Feng Tan Nicholas Kwok Gary Breen

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