Yang Angela Liu, Ph.D. Pfizer Worldwide Research & Development Groton CT, USA

Transcription

1 On the horizon: The integrated PAT control strategy for PCMM (portable, continuous, miniature, modular) - an agile development and manufacturing platform Yang Angela Liu, Ph.D. Pfizer Worldwide Research & Development Groton CT, USA This document provides an outline of a presentation and is incomplete without the accompanying oral commentary and discussion. Conclusions and/ or potential strategies contained herein are NOT necessarily endorsed by Pfizer management. Any implied strategy herein would be subject to management, regulatory and legal review and approval before implementation.

2 Outline Introduce PCMM OSD Agile, small foot print, fast change over, knowledge accural The design sweet spot integrated control strategy starting from the design Engineering design Engineering model PAT APC Integrated attribute based monitoring system Maximize value in the early development life cycle to cover critical control strategy components Stage appropriate approach in an accelerated development timeline Conclusion 1

3 PCMM OSD: A Factory in a POD Continuous Processing Platform Technology for Solid Oral Dosage Forms (HSWG and CDC) Skids Pre-fabricated in Belgium Integrated into a Portable cgmp POD 6 Modules Pre-fabricated in College Station Texas FAT in Belgium Shipped to Groton Building 90 Mock-up Equip. Skids FAT in Texas Shipped to Groton and re-assembled into a grey space warehouse in Groton, CT 1. Phillip R. Nixon, Changing the Pharmaceutical Industry Paradigm: Portable, Continuous, Miniature & Modular Development and Manufacturing, 2015 ISPE/FDA/PQRI Quality Manufacturing Conference, June 1, 2015

4 PCMM OSD POD Layout Raw Materials Tech Space cgmp Space Airlock & Cleaning Corridor/Entrance POD 3

5 Future State PCM&M Platform Technology Current State (dry granulation / roller compaction) Phase IIB Clinical Supplies Drug Product Quantities Future State (dry blend / direct compaction) <1 hour x Tech Transfer & Process Scale Up <10 kg time Phase III Clinical Supplies x Tech Transfer & Process Scale Up <100 kg several hours time Commercial Supplies 100 to 1000 kg Flexible time 4

6 Future State PCM&M Platform Technology Platform Technology Experiments Engineering Models Process Analytical Technology Drug Product Quantities Phase IIB Clinical Supplies <10 kg Phase III Clinical Supplies <100 kg Future State (dry blend / direct compaction) <1 hour several hours time Advanced Process Control Reduced Time, $, Resources Commercial Supplies 100 to 1000 kg time Flexible time 2. Daniel Blackwood, Portable, Continuous, Miniature and Modular (PCM&M) Approach to Redefining the Development and Manufacturing Paradigm, 5 AAPS - Arden House Conference, Baltimore, MD, March 17, 2015

7 Future Continuous Knowledge Accrual Paradigm with PCMM Within R&D Tech Transfer R&D to Commercial Tech Transfer Within Commercial Tech Transfer Product A Process Knowledge Build Knowledge from Product A directly informs Product B Product B Knowledge Accrual Ac Knowledge Accrual Knowledge Accrual Process Knowledge Build Within R&D Tech Transfer R&D to Commercial Tech Transfer Within Commercial Tech Transfer 3. Phillip Nixon, Broad Implementation of Continuous Manufacturing for Solid Oral Drug Products: What Can the Future Look Like? AAPS - Arden House Conference, Baltimore, MD, 2015 March 17, 2015

8 An Integrated Approach to a Platform Technology World-class Materials Science & Formulation Development Practices Advanced Integrated System Equipment Design Process World-class Commercial Manufacturing Process Analytical Control Technology Particle Engineering for API and Excipients Engineering Models ~500 MM tab/year 24/5 operation, 30% downtime 7

9 PCMM OSD Prototype Processing Equipment CMT Mixer Feeders CMT Mixer Feeders Tablet Press Granule Conditioning Unit HSWG Wet Granulation Dryer Total Elevation ~14.5 ft Continuous Mixing & Direct Compression ConsiGma TM WG Raw Material Dispensing

10 Continuous Mixing Technology (CMT) Engineering Design Gravimetric Feeders In-Line Mixer Tablet Press Continuous Mixing Technology Goals Powder mixing as close to dosage form creation as possible Independent control of Powder Hold Up Mass, Mass Throughput, and Impeller RPM Residence Time Distribution Based on simple CSTR model Consistent RTDs over a wide range of process conditions Integrated powder de-lumping capabilities Integrated PAT sensors Minimal/Zero Waste Start Up & Shutdown 2. Daniel Blackwood, Portable, Continuous, Miniature and Modular (PCM&M) Approach to Redefining the Development and Manufacturing Paradigm, AAPS - Arden House Conference, Baltimore, MD, March 17,

11 What Is PAT Expected To Achieve Fast development of processing Optimization of product processing Condition monitoring / fault diagnostics Know if something deviates from normal Check correctness of each unit operation Support for the use of Advanced Process Control Fast Release of product Mission statement - Maximize the value and knowledge starting from the early design and development stage 4. Steve Hammond, Sonja Sekulic, Fast Release and Continuous Processing: A Vision of the Future, Going Continuous - Advanced PAT and Real Time Release, Graz, Austria, September 16th,

12 PCMM OSD PAT and Product Diversion Diversion 1 Post Fluid Bed Drying PAT 1 (NIR) Post CMT Potency & Blend Uniformity PAT 5 (NIR) Feed Frame Potency & Blend/Granule Uniformity Combi Tester Weight Hardness Thickness PAT 3 (NIR) Post Granule Sizing Potency & Granule Uniformity, Moisture PAT 4 (FBRM) Post Granule Sizing PSD PAT 2 (NIR) Post TSWG Granule Formation Diversion 3 Tablet Eject Chute Continuous Mixing & Direct Compression Diversion 2 Post Granule Sizing ConsiGma TM WG

13 The Integrated PAT Platform Analyzers: reliable, fast sensing, consistent, standardized. Sample interfaces : Representative sampling No probe fouling Minimal process intrusion Foundation of robust real time monitoring Communication platform PAT Real Time Manager system Supported by automation and IT infrastructure PAT devices, data and model are centrally control and managed Data exchange with process SCADA: acquisition triggering, alarming, diversion PAT data and process data are synchronized: trending and modeling Chemometrics /modeling Large, real time, multivariate data Robust and minimal calibration approaches Connection with APC Intelligence Center 12

14 API potency trend PAT1 Mixing Dynamic Characterization PAT1 tracks the blend potency out of CMT. Important to characterize the CMT mixing dynamic and residence time distribution 3.5 x % Tracer Spike CMT trial DoE Run Run #15 Mass throughput: 7.5kg/hr Hold up mass: 460g Upper impeller: 1000 Lower impeller: Samples (elapsed time)

15 Scores on PC 1 (68.04%) PAT2 NIR at Twin Screw Wet Granulator Outlet 3 x 10-3 Samples/Scores Plot of px Liquid addition ramp: 15% to 18% Sample Segmented dryer

16 PC 1 (59.99%), PC 2 (19.14%) Scores on PC 2 (18.07%) PAT2 - Granule Condition Monitoring Granules from different conditions showed in clusters based on their overall spectral feature Variables/Loadings Plot for px 4 x Samples/Scores Plot of px Low moisture, high potency Variable Scores on PC 1 (59.91%) x 10-3

17 PAT5 - Feed Frame Monitoring Innovated sample interface design to achieve robust spectral signal. Location advantage: Characterize the blend right before tablet compression: potency and the extent of lubrication. Real time characterize process dynamic. Enable diversion, feed back/forward control. Platform technology: no impact from tablet size, commercial image Micrometer NIR probe Sensitivity for low dosage product demonstrated 6% (120% potency) 4% (80% potency) *assume 5% as target potency (100%) Modified paddle wheel 16

18 PAT and Process Variables For Process Dynamic Understanding API% setpoint change Potency in feed frame change onset CSTR Potency decrease observed by PAT 5 Hold up mass sudden drop Impeller set point change

19 API% API% Product Tracking and Condition Monitoring Feeders PAT 3 (NIR) Post Granule Sizing PAT 1 (NIR) Post CMT Time 0:00 Time Time 1:15 Time 11:00 22:00 Feeders Set Point Blends Step Milled Change Post Granules CMT In feed frame in immediate GCU before tableting PAT 5 (NIR) Feed Frame 25 Case study: Results are for the specific operating conditions of the trial Set Point 15 PAT1 Post CMT PAT3 GCU PAT5, Feed Frame PAT1, PAT3, Feeders Post GCU 75sec 10 PAT5 FeedFrame Set CMT Point Step Change 5 ~75sec 11min 11min 22min 22min Time/Min Time/Min Time/Min

20 Value of PAT For Control Strategy and Quality Assurance Fast, real time monitoring Map out critical control strategy components at early design stage by leveraging effective experiment design Characterize process dynamic Product tracking Condition monitoring/fault detection: Besides potency, potentially on other components and physical properties 19

21 Advanced Process Control PCMM is equipped with APC platform capability POC demonstrated on prototype equipment Model predictive control on critical process parameters Feed back control with PAT and soft sensor Ongoing effort on: MSPC and fault detection Hybrid soft sensors End-to-end APC system 20

22 Impact Stage Appropriate Control Strategy: A Development Continuum The platform is equipped with monitoring, modeling and control capability to ensure product quality higher level control with combination of different components. To realize the vision of an adaptable and agile manufacturing paradigm, there is a need to balance the online and offline analytics to the stage of development.. High Medium Process Monitoring/Control: SPC/MSPC/SQC, (parameters & attributes) Release: Offline Process Control: MSPC/SQC (parameters & attributes), MPC on CPP Release: Combination of Online and Offline Process Control: Comprehensive Closed loop control strategy Release: Online (RTRt) Low Stage 1 Clinical Stage 2 Co-Development Development Stage Stage 3 Commercial

23 Managing Variable Inputs: Part of the Journey to Six Sigma Current State Variable Input & Limited Understanding (Optimized) Constant Process Variable Output Preferred State Variable Input & Advanced Understanding Variable Process (APC) Constant Output (Robust Process) Feed Back Feed Forward Stage-appropriate!

24 Conclusion The PCMM control strategy roots from its integrated design concept. The sweet spot of engineering design, engineering models, PAT and APC ensures quality and maximizes the continuous process benefit. The state appropriate control strategy enables agile product development and manufacturing. 23

25 References 1. Phillip R. Nixon, Changing the Pharmaceutical Industry Paradigm: Portable, Continuous, Miniature & Modular Development and Manufacturing, 2015 ISPE/FDA/PQRI Quality Manufacturing Conference, June 1, Daniel Blackwood, Portable, Continuous, Miniature and Modular (PCM&M) Approach to Redefining the Development and Manufacturing Paradigm, AAPS - Arden House Conference, Baltimore, MD, March 17, Phillip Nixon, Broad Implementation of Continuous Manufacturing for Solid Oral Drug Products: What Can the Future Look Like? AAPS - Arden House Conference, Baltimore, MD, 2015 March 17, 4. Steve Hammond, Sonja Sekulic, Fast Release and Continuous Processing: A Vision of the Future, Going Continuous - Advanced PAT and Real Time Release, Graz, Austria, September 16th, Yang (Angela) Liu, PAT and multivariate condition monitoring for drug product continuous process, SciX, Providence, RI, September 29, Yang (Angela) Liu, Daniel Blackwood, Jeffrey Moriarty, NIR In-Line Monitoring for Drug Product Continuous Process: From Understanding to Control, BioPharma Asia, June 16th, Koji Muteki, Daniel O. Blackwood, Brent Maranzano, Yong Zhou, Yang A. Liu, Kyle R. Leeman, and George L. Reid, Mixture component prediction using iterative optimization technology (calibration-free/minimum approach), Industrial & Engineering Chemistry Research, 52(35), Yang (Angela) Liu, Koji Muteki, Daniel O. Blackwood, Online Feed Frame Monitoring of Blends/Granules During Tablet Compression, IFPAC, Baltimore, Jan 22-25, Howard W. Ward, Daniel O. Blackwood, Mark Polizzi, Hugh Clarke, Monitoring Blend Potency in A Tablet Press Feed Frame Using Near Infrared Spectroscopy, Journal of Pharmaceutical and Biomedical Analysis, 80 (2013), Yang Liu, Daniel O. Blackwood, Sample Presentation in Rotary Tablet Press Feed Frame Monitoring by Near Infrared Spectroscopy, American Pharmaceutical Review, May

26 Acknowledgement PCMM OSD Prototype Team PCMM Implementation Team PCMM PAT Team PCMM Analytical support team Perceptive Engineering Colleagues from GEA and G-Con Slides and references courtesy Daniel Blackwood Phil Nixon Steve Hammond Sonja Sekulic 25

27 Questions? 26

28 Backup 27

29 A PCMM campaign as an example of large data mining 5 days. 1 day of DC integrated run, 1 day of WG integrated run. DC integrated run: 6 hours of run time, 19 DoE runs on process parameters. 1 PAT (PAT5) with ~60 process parameters simultaneously tracked in every 4 sec interval. ~110Mb data WG integrated run: 6 hours of run time, 18 DoE runs on process parameters. 5 PATs, 200+ process parameters simultaneously tracked. ~500Mb data Rich process understanding info. Great opportunity for utilizing data mining and modeling to gain process understanding for development and control.