“On-Demand Manufacturing of Pharmaceuticals�
End-to-End, Integrated Continuous Manufacturing (ICM): A Development Pilot Plant Implementation Salvatore Mascia ISCMP 2018 October 3rd, 2018 London, UK
Finalist 2013
Technology Innovation Award
Boston, MA (USA) Facility
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ICM Facility Floor Plan
CONTINUUS’s Facility 10/7/2018
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Control Architecture for ICM Materials Management Equipment Tracking Operator Workflows Reporting
Raw Materials
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PAT Data
PAT Interface Measurement
Measurement
Control
Integrated Control System
PAT Data
Process Data
Dynamic Process Modeling Model Data
Coordination
Equipment Status
Manufacturing Execution System
ICM Plant
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Product Tablets
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ICM Development Plant is Operational!
CONTINUUS ICM Development Plant 10/7/2018
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Feeding and Dissolution of Raw Materials
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Feeding Performance Results FM1 wt. fraction
Weight fraction (-)
0.50
Expected FM1 wt. fraction
0.45 0.40 0.35 0.30 0.25 0.20 0
10
20
30
40 Time (h)
FM2 wt. fraction
0.50
50
60
70
80
Expected FM2 wt. fraction
Weight fraction (-)
0.45
0.40 0.35 0.30 0.25 0.20
0
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10
20
30
40 Time (h)
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50
60
70
80
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Continuous Clarification Bypass • Automated clarification bypass with cleaning in place (CPI)
Clarification through PTFE Filters
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Fully Automated
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Clarification Results
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Turbidity - filtered mix
Turbidity - unfiltered mix
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Turbidity (NTU)
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Unfiltered pre-reaction mixture: 5.78 NTU Turbidity calibration standard: 10 NTU (Nephelometric Turbidity Unit)
3 2
1 0 0
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10
20
30
40
50 Time (h)
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60
70
80
90
100
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Reaction & Crystallization
X1 X2
X3 X4
X5 Multi-stage cascade rectors with PATs : ReactIR and FBRM in X5 10/7/2018
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Reactive-Crystallization Results
Hu, C.; Finkelstein, J.; Wu, W.; Shvedova, K.; Testa, C.; Born, S.; Takizawa, B.; O'Connor, T.; Yang, B.; Ramanujam, S.; Mascia, S. (2018). Development of an automated multi-stage continuous reactive crystallization system with in-line PATs for high viscosity process. Reaction Chemistry & Engineering ID: RE-ART-05-2018-000078.R1
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PAT Results ReactIR: monitoring [FM1] w.r.t. API [FM1] w.r.t. API (wt%)
[FM1] > 3.5: reaction is not completed
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PAT Results FBRM: monitoring chord length distribution in last R.C. vessel
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Continuous Filtration
Filter plate side view
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Continuous Filtration Results
FM2 and other impurities < 0.05%
FM1 < 0.02%
Impact of crystallization temperature on API purity
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PAT Results ReactIR: monitoring [FM1] w.r.t. all solids in resuspension vessel DeltaV Time Stamp for HPLC Sampling
Sampling Location for HPLC analysis
DeltaV Time Stamp for ReactIR Prediction
ReactIR Measurement Location
30-Jun-2018 8:00 am
Dryer Exit*
30-Jun-2018 7:30 am to 7:55 am
Resuspension vessel
[FM1] w.r.t. Solids (wt%) HPLC
ReactIR Prediction
0.01
0.01 to 0.02
*Note: since the dryer does not remove any FM1, [FM1] w.r.t. solids should NOT change after being processed by the dryer.
ReactIR: monitoring [S1] w.r.t. slurry in resuspension vessel Sample Time
S1 (wt% w.r.t. slurry from GC)
ReactIR Prediction (wt% w.r.t. slurry)
6/30/2018 10:36
0.107
0.108
6/30/2018 15:00
0.0751
0.0754
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[S1] < 0.6% filtration is performing well
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Continuous Drying
nIR n-IR
Insitec (PSD) Raman 10/7/2018
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Continuous Drying Results
S1 < 880 ppm
S2 < 500 ppm
Residual solvent content (GC)
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PAT Results Raman: monitoring API crystallinity after drying
Evolution of API Crystal Peak Height
API Crystal. Peak
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PAT Results n-IR: monitoring [S1] & [S2] in API after drying
[S2] w.r.t. API (ppm)
[S1] w.r.t. API (ppm) 900
500 450 400 350 300 GC 250 n-IR Pred. for S1 200 S1 Specification 150 100 50 0
800 700 600 500 400
300 200 100 0 1
2
3
4
5
6
7
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n-IR Pred. for S2 S2 Specification
1
As time passed 10/7/2018
GC
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3
4
5
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7
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As time passed CONFIDENTIAL
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PAT Results In line Malvern for PSD Average Malvern PSD vs. Digisizer 600 500
um
400 Digisizer
300
Malvern
200 100 0 Dv(5)
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Dv(10) Dv(50) Dv(90) Dv(95)
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Extrusion-Molding-Coating (EMC)
Three-in-one drug product manufacturing
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Results Process and Formulation Development Steps: 1. Processability in the EMC machine: Multiple polymer + plasticizer combinations tried at varied temperatures and ratios 2. Increase of drug load: Gradual increase in drug loading simultaneously optimizing plasticizer content helped us achieve drug load of 60% by weight 3. API crystallinity: Confirmed the API crystallinity by XRPD of formulations processed by the machine 4. Evaluation of the target product profiles: Development ongoing
EMC Tablets 10/7/2018
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Commercial Business Case Study • COGS reduction vs batch is 30%-35% • Reduction in CapEx 40%-50% High volume generic drug
• Reduction in number of unit operations 80%-85% • Energy savings 50%-60% • Reduction in solvent usage > 60% • Footprint reduction > 90%
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Conclusions • ICM and its novel technologies can radically transform pharmaceutical manufacturing – Significant advantages in production time, cost, footprint and quality – Novel unit operations to enable integration and improve overall process performance – End-to-end, integrated control strategy to consistently achieve high product quality
• Status of the ICM Process: – Development pilot plant is operational – Plan for cGMP commercial implementation in 2019 – R&D project with FDA ETT to further inform future regulatory guidelines on ICM 10/7/2018
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Thank you! The CONTINUUS Pharmaceuticals Team www.continuuspharma.com info@continuuspharma.com
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