Dr Salvatore Mascia of CONTINUUS End-to-End Integrated Continuous Manufacturing

“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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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

8

n-IR Pred. for S2 S2 Specification

1

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GC

2

3

4

5

6

7

8

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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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