ConsiGma™

A platform for Continuous Solid

Dosage manufacturing enabling

Quality by Design and Lean

Manufacturing

O. GOLDSTEIN

CONTINUOUS MANUFACTURING IN THE PHARMACEUTICAL INDUSTRY

DANISH PHARMACEUTICAL SOCIETY 26TH OF APRIL, 2017

2APC Pharma

Why Continuous Processing ?

• Post blockbuster era

• New Chemical Entities in development are more targeted medicines, smaller

quantities, more variants requiring more flexibility and agility

• Pressure to reduce manufacturing costs.

• Pressure to bring products faster to the market by accelerating R&D : faster data

collection with less kgs of API, avoiding scale-up, fast launch plants

• « Quality by intelligence » instead of simple « Quality by compliance » to

guarantee security of quality and delivery to patients.

• Authorities vision is to promote an agile, flexible pharmaceutical sector that

reliably produce high quality drugs without extensive regulatory oversight.

Current challenges in the pharmaceutical industry

Our Vision is to be at the forefront of the Pharma Industry’s transition from batch to

continuous processing. We are uniquely positioned to achieve this because we are

able to combine:-

GEA’s vision for Continuous Processing

GEA Pharma expertise from over 50 years in solid dosage production

GEA’s continuous processing experience from the installation of over 5,000 continuous

production systems in the food and chemical industries

Turn-key solutions which offer our customers the security of working with a

single provider

Integration of the complete production line - from powder to coated tablet -

including modular options for wet granulation, direct compression and roller-

compaction with (PAT) controls to ensure end product quality

GEA’s Strategy for Continuous Processing

• 2005 Start development of the ConsiGma™

wet granulation concept

• 2006 First working prototype

• 2007 First commercial project with customer

• 2008 Formal launch of ConsiGma™ ‘powder-

to-granule’ at Interpack

ConsiGma™ milestones

• 2009 Formal launch of ConsiGma™

‘powder-to-tablet’ at Achema

• 2010 Realization of new Process

Development Centre

• 2011 Launch of ConsiGma™ 1 for R&D

applications at Interpack

ConsiGma™ milestones

• 2012 First prototype of ConsiGma™ for

direct compression (CDC) at Achema

• 2013 First prototype and commercial

project of the ConsiGma™ coater

• 2014 Official launch of the ConsiGma™

coater and CDC at Interpack

ConsiGma™ milestones

ConsiGma™

Our product range & How does it work?

GEA’s ConsiGma R&D and manufacturing platform

10APC Pharma

DispensingFeeding

Dry BlendingFB DryingDry Milling / Ext. Phase Blending

CompressionTablet Coating Wet Granulation

DispensingFeeding

1st step Dry Blending

Compression

DispensingFeeding

FB Drying Wet Granulation

Dispensing Feeding1st step

Dry Blending

Tablet Coating 2nd step Ext. PhaseBlending

2nd step Ext. PhaseBlending

ConsiGma™ Product Portfolio

Continuous Granulation & Tableting Lines (ConsiGma™ 25, 50, 100)

Roller Compaction

Melt Granulation

ConsiGma™ 1

Continuous Direct Compression (ConsiGma™-DC 50)

ConsiGma™ CDBU

Wet granulation, tableting & coating line

Powder feedBlending

GranulationDrying

Milling

Ext. Phase

Lubricant

CompressionCoating

ConsiGma™: how does it work?

Excipient +

API

Preblend

Ext.PhaseLubricant

GranuleTablet

Coating liquid

Gran. liquid

Wet granule formation in the TSG is based on understanding the fundamentals of the twin screw

granulation process.

Dry Powder

dosed to system

Liquid pumped

into barrels

High shear

kneading zone

Transport

screws

High shear

kneading zone

Transport

screws

Final breakage

zone

A B C

D

EF

Powder Flow Through Twin Screw Granulator

A) Dry powder mixing in zone 1,

B) over and under wetting of powder in zone 2 depending upon the barrel position,

C) Breaking of saturated agglomerated and mixing with remaining dry powders in zone 3 to create primary granules,

D) low shear forces exerted in zone 4 gives liquid limited time to pull particles together due to capillary forces,

E) secondary agglomeration of primary granules in zone 5,

F) breakage of oversized clusters in zone 7.

PSD optimization in Twin Screw Granulation Process

GEA tabletpress with constant dwelltime

& Exchangeable Compression Module

ConsiGma™ : How does it work - Compression

GEA tabletpress with constant dwelltime

& Exchangeable Compression Module

ConsiGma™ : How does it work - Compression

GEA tabletpress with constant dwelltime

& Exchangeable Compression Module

ConsiGma™ : How does it work - Compression

GEA tabletpress with constant dwelltime

& Exchangeable Compression Module

ConsiGma™ : How does it work - Compression

ConsiGmaTM Coater

18

ConsiGmaTM Coater: How does it work?

ConsiGmaTM Line Configurations

21APC Pharma

ConsiGma™ 25, 50, 100: your production facility in 1 room

22APC Pharma

ConsiGma™ 25, 50, 100: your production facility in 1 room

23APC Pharma

ConsiGma™ 25, 50, 100: your production facility in 1 room

24APC Pharma

ConsiGma™ 25, 50, 100: your production facility in 1 room

R&D – No Scale-up

ConsiGma-1 GMP granulator with integrated FB dryer

21 CFR Part 11

compliant HMI & PLC

control system incl.

UPS

Loss-in-weight powder feeder

Mass-flow controlled

liquid dosing system

Modular Twin Screw

granulation system w/

split barrel and torque

measurement

Fluid bed dryer

w/ blow back

filter bags and

HVAC system

Temperature

control system

w/ compressor

chiller for

TS granulator

Stand alone & mobile unit !

ConsiGma-1 - Flexible granulator screws and barrel design

Segmented

co-rotating

intermeshing

screw & barrel

system

Clam shell barrel

Heating & cooling of the

top- and the buttom

part of the process

section

Screw tip bearing

ConsiGma™ for Direct Compression CDC-50

GEA’s ConsiGma R&D and Manufacturing Platform

29APC Pharma

DispensingFeeding

Dry BlendingFB DryingDry Milling / Ext. Phase Blending

CompressionTablet Coating Wet Granulation

DispensingFeeding

1st step Dry Blending

Compression

DispensingFeeding

FB Drying Wet Granulation

Dispensing Feeding1st step

Dry Blending

Tablet Coating 2nd step Ext. PhaseBlending

2nd step Ext. PhaseBlending

ConsiGma™ Product Portfolio

Continuous Granulation & Tableting Lines (ConsiGma™ 25, 50, 100)

Roller Compaction

Melt Granulation

ConsiGma™ 1

Continuous Direct Compression (ConsiGma™-DC 50)

ConsiGma™ CDBU

Level of innovation – space reduction

30

GMP area

Surface: 46 m2

Volume: 232 m3

GMP area

Surface: 129 m2

Volume: 605 m3

From large factory to small

footprint machine!

Incredible space reduction!

31GEA Pharma Systems CONFIDENTIAL

ConsiGmaTM DC; Integration of key GEA technologiesCompact Feeder

• accurate loss-in-weight feeder

• Contained exchangeable feeder

module

Continuous Dry Blender

• adjustable mixing paddles to

select ideal mixing conditions

• narrow residence time

distribution

LightHouse™ Probe

• process interface for online

measurement of Critical Quality

Attributes (e.g. blend

homogeneity)

Courtoy Modul S tablet press

• air compensator for extended and controlled dwell

time

• exchangeable Compression Module

ConsiGma™ CDC in our PDC

ConsiGma™ CDC in our PDC

Process Controls Strategy & PAT

Optional PAT measurements

• Lighthouse Probe™ NIR for LOD

• Lighthouse Probe™ NIR for Blend Homogenity

• Weight-Thickness-Hardness Tester with incorporated CU

measurement on tablets

• Raman Spectrometer for Coating quality

Process Control Strategy: PAT measurements

1

39

2

4

5

67

8

Basic PAT measurement

1. Powder Feed Factor(s)

2. Liquid addition (mass & density)

3. Torque measurement

4. Product Temperature/drying curves

5. Air inlet/outlet temperature

6. Differential Pressure over filter

7. rH dryer outlet

8. Mill temperature

9. Compression force

10. …

• Multivariate tools for design, data acquisition and analysis

• Process analyzers

Lighthouse Probe™ - Functional principle

Optimizing PAT – Measurement above forced paddle feeder

37

ConsiGmaTM Business cases

• Batch Production vs Continuous Production Product X

• Vertex, Boston US Business Case; streamline and accelerate drug

development

• Pfizer G-CON GEA Portable Compact Miniaturized Manufacturing; POD

Concept

Vertex Business Case: AAPS Mag, Aug 2013

Stage Batch manufacturing Continuous Manufacturing

API used API used

Formulation

Development90 kg 35 kg

Pilot Scale 120 kgTogether

with Formulation development

Commercial 1650 kg 350 kg

Total Amount

of API used1860 kg 385 kg

Difference in API consumption: approx. 1475 kg (huge potential savings !)

Vertex business case: API consumption

API Consumption: Batch vs Continuous

Material Handling

Powder Feeding

Inline Blending

Liquid Addition

Wet Granulation

Roller Compaction

Direct Compression

Tablet Relaxation

Tableting

Tablet Coating

ConsiGma-25; Vertex Continuous RTR Tableting Line

Wet Granulation

ConsiGma-25; Vertex Continuous RTR Tableting Line

Wet

Granulation

Raman for

end-point of coating

Raman for

Assey

LHP for

Blend Homogeneity

On line LOD

ConsiGma-25; Vertex Continuous RTR Tableting Line

Roller

Compaction

ConsiGma-25; Vertex Continuous RTR Tableting Line

Direct

Compression

ConsiGma-25; Vertex Continuous RTR Tableting Line

ConsiGma-25: Vertex Boston - USA

ConsiGmaTM Business cases

• Batch Production vs Continuous Production Product X

• Vertex, Boston US Business Case; streamline and accelerate drug

development

• Pfizer G-CON GEA Portable Compact Miniaturized Manufacturing; POD

Concept

ConsiGma-25: Pfizer Groton – USA PCMM

ConsiGma-25: Pfizer Groton – USA PCMM

ConsiGma-25: Pfizer Groton – USA PCMM

Strictly Confidential

ConsiGma-25: Pfizer Groton – USA PCMM

Today more then 50 ConsiGmaTM References

ConsiGma 25: PDC Testcenter