Continuous Manufacturing: Technologies and Economic Benefit

2nd Symposium on Continuous Flow Reactor Technology for

Industrial Applications Oct. 4, 2010, Paris

Dr. B. Schenkel

Novartis Pharma AG:

Chemical Manufacturing of API’s in 800 stirred vessels with a total volume of 3000 m3 in batch mode. Why?

• Copy of lab

• Flexibility in production capacity (number of batches)

• Flexibility to combine reaction with distillation and extraction

• Broad ranges of reaction parameter possible, e.g. exothermic reactions can be safely run in semibatch mode

2 initiatives in Novartis to challenge the situation

and to shift to conti. manufacturing:

•Technology Platfom Conti. Manufacturing of API

• MIT/Novartis Project for Conti. Manufacturing

API manufacturing in Pharmaceutical Industry

2 | Oct. 4, 2010

Continuous Manufacturing (CM): Which Equipment is available in Chemical Development of Novartis

Installed are Microreactor/Flow reactor Units in different scale,

different labs for Early Phase Supply and Development of Production

Processes

We are planning to implement in 2011

a multipurpose Pilot Plant CM

under GMP, production capacity

of 50 kg ... 15 t/a.

15 g/

10 h

MIT

Unit

150 g/

10 h

1.5 kg/

10 h

30 kg/

10 h

Early Phase

Development

Units

Process

Development

Units

Pilot

Plant CM

(planned)

-30

°C

...

+20

0 °

C

0 b

ar

..

1

0 b

ar

(40 b

ar)

3 | Oct. 4, 2010

Continuous Manufacturing (CM): Which Equipment is available in Novartis

Syringe

pumps

and micro

gear

pumps

Feed solutions

Autosampler

Different

types of

Micro-

reactors

Standardized Flow Reactor Units

in the labs:

- Flexible equipment, design and

size

- Standardized control system

4 | Oct. 4, 2010

Successful Examples in Flow Lab: TEMPO Oxidation

R

NH

PG

OH

+ TEMPO + TBAB

NaOCl + NaHCO3

Quench

Na2S2O3

R

NH

PG

O

H Product

Starting Material (red)

Side Products (green)

Product

Starting Material

Side Products

Micro-

reactorMicro-

reactor

5 | Oct. 4, 2010

Batch

Improved

selectivity

because of

reduced over-

oxidation to

acid

Micro

reactor

Successful Examples in Flow Lab:Nitro Michael Addition

Highly energetic Nitroethylene used in Nitro Michael Addition step of a new API synthesis

CM is enabling the new synthesis: continuous Nitroethylene production and consumption

Successful process development in flow reactors of different scale:

Reaction time: 60 min

MIT microreactor/ ETFE tube 0,5mm x 100 m / static mixer 5mm x 5..20 m, Bo>300: identical

yield and enantioselectivity as in batch, robust and safe continuous process

R

H

O

H

O

R

N+

O

O

N+ O

O +Toluene

Organ. Cat. , acetic acid

Tube and Static

Mixer Reactors in lab

scale

6 | Oct. 4, 2010

Li

Mg Cl

Ar

O

N

OBoc

NH

Boc

+3

Li + . LiClAr Br Ar Mg -

( )n

( )n

Successful Examples in Flow Lab:Coupling of Grignard-like Reagent

Consecutive (over reaction) and parallel formation of byproducts can be reduced in conti. mode by adding simultaneously the starting materials into the coupling reaction. Optimal concentration profiles achieved which are not possible in batch

Yield can be increased by 6% compared to batch

Significant reduction of raw material costs in production

Cost savings justify to switch the current batch production on this step to continuous

Conti. production process will be integrated in existing batch equipment at minor cost

7 | Oct. 4, 2010

For the above shown reactions Microreactors would be ideal reactors because of

• plug flow

• mixing power

• heat exchange

• low consumption of starting materials in development

Successful Examples in Flow Lab:Transforming reactions into production scale

8 | Oct. 4, 2010

1

10

100

1000

10000

100000

20*10-6 .... 0.4Microreactor 0.1

Stirred Vessel 6000 Stirred Vessel

Mixing power[ W / L]

Reactor Volume [Liter]

Ranges of Mixing Power

1

10

100

1000

10000

100000

20*10-6 .... 0.4Microreactor 0.1

Stirred Vessel 6000 Stirred Vessel

Heat transfer [ W / L K]

Reactor Volume [Liter]

Ranges of Heat Transfer

0

200000

400000

600000

800000

1000000

1200000

0 2000 4000 6000

Cost [CHF]

Volume of Reactor [ L ]

Stirred vessel

Reaction Column

Microreactors (Volumes 90 ...360 ml)

Limitations of microreactors

• Microreactor costs at reaction times > 2 .. 10 min get highIn many cases the reactions in our portfolio cannot be shortened below 2..10min selectivity issue at higher temperatures

Is CM limited to short reactions?

There are cost efficient solutions for longer reaction times

Successful Examples in Flow Lab:Transforming reactions into production scale

9 | Oct. 4, 2010

RCl

R'R

R'

R' R

R'

R'

+Cat.

Product Byproduct

Side Reaction

+

Sonogashira Coupling Reaction

Reaction time of Sonogashira Coupling Step reduced from 7h to 1 h for continuous processing

Highly exothermic reaction (adiabatic heat increase 164 °C), possible heat accumulation in batch reactor in case of inactive catalyst

Situation at project start: large production capacity >100 t/a expected

Identical selectivity in continuous mode, safe reaction conditions, economic equipment possible compared to batch manufacturing?

Transforming reactions into production scaleExample Pd- catalyzed Reaction

Terbinafin

10 | Oct. 4, 2010

Pd-Cat.

CuCl

0

1

2

3

4

5

6

7

1 10

N/S

= (

1/S

e)

[ -

]

S [ - ]

Reactor variant:

1 Microreactor and

4 static mixer reactors in series

• Simulation of reaction

• Selection of optimal reactor design

based on Semenov number

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0.09

0.10

59.3

59.8

60.3

60.8

61.3

61.8

0 20 40 60 80 100 120

Co

nve

rsio

n

[ -

]

Tem

pe

ratu

re [

°C ]

Reactor Volume [mL]

MicroreactorReaction in 3 plates

Temperature / °C

Wall Temperature / °C

(T in pre-heating / °C)

conversion [ - ]

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

0

10

20

30

40

50

60

70

80

90

100

0 2000 4000 6000 8000 10000 12000 14000

Co

nve

rsio

n

[ -

]

Tem

pe

ratu

re [

°C

]

Reactor Volume [ mL ]

Static Mixer Reactor4 Moduls of different type/size

Temperature / °C

Wall Temperature / °C

Conversion / -

0.0

0.5

1.0

1.5

2.0

2.5

0

20

40

60

80

100

120

140

0 2000 4000 6000 8000

Co

nve

rsio

n

[ -

]

Tem

pe

ratu

re [

°C

]Reactor Volume / mL

Fluitec

Temperature / °C

Wall Temperature / °C

Conversion / -

Transforming reactions into production scale Flow Reactors for longer reaction times

11 | Oct. 4, 2010

Static Mixer Reactor

2 Moduls of different type/size

.

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

40

50

60

70

80

90

100

110

120

130

140

0 5 10 15 20 25

Yie

ld

Te

mp

era

ture

[°

C]

Stirred Chambers

Simulation Pilotplant (two temperature levels)

Temperature / [°C]

Jacket temperature / [°C]

Yield

Maximum yield of 95.3 %

Reactor variant: Reaction Column

Typical reaction times 0.5<tr<2 h

Small reaction volumes in conti. mode

Large production capacity

First simulations showed lower yield

in reaction column: 91 %

compared to batch: 96 %

Lower yield in Reaction Column

results from

- High conversion rate at reactor entrance

- Strong temperature increase

- Increased byproduct formation

Limit the reaction rate in the first reaction chambers

Introduce 2 temperature levels along the column

Max. yield in reaction column: 95.3%

Simulation confirmed in lab and pilot experiments

12 | Oct. 4, 2010

Transforming reactions into production scale Flow Reactors for longer reaction times

• Sonogashira Step combined with precedent reaction step to a 2 step conti. process

• Solvents in both synthesis steps identical to avoid solvent switch between the steps

• No solid handling, no crystallization in conti. process chain

• Process piloted and basic engineering done

Continuous process reduces plant costs by 25% compared to new batch plant

Continuous production process for Sonogashira Coupling Reaction

• Work up steps focused

on conti. extraction and conti. destillation

13 | Oct. 4, 2010

Transforming reactions into production scale Continuous Manufacturing Process for Terbinafin

M

Educts

O2 /

N2

Water

Cyclohexane

to

recovery

Raw

Product

HCl

waste

Reaction Column Static Mixer Extraction

Column

Mixer Settler Falling Film

Destillation Unit

Waste Gas

Current state: 2..3 chemical steps in continuous mode are possible in API synthesis

Yield improvement is possible for selected reaction steps by continuous manufacturing. Huge economic benefits can be achieved

Continuous plant equipment can be 25% cheaper than corresponding batch equipment

• Reaction times have to be relatively short (e.g. <2 hours), work up steps have to be adapted to continuous, expensive solid handling has to be avoided

Conclusions from experiments and experience for Continuous API Processing

14 | Oct. 4, 2010

Economic impact of continuous manufacturing of full API

syntheses was investigated in 3 case studies in Novartis

Total continuous API syntheses (upstream) were

combined with galenical production processes

(downstream)

Short summary on selected aspects with an emphasis on

upstream

Case study on economic impact of CM

15 | Oct. 4, 2010

• Step 1: Design of a conti. process starting from batch process

without experimental verification, Process Flow Diagram,

Material Balance

Step 2: Equipment sizing

• Step 3: Estimation of equipment cost

• Step 4: Estimation of raw material cost

• Step 5: Total capital costs, Operational costs

• Step 8: Total production costs (TPC)

• Step 9: Study on parameter sensitivity

Case study: applied approach in the study

16 | Oct. 4, 2010

: reaction steps

Case study: PFD of 3 conti.steps of the selected 6-step-synthesis

17 | Oct. 4, 2010

0

50

100

150

200

250

Conti. Process with Extrusion

Batch Process with Extrusion

Total Capital

Cost[CHF/kg]

Upstream

Downstream

Equipment Costs CalculationTotal Equipment Costs = Sum of costs of equipment in final size + additional costs (Erection, Piping,

Automation, Engineering) + building related costs

Assumptions: 100 Tons / year DS, 335 working days / year

Capital Costs of Batch and CM Plant for selected 6-step-synthesis

18 | Oct. 4, 2010

Capital Costs for Upstream Plant 53% lower than batch

0

100

200

300

400

500

600

Conti. Process with Extrusion

Batch Process with Extrusion

Total cost[CHF/kg]

Total Production CostTotal Operating Cost

Total Capital Cost

0

5

10

15

20

25

30

35

40

Conti. Process with Extrusion

Batch Process with Extrusion

Operating Cost

[CHF/kg]

Upstream Downstream

Operating Costs- costs for raw materials, utilities, labor

-Number of operators reduced by 50%

Operating Costs for Upstream reduced

by 15% compared to batch

Total Production Costs

TPC reduced by 25% for combined

upstream & downstream CM process

TPC reduced by 23% in upstream

manufacturing

Operating Costs and Total Production Costsof selected 6 step synthesis

19 | Oct. 4, 2010

13.0%

18.5%

23.6%

28.2%

32.4%

36.3%

39.9%

0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

30.0%

35.0%

40.0%

45.0%

50% 75% 100% 125% 150% 175% 200%

Fra

cti

on

of

Lab

or

Co

st

in T

PC

Fraction of Labor Requirement

Base Case

Base case labor requirement:

10 full time workers per shift

= 50% of batch operation

Fraction of Labor in TPC depends

significantly on Labor Requirement

Opportunity for Continuous Manufacturing

Sensitivity Study: Impact of Labor on Total Production Cost

20 | Oct. 4, 2010

Motivation:

• Batch Plants are used in manufacturing

for more than one API/Drug.

• Difference in flexibility between batch and

continuous manufacturing schemes

Cost benefits of Multipurpose Plant:

• Capital cost divided between products

• Economies of scale

Downside:

• Storage cost for API/Drug

• Setup and cleaning operations adding to

operation cost

1 year

Num

ber

of P

roducts

per

Lin

e

1

2

3

4

5

Pla

nt S

ize

Sensitivity Study: Impact of Multipurpose vs. Dedicated Operation of Manufacturing Plants

21 | Oct. 4, 2010

717

504430

392 368

1192

777

631555

508

0

200

400

600

800

1000

1200

1400

1 2 3 4 5

Number of P roduc ts per L ine

TP

C (

CH

F/k

g)

C ontinuous

B atc hTPC per kg of Product

• CM has lower TPC for each

of the schemes

• TPC decreases for

multipurpose plants

• If CM is run in dedicated and

Batch is run in multipurpose

equipment Batch is cheaper

Sensitivity Study: Impact of Multipurpose vs. Dedicated Operation of Manufacturing Plant

22 | Oct. 4, 2010

Case studies on combined API/DP continuous manufacturing show TPC

reduction up to 25 % in continuous compared to batch manufacturing

Continuous Plants result in lower production costs (TPC) compared to batch Identical flexibility has to be achieved in conti. mode compared to batch mode

Concepts for flexible multipurpose plants should be worked out.

Operation Costs are dominated by raw material cost in upstream optimal synthesis regarding raw material cost and work up steps is key

yield is key

Capital cost and personnel cost are important and can be reduced by CM

Equipment will be dominated in number and cost by work up equipment Efficiency and cost of purification processes are important

Case study on economic impact of CM was based on assumptions which

have to be further proven

Conclusions from Case Study

23 | Oct. 4, 2010

Vision of Novartis and MIT to transform the current batch manufacturing of its drug substances and drug products to a fully continuous sequence of process steps for each drug substance and drug product

New and enabling technologies will be developed within 10 years with significant economic advantages compared to batch manufacturing

Novartis / MIT Center for Continuous Manufacturing

24 | Oct. 4, 2010

Prof. T. Roeder, Dr. J. Hollmann, Dr. G. Paredes, Dr. F.

Kollmer, M. Rentsch, Dr. L. Padeste, M. Aubry, Dr. H.

Hirt, Dr.C. Fleury. U. Scholer, D. Plaziat, Dr. G. Penn,

Dr. U. Beutler, Dr. B. Wietfeld, S. Bourne, Dr. B. Martin

All external partners in numerous co-operations

Students of MIT Practice School Programs Feb, June

2008, Prof. C. Lupis

Novartis/MIT CM Team

Acknowledgements

25 | Oct. 4, 2010