Benefits and Opportunities of Continuous Manufacturing · Benefits and Opportunities of Continuous...

Property of Merck Manufacturing Division 2012

Merck & Co., Inc, Whitehouse Station, NJ,. All rights reserved

1

Benefits and Opportunities of

Continuous Manufacturing

Dr. Gert Thurau

MSD Manufacturing Division



2

Continuous Manufacturing is in

the Spotlight “Continuous processing is well controlled and the controls

are not just equal to, but are superior to batch methods.”

Sources: Pham Tech Sept 2008

“Next Wave Model” (www.worldpharmaceuticals.net)

“One lot a week:, Pharmamanufacturing.com, 2010

http://www.worldpharmaceuticals.net/



3

Definition of Continuous

Manufacturing

= In contrast to batch manufacturing

•Many variations

–Fully continuous - flow

–Semi-continuous – with or without buffer

•For drug substance (“flow chemistry”) and

drug product

–Oral solid dosage and biologics processes



4

Focus of Today’s talk:

Drug Product Continuous Manufacturing

• Potentially Available/Available Technologies

Unit Operations Equipment Technologies/Vendors

Feeding Gericke, K-Tron, Scheneck-Accurate, Colortronic…

Blending Acrison, Buck, Gericke, Hosokawa, Lestreis, Lodige,

Patterson-Kelley, Company’s Internal proprietary

continuous mixers

Granulation Glatt, Hosokawa, Lodige, LB Bhole,

GEA Consigma

Drying Glatt, Lodige, GEA Consigma

Radio-Frequency, Witt…..

Coating O’Hara, Thomas Engineering..



5

We are already routinely using some

(quasi-) continuous unit operations

• Roller compaction

• Tablet compression

• Encapsulation

• Packaging lines

Experiences gained with

operation of these unit

operations can translate into

fully integrated continuous

systems



6

Fully Integrated Lines

Commercially Available

Courtesy of GEA/Consigma Product Line



7

Fully Integrated Lines

Commercially Available

Courtesy of GEA/Consigma Product Line



8

Continuous Manufacturing Processes:

A Technological Reality

• Company A (large scale global pharma) has developed1:

– 3 continuous drug substance manufacturing lines

– 3 continuous drug product manufacturing lines

• Company B (mid-size European pharma) 1

– Initially developed drug substance continuous process

– Based on success now working on drug product

• All top 10 pharma companies have development

programs on continuous manufacturing2

However: Number of actual implementations is still very limited

1: AAPS workshop on Continuous Processing, Baltimore, US, 2010

2: GEA Pharmasystem promotional material



9

Potential Benefits of Continuous

Processing

Typical benefits quoted include:

1. Development cycle benefits (i.e. scale-up,

tech transfer)

2. Operational benefits (capital/cost savings)

3. Quality benefits (Consistency of output

material)



10

1. Development Cycle Benefits

• Scale-up for new products has typical challenges – Engineering scale-up challenges

– Volume projection for new products unreliable – how much scale do I need?

• Material output of continuous system is dependent on scale and run time – By increasing continuous run time could compensate for smaller scale

– Potential to delay or defer use of larger scale equipment

– Allows to avoid or reduce scale-up challenges

• For products not dependent on clinical timelines potential for “fast to market”

• Technology transfer – In principle smaller foot print systems are more portable from R&D to

Manufacturing site



11

2. Operational Benefits

• Smaller foot print = improved manufacturing space utilization – Significant resulting cost reduction for buildings and utilities/running

costs

• Prospect of more portable systems – Manufacturing line in container?

• Batch size determined by run time – (Much increased) flexibility to volume demand fluctuations

• Generally less in-process material – Reduced waste generated

• Faster processing times (“From powder to tablet in 20 min”) – Quicker response to demand

• (Drug substance, flow chemistry) catalyst can be immobilized on substrate – Less loss of expensive catalysts, reduced work-up of product



12

3. Quality Benefits

• A continuous process in steady state will deliver very consistent material – No batch trajectory to compensate for

• Drug substance – reactions enabled by flow – Fast heat transfer beneficial

– Removal of reaction inhibitors

• Improved ability/benefit of applying PAT controls – Feed-back and feed-forward

– Larger number of data points for evaluation of product

• No hold times of product in between unit operations – Reduced potential for chemical or physical degradation,

“settling/aging/curing” of material



13

Continuous Processing

Case study/data examples



14

Continuous

blending/tableting

system

Continuous blender

Tablet press

Loss in weight

powder feeders



15

Continuous blending/tableting system

Detail view

• Number of feeders

will be dependent

on formulation

• PAT-enabled

process throughout

• Opportunity for

advanced process

models



16

Continuous blending DOE

0

10:2

6:5

4

10:3

9:4

1

10:4

1:4

3

10:4

3:4

6

10:4

5:4

9

10:4

7:5

2

10:4

9:5

4

10:5

1:5

7

10:5

4:0

0

10:5

6:0

2

10:5

8:0

5

11:0

0:0

9

11:0

2:1

2

11:0

4:1

4

11:0

6:1

7

11:0

8:2

0

11:1

0:2

2

11:1

2:2

5

11:1

4:3

3

11:1

6:3

6

11:1

8:3

8

11:2

0:4

1

11:2

2:4

4

11:2

4:4

6

11:2

6:4

9

11:2

8:5

2

11:3

0:5

4

11:3

2:5

7

11:3

4:5

9

11:3

7:0

2

Time

Pre

dic

ted

co

mp

on

en

t B

co

nc

en

tra

tio

n

Component B wt%

Process note

ComponentB was

spiked as a tracer at a

blending condition to

show RTD (Residence

Distribution Time) for

process development.

Data showed different

RTD at two blending

conditions.

Real-time predictions of Active on in-line NIR:

System characterization (residence time

distribution)



17

Real-time predictions of Active on in-line NIR:

Change-over dynamics

Continuous blending DOE

40

10:2

6:5

4

10:4

3:1

1

10:4

8:4

4

10:5

4:1

7

10:5

9:5

2

11:0

5:2

4

11:1

0:5

7

11:1

6:3

6

11:2

2:0

9

11:2

7:4

1

11:3

3:1

4

11:3

8:4

7

11:4

4:3

7

11:5

0:1

0

11:5

5:4

6

12:0

1:1

9

12:0

6:5

2

12:1

2:2

4

12:1

8:0

7

12:2

3:3

9

12:2

9:1

4

12:3

5:0

4

14:2

0:4

4

14:2

6:2

6

14:3

1:5

9

14:3

7:3

7

14:4

3:1

0

14:4

8:4

4

14:5

4:1

9

15:0

0:1

0

15:0

5:4

4

Time

Pre

dic

ted

Co

mp

on

en

t A

wt%

Component A wt%

Process notes

Steady state of

blending condition A

Steady state of

blending condition B

Condition C

PAT real-time predictions

for:

•Concentration of active. A

different lot of active

charged at Condition C

than Condition A and B.

•Blending uniformity using

moving block RSD.

Condition A showed lower

RSD than that of Condition

B.

•Real-time release??



18

Challenges of Continuous

Processing

Real and potential challenges include:

1. Technical/engineering challenges

2. Quality definition/regulatory challenges

3. Commercial Reality



19

1. Technical/Engineering

Challenges Powder processing is often poorly characterized to begin

with; running continuous vs. batch can add further challenges:

• Feeding accuracy and precision

• In-line blender efficiency – blend uniformity

• Managing Start-up and Shutdown

• Balancing system throughput

• PAT applications development

• Control strategy- Perturbations

• Integration/automation



20

2. Quality Definition/Regulatory

Challenges • Single-most discussed Quality/Regulatory

Topic?

“Definition of a batch in a continuous process”

• Discussion points:

– Batch definition based on unit time vs. material dispensed in batch equipment

– Requires process monitoring in periodic intervals to allow segregation of material in case of atypicals

– Validation of flexible batch sizes – validate every potential size separately?

– Increased complexity of overlapping raw material and excipient lots

Rodin “The Thinker”

Rodin Museum, Philadelphia USA



21

2. Quality Definition/Regulatory

Challenges, cont. Other hot topics:

• No easy way to “pause” batch in case of issues – Very difficult to quarantine in-process material

• PAT real-time control strategies can be complex – PAT method analytical aspects, including regulatory acceptance

– More involved automation/process control loops than in conventional batch processing

• Generally continuous processing is very innovative approach – risk of regulatory non-acceptance in global marketplace – Discussion still very actively ongoing even in US and Europe



22

3. Commercial Reality

• Obvious benefit for high-volume products – How many in pharma future?

– Pharmaceutical industry in general has excess capacity

• While less capital than batch processing, initial investment still high due to complexity of equipment/control system

• Potential value for multi-product, platform technologies – Continuous dry granulation (CDG), high shear wet granulation

(HSWG), fluid bed granulation/drying (FBGD), tablet coating

• Currently limited interest for small volume, high value products – Startup/shutdown losses

– Use existing capacity



23

Continuous Manufacturing Processes: A Technological Reality – A Realization Challenge?

• Company A (large scale global pharma) has developed: – 3 continuous drug substance

manufacturing lines

– 3 continuous drug product manufacturing lines

• All top 10 pharma companies

have development programs on continuous manufacturing

Only 1 out of 6

lines operational

Very careful and

deliberate speed

and capital

investment



24

Conclusions

• Continuous manufacturing holds many

technological and operational promises

• Many projects underway, by diverse set of

players, in various stages of completion

– We will see more of this in the future

• However actual manufacturing lines running

very few (or none)

– Jury is still out on realized benefits



25

Acknowledgements

• Bob Meyer, Fan Zhang-Plasket

• ERC-SOP

• GEA Pharma Systems

Benefits and Opportunities of Continuous Manufacturing · Benefits and Opportunities of Continuous...

Documents

Transcript of Benefits and Opportunities of Continuous Manufacturing · Benefits and Opportunities of Continuous...