benefits and opportunities of continuous manufacturing · benefits and opportunities of continuous...
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Benefits and Opportunities of
Continuous Manufacturing
Dr. Gert Thurau
MSD Manufacturing Division
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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
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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
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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..
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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
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Fully Integrated Lines
Commercially Available
Courtesy of GEA/Consigma Product Line
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Fully Integrated Lines
Commercially Available
Courtesy of GEA/Consigma Product Line
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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
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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)
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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
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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
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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
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Continuous Processing
Case study/data examples
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Continuous
blending/tableting
system
Continuous blender
Tablet press
Loss in weight
powder feeders
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Continuous blending/tableting system
Detail view
• Number of feeders
will be dependent
on formulation
• PAT-enabled
process throughout
• Opportunity for
advanced process
models
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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)
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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??
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Challenges of Continuous
Processing
Real and potential challenges include:
1. Technical/engineering challenges
2. Quality definition/regulatory challenges
3. Commercial Reality
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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
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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
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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
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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
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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
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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
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Acknowledgements
• Bob Meyer, Fan Zhang-Plasket
• ERC-SOP
• GEA Pharma Systems