Throughput Analysis, Debottlenecking, and Economic
Evaluation of Integrated Biochemical Processes
Demetri Petrides, Ph.D.
President
IBC Conference
La Jolla, CA
November 15, 2000
INTELLIGEN, INC.
Simulation and Design Tools
for the Process and Environmental Industries
Outline
• Introduction
• Motivation
• Debottlenecking Theory
• Debottlenecking Example
• Cost Analysis
• Conclusions
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Computer-Aided Process Design and Simulation
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Debottlenecking Questions
• How much product can I make in this plant?
• What limits the current production level?
• What is the min capital investment for increasing production?
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Cost Analysis Questions
• How much would it cost to make a kilo of product?
• What is the required capital investment for a new plant?
• Which process is better for making this product? A or B?
• How can I reduce the operating cost of a process?
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The Role of CAPD and Simulation in
Product Development and Commercialization
IDEA GENERATION
Project Screening, Strategic Planning
Development Groups
PROCESS DEVELOPMENT
Evaluation of Alternatives
Common Language of Communication
FACILITY DESIGN
Equipment & Utility Sizing and Design
Development Groups
Process Engineering
Corporate Environmental
Manufacturing
MANUFACTURING
On-Going Optimization, Debottlenecking
Process Scheduling, Production Planning
Manufacturing
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Who is Intelligen,
Inc.?
Established in the early 90’s - MIT spin off
SuperPro Designer
BioPro Designer
BatchPro Designer
EnviroPro Designer
Biotechnology
Food Processing
Synthetic
Pharmaceuticals
Specialty Chemicals
AgriChemicals
Water Purification
Wastewater Treatment
Air Pollution Control
INTELLIGEN, INC.
Tool Description - Overview
• Intuitive User Interface
• Wide Variety of Unit Operation Models
• Databases for Components and Mixtures
• M&E Balances of Integrated Processes
• Equipment Sizing and Costing
• Project Economic Evaluation
• Process Scheduling
• Throughput Analysis & Debottlenecking
• Waste Stream Characterization
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Intuitive User Interface
Detailed Modeling using Unit Procedures and Operations
Double-Click
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Flexible Operation Models (Column Elution)
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Operations Gantt Chart
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Throughput Analysis
and Debottlenecking Theory
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Debottlenecking of Batch Operations
Types of Bottlenecks
Equipment
Annual
Throughput
=
Resources
Batch
Throughput
x
Number of
Batches per Year
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Equipment Scheduling (Time) Bottlenecks
Scheduling (Time) Bottleneck = Tank (V-101)
Auxiliary Equipment (e.g., CIP and SIP skids) and resources also can become time bottlenecks.
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Equipment Capacity Utilization
Equipment
Capacity
Utilization
Equipment
Capacity
Utilization
Liquid Volume
=
Max Liquid Volume
Operating Throughput
=
Max Throughput
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Equipment Time Utilization
EPBT
Equipment
Uptime
Total Time Equipment is Utilized per Batch
=
Effective Plant Batch Time (EPBT)
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Equipment Throughput Bottlenecks
Combined
Utilization
=
Equipment
Capacity
Utilization
x
Equipment
Uptime
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Potential for Throughput Increase
Equipment
Capacity
Utilization
EPBT
Current
Equipment
Uptime
Realistic
Theoretical
Current
Batch
Throughput
Conservative Max
Realistic Max
Theoretical Max
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Equipment Throughput Bottlenecks
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Resource Bottlenecks
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Debottlenecking Strategy
Annual
Throughput

Batch
Throughput
/
Effective
Batch Time
 Increase batch throughput until a size bottleneck is reached.
Then,
• Increase number of cycles of limiting procedure;
• Rearrange equipment, or;
• Use new equipment (stagger operation).
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Throughput Analysis Example
Production of Therapeutic
Monoclonal Antibodies
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Base Case Data
Broth Volume
=
4,000 L
Bioreactor Volume
=
6,500 L
Max Working Volume
=
6,175 L
Product Titer
=
1 g/L
Recovery Yield
=
56%
Fermentation Time
=
10 days
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Equipment Utilization Chart (Base Case)
Scheduling (Time) Bottleneck = V-101
EPBT = 11 days
Batch Throughput = 2.3 kg
Batches per Year = 29
Annual Throughput = 67 kg
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Capacity, Time, and Combined Utilization Chart (Base Case)
Capacity Utilization
of Bottleneck Equipment
=
65%
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Scenario 1
Action
Increase batch size by 54% (broth volume 4,000 L  6,175 L)
Warnings
Chromatography columns cannot handle new batch in 2 cycles.
Action  Increase # of cycles per batch from 2 to 3.
New Results
Batch throughput
Number of Batches per Year
Annual Throughput
3.55 kg
29
103 kg
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Capacity, Time, and Combined Utilization Chart (Scenario 1)
Capacity Utilization
of Bottleneck Equipment
EPBT = 11 days
Batch Throughput = 3.55 kg
Batches per Year = 29
Annual Throughput = 103 kg
= 100%
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Scenario 2
Observation
Downstream section is underutilized in time.
Action
Introduce new bioreactor and stagger its operation based on
the new time bottleneck equipment.
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Capacity, Time, and Combined Utilization Chart (Scenario 2)
Scheduling (Time) Bottleneck = DF-102
EPBT = 196 h (initial 264 h)
Batches per Year = 39 (initial 29)
Annual Throughput = 138 kg
Number of Bioreactors = 2
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Scenario 3
Action
Add extra diafilter to eliminate current time bottleneck.
New Results
Batch throughput
Number of Batches per Year
Annual Throughput
3.55 kg
44 (29  39  44)
156 kg
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Capacity, Time, and Combined Utilization Chart (Scenario 3)
Scheduling (Time) Bottleneck = V-103
EPBT = 171.5 h (264 h  196 h  171.5)
Batches per Year = 44 (29  39  44)
Annual Throughput = 156 kg
Number of Bioreactors = 2
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Scenario 4
Action
Add extra storage tank to eliminate current time bottleneck.
New Results
Batch throughput
Number of Batches per Year
Annual Throughput
3.55 kg
58 (29  39  44  58)
206 kg
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Capacity, Time, and Combined Utilization Chart (Scenario 4)
Scheduling (Time) Bottleneck = V-101
EPBT = 130.3 h (264 h  196 h  171.5  130.3)
Batches per Year = 58 (29  39  44  58)
Annual Throughput = 206 kg
Number of Bioreactors = 2
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Scenario 5
Action
Add extra bioreactor and diafilter.
New Results
Batch throughput
Number of Batches per Year
Annual Throughput
3.55 kg
84 (29  39  44  58  84)
298 kg
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Capacity, Time, and Combined Utilization Chart (Scenario 5)
Scheduling (Time) Bottleneck = V-105
EPBT = 89.7 h (264 h  196 h  171.5  130.3  89.7)
Batches per Year = 84 (29  39  44  58  84)
Annual Throughput = 298 kg
Number of Bioreactors = 3
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Comparison
Scenario Bioreactor Membrane
Number
Vessels
Diafilters
Storage
Tanks
Batches
per Year
Batch
Throughput
Annual
Throughput
0
1
3
3
29
2.3 kg
67 kg
1
1
3
3
29
3.5 kg
103 kg
2
2
3
3
39
3.5 kg
138 kg
3
2
4
3
44
3.5 kg
156 kg
4
2
4
4
58
3.5 kg
206 kg
5
3
5
4
84
3.5 kg
298 kg
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Labor Demand as a Function of Time
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WFI Demand as a Function of Time
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Cost Analysis
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Cost Analysis Results (Base Case)
Production Rate
67 kg/yr
Equipment Cost
$2.3 M
Total Investment
$25.4 M
Operating Cost
$12.9 M/yr
Lab/QC/QA
1%
Consumables
29%
Labor-Depended
5%
Unit Cost
$193/g
Waste Disposal
4%
Raw Materials
27%
DFC-Dependent
34%
Distribution per Section
Upstream
43 %
Downstream 57 %
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Comparison of Various Options
300
250
200
150
Unit Cost ($/g)
Annual Throughput (kg)
100
50
Scenario 5
Scenario 4
Scenario 3
Scenario 2
Scenario 1
Base Case
0
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Cost Analysis Results (Scenario 5)
Lab/QC/QA
1%
Production Rate
298 kg/yr
Operating Cost
$41.1 M/yr
Unit Cost
$138/g
Consumables
39%
Labor-Depended
6%
Key Assumption
Unit cost of raw materials and
consumables remained unchanged
Waste Disposal
5%
Raw Materials
36%
DFC-Dependent
13%
Distribution per Section
Upstream
38 %
Downstream 62 %
INTELLIGEN, INC.
SuperPro Designer v5.0
Spring 2001
INTELLIGEN, INC.
From Single to Multiple-Recipe Projects
SuperPro v4.5 (current)
SuperPro v5.0
Single-Recipe Project
Multi-Recipe Project
Perform at the Facility Level
•
•
•
•
Scheduling and Planning
Resource Tracking
Equipment Utilization
Debottlenecking
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Project Architecture
SuperPro Project
Databases
Recipe 1
Sites
Recipe 2
Recipe 3
Facilities
Utilities
Multi-Product
Manufacturing
Facility
Labor
Equipment
Construction
Materials
Raw
Materials
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Display of Multi-Recipe Projects
Worksheets (recipes)
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Summary
Process Simulation can play a role in:
• Facilitating Process Development
• Improving Team Communication
• Increasing Plant Throughput
• Reducing Capital and Operating Cost
INTELLIGEN, INC.
For a fully functional demo of
SuperPro Designer
&
A book chapter on
Bioprocess Design & Economics
Go to
www.intelligen.com