Throughput Analysis, Debottlenecking, and Economic Evaluation

of Integrated Biochemical Processes

INTELLIGEN, INC.Simulation and Design Tools

for the Process and Environmental Industries

Demetri Petrides, Ph.D.President

IBC ConferenceLa Jolla, CA

November 15, 2000

Outline

• Introduction

• Motivation

• Debottlenecking Theory

• Debottlenecking Example

• Cost Analysis

• Conclusions

INTELLIGEN, INC.

Computer-Aided Process Design and Simulation

INTELLIGEN, INC.

• How much product can I make in this plant?

• What limits the current production level?

• What is the min capital investment for increasing production?

Debottlenecking Questions

INTELLIGEN, INC.

• 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?

Cost Analysis Questions

INTELLIGEN, INC.

IDEA GENERATIONProject Screening, Strategic Planning

PROCESS DEVELOPMENTEvaluation of Alternatives

Common Language of Communication

FACILITY DESIGNEquipment & Utility Sizing and Design

MANUFACTURINGOn-Going Optimization, Debottlenecking

Process Scheduling, Production Planning

Development Groups

Development GroupsProcess EngineeringCorporate EnvironmentalManufacturing

Manufacturing

The Role of CAPD and Simulation inProduct Development and Commercialization

INTELLIGEN, INC.

INTELLIGEN, INC.

Water PurificationWastewater TreatmentAir Pollution Control

BioPro Designer

SuperPro Designer

BatchPro Designer

EnviroPro Designer

BiotechnologyFood Processing

Synthetic PharmaceuticalsSpecialty ChemicalsAgriChemicals

Who is Intelligen, Inc.?

Established in the early 90’s - MIT spin off

Tool Description - Overview

INTELLIGEN, INC.

• 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

Intuitive User Interface

INTELLIGEN, INC.

Double-Click

Detailed Modeling using Unit Procedures and Operations

Flexible Operation Models (Column Elution)

INTELLIGEN, INC.

Operations Gantt Chart

INTELLIGEN, INC.

Throughput Analysis and Debottlenecking Theory

INTELLIGEN, INC.

Debottlenecking of Batch Operations

INTELLIGEN, INC.

Equipment Resources

Types of Bottlenecks

AnnualThroughput

BatchThroughput

xNumber of

Batches per Year=

INTELLIGEN, INC.

Equipment Scheduling (Time) Bottlenecks

Auxiliary Equipment (e.g., CIP and SIP skids) and resources also can become time bottlenecks.

Tank (V-101)=Scheduling (Time) Bottleneck

Equipment Capacity Utilization

INTELLIGEN, INC.

EquipmentCapacity

Utilization

Liquid Volume

Max Liquid Volume=

EquipmentCapacity

Utilization

Operating Throughput

Max Throughput=

Equipment Time Utilization

INTELLIGEN, INC.

EquipmentUptime

Total Time Equipment is Utilized per Batch

Effective Plant Batch Time (EPBT)=

EPBT

Equipment Throughput Bottlenecks

INTELLIGEN, INC.

CombinedUtilization

=EquipmentCapacity

Utilizationx

EquipmentUptime

Potential for Throughput Increase

INTELLIGEN, INC.

EquipmentCapacity

Utilization

CurrentBatch

Throughput Conservative Max

EquipmentUptime

EPBT

Current

Realistic

Theoretical

Realistic Max

Theoretical Max

Equipment Throughput Bottlenecks

INTELLIGEN, INC.

Resource Bottlenecks

INTELLIGEN, INC.

Debottlenecking Strategy

INTELLIGEN, INC.

AnnualThroughput

BatchThroughput / 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).

Throughput Analysis Example

INTELLIGEN, INC.

Production of TherapeuticMonoclonal Antibodies

INTELLIGEN, INC.

Base Case Data

INTELLIGEN, INC.

Broth Volume 4,000 L=

Product Titer 1 g/L=

Bioreactor Volume 6,500 L=

Recovery Yield 56%=

Fermentation Time 10 days=

Max Working Volume 6,175 L=

INTELLIGEN, INC.

Equipment Utilization Chart (Base Case)

V-101=Scheduling (Time) Bottleneck

EPBT = 11 daysBatch Throughput = 2.3 kg Batches per Year = 29Annual Throughput = 67 kg

INTELLIGEN, INC.

Capacity, Time, and Combined Utilization Chart (Base Case)

65%=Capacity Utilization of Bottleneck Equipment

Scenario 1

INTELLIGEN, INC.

New Results

ActionIncrease batch size by 54% (broth volume 4,000 L 6,175 L)

Batch throughputNumber of Batches per YearAnnual Throughput

3.55 kg29 103 kg

WarningsChromatography columns cannot handle new batch in 2 cycles.Action Increase # of cycles per batch from 2 to 3.

INTELLIGEN, INC.

Capacity, Time, and Combined Utilization Chart (Scenario 1)

100%=Capacity Utilization of Bottleneck Equipment

EPBT = 11 daysBatch Throughput = 3.55 kg Batches per Year = 29Annual Throughput = 103 kg

Scenario 2

INTELLIGEN, INC.

ObservationDownstream section is underutilized in time.

ActionIntroduce new bioreactor and stagger its operation based on the new time bottleneck equipment.

INTELLIGEN, INC.

Capacity, Time, and Combined Utilization Chart (Scenario 2)

DF-102=Scheduling (Time) Bottleneck

EPBT = 196 h (initial 264 h) Batches per Year = 39 (initial 29)Annual Throughput = 138 kgNumber of Bioreactors = 2

Scenario 3

INTELLIGEN, INC.

New Results

ActionAdd extra diafilter to eliminate current time bottleneck.

Batch throughputNumber of Batches per YearAnnual Throughput

3.55 kg44 (29 39 44) 156 kg

INTELLIGEN, INC.

Capacity, Time, and Combined Utilization Chart (Scenario 3)

EPBT = 171.5 h (264 h 196 h 171.5) Batches per Year = 44 (29 39 44)Annual Throughput = 156 kgNumber of Bioreactors = 2

V-103=Scheduling (Time) Bottleneck

Scenario 4

INTELLIGEN, INC.

New Results

ActionAdd extra storage tank to eliminate current time bottleneck.

Batch throughputNumber of Batches per YearAnnual Throughput

3.55 kg58 (29 39 44 58) 206 kg

INTELLIGEN, INC.

Capacity, Time, and Combined Utilization Chart (Scenario 4)

EPBT = 130.3 h (264 h 196 h 171.5 130.3) Batches per Year = 58 (29 39 44 58)Annual Throughput = 206 kgNumber of Bioreactors = 2

V-101=Scheduling (Time) Bottleneck

Scenario 5

INTELLIGEN, INC.

New Results

ActionAdd extra bioreactor and diafilter.

Batch throughputNumber of Batches per YearAnnual Throughput

3.55 kg84 (29 39 44 58 84) 298 kg

INTELLIGEN, INC.

Capacity, Time, and Combined Utilization Chart (Scenario 5)

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 kgNumber of Bioreactors = 3

V-105=Scheduling (Time) Bottleneck

Comparison

INTELLIGEN, INC.

Scenario Number

BioreactorVessels

Batchesper Year

AnnualThroughput

1 1 29 103 kg

2 2 39 138 kg

3 2 44 156 kg

MembraneDiafilters

3

3

4

BatchThroughput

3.5 kg

3.5 kg

3.5 kg

3.5 kg4 2 4 58 206 kg

0 1 29 67 kg3 2.3 kg

3.5 kg5 3 5 84 298 kg

StorageTanks

3

3

3

4

3

4

Labor Demand as a Function of Time

INTELLIGEN, INC.

WFI Demand as a Function of Time

INTELLIGEN, INC.

Cost Analysis

INTELLIGEN, INC.

Cost Analysis Results (Base Case)

Equipment Cost

Total Investment

Operating Cost

Unit Cost

$2.3 M

$25.4 M

$12.9 M/yr

$193/g

Production Rate 67 kg/yr

Distribution per Section

Upstream

Downstream

43 %

57 %

DFC-Dependent

34%

Consumables29%

Raw Materials27%

Waste Disposal4%

Labor-Depended5%

Lab/QC/QA1%

INTELLIGEN, INC.

Comparison of Various Options

Ba

se

Ca

se

Sc

en

ari

o 1

Sc

en

ari

o 2

Sc

en

ari

o 3

Sc

en

ari

o 4

Sc

en

ari

o 5

0

50

100

150

200

250

300

Unit Cost ($/g)

Annual Throughput (kg)

INTELLIGEN, INC.

Cost Analysis Results (Scenario 5)

Operating Cost

Unit Cost

$41.1 M/yr

$138/g

Production Rate 298 kg/yr

Distribution per Section

Upstream

Downstream

38 %

62 %

DFC-Dependent

13%

Consumables39%

Raw Materials36%

Waste Disposal5%

Labor-Depended6%

Lab/QC/QA1%

INTELLIGEN, INC.

Key Assumption

Unit cost of raw materials andconsumables remained unchanged

SuperPro Designer v5.0

INTELLIGEN, INC.

Spring 2001

INTELLIGEN, INC.

SuperPro v4.5 (current)

• Scheduling and Planning• Resource Tracking• Equipment Utilization• Debottlenecking

Single-Recipe Project Multi-Recipe Project

Perform at the Facility Level

From Single to Multiple-Recipe Projects

SuperPro v5.0

SuperPro Project Databases

Recipe 1

Recipe 2

Recipe 3

Multi-ProductManufacturing

Facility

Facilities

Equipment

ConstructionMaterials

Labor

Utilities

RawMaterials

INTELLIGEN, INC.

Project Architecture

Sites

Display of Multi-Recipe Projects

INTELLIGEN, INC.Worksheets (recipes)

Summary

• Facilitating Process Development

• Improving Team Communication

• Increasing Plant Throughput

• Reducing Capital and Operating Cost

INTELLIGEN, INC.

Process Simulation can play a role in:

For a fully functional demo of SuperPro Designer

&A book chapter on

Bioprocess Design & EconomicsGo to

www.intelligen.com