Process Simulation
Value: A Case Study
ISPE Central Canada – September 29 2005
John Rydall
Director of Operations
Hemosol Corporation
Joe Weiss
Manager of Plant Simulation
Alfa Laval Biokinetics
Introduction
•
Hemosol
– Hemosol is an Integrated Biopharmaceutical
company developing blood derived therapeutics.
In addition the company offers contract
bioprocess manufacturing as well as aseptic
filling services.
•
Alfa Laval Biokinetics
– Alfa Laval is a leading global supplier of
specialized products and engineered solutions.
Our equipment and services are dedicated to
helping customers optimize the performance of
their processes – time and time again
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Overview
•
•
•
•
•
Value of Simulation
Case Study – Initial Approach
Simulation
Results – Short term / Long term
Areas of Impact
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Biotech Facilities
•
Typically built around one product with some flexibility to do
unknown others.
•
Need to be built quickly once the “go” decision has been made
– Minimize risk by delaying construction
– However, each day without product can be significant loss
of revenue
•
Can become obsolete for initial product once patent ends, so
needs to be converted/retrofitted to new products quickly
•
Typically lag behind other industries in facility efficiency
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
The Challenge
Ensuring the production facility achieves and
exceeds requirements is a complex puzzle
requiring interaction of process equipment,
piping, automation, utilities, production
schedules, staffing, warehousing and so on.
Solving this complex puzzle takes a qualified team
and the right simulation tool.
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Typical Facility Goals
Corporate
•
•
Operations
Minimize schedule
Minimize capital cost
•
•
Robust design
Flexible
•
•
•
•
ISPE Central Canada – September 29 2005
Hemosol
Production
Automation
Maintainable
Cleanable
Alfa Laval
John Rydall Joe Weiss
Advantages of Plant Simulation
•
•
•
•
Visualize plant operation
•
Determine impact of routine maintenance or
sanitization
•
Ensure proper sizing of support areas and utilities
Assess equipment and space sizing and utilization
Identify bottlenecks and methods to overcome them
Identify savings and reduce production costs and
capital investment
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
K-TOPS® Simulation
•
Total Optimum Plant Simulation Software
– Dynamic tool for total plant optimization
•
Used in Planning, Analysis and Optimization of
biopharmaceutical processes and facilities
•
•
•
Can be used at any project stage
Provides fast, effective solutions to process or facility issues
Combination of tool with biopharmaceutical expertise
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Alternate Methods
Real World Trial and Error
•
Risky & Expensive
Manual Calculations/Rules of Thumb
•
•
Difficult to analyze multiple scenarios
Higher contingency/cost for facility due to reduced confidence/
accuracy
Spreadsheets
•
•
Static calculations do not capture dynamics and variability
Difficult to manage large analysis
Rigorous Computer Simulation
•
•
Highly time consuming
May require entering data not required for final output/objectives
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Simulation Modeling in Biopharm
More readily desired than in past
•
Hemosol, ProMetic BioSciences, Amgen, Bayer,
Bristol-Myers Squibb, Centocor, Chiron,
GlaxoSmithKline, ImClone, J&J, Lonza, Merck,
Pfizer, Regeneron, SemBioSys, Wyeth are just
some examples of companies incorporating
simulation modeling into their approach
•
Evolution of tools for speed and flexibility
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Identify Key Objectives
•
Optimization means different things to different
people/groups/companies
•
Achieve a particular capacity at minimal capital cost
with some flexibility
•
•
•
•
What would it take to go beyond this capacity
Are the support systems adequate
Are the root utility systems adequate
Make sure we address the true problem/objective
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Modeling Sequence
Root Utility
Systems
Media
Preparation
Generation
Components /
Buffer
Preparation
Component
Prep
Purification
Packaging
Filling
Warehousing
Waste Systems
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Range of Inputs for Simulation
•
A “defined” process:
– Process is often not locked down; as process is still being
developed, define a process range
– Unit operation times – including set-up, sampling
– Process hold points / times
– Equip prep / support times
– Buffer/media prep times
– Buffer hold/expiration times
– CIP & SIP times
– Dependencies
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Inputs
Process Recipe
• Steps with Times
• Required Resources
• Interdependencies
Equipment List
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Simulation Cycle
Simulate
Increase
Throughput
Identify
Bottlenecks
Propose
Solution
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Outputs - Manufacturing Timeline
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Outputs
$80
9
15
18
$70
6
Column 1 T1 Elute
BufferA Hold
Tank(2000L) T
f
1
BufferA Hold
Tank(2000L) T
f
BufferA Hold
Tank(2000L) T
f
4
$60
$50
$40
$30
$20
$10
$-
12
16
3
8
11
2
5
Process Flow
Column
Receiver Tank
T1
Stream Description
ProcVol (Additions)
Buffer A (Liters)
Buffer B (Liters)
Buffer C (Liters)
Buffer D (Liters)
Buffer E (Liters)
W FI-Process (Liters)
1
2
Column
Receiver Tank
T1
Receive
Column
Receiver Tank
T1
Transfer
150
150
TFF Tank T1
3
TFF Tank T1
Filter
4
TFF Tank T1
Displace
Product
150
5
TFF Tank T1
Transfer
Column 2 Feed
Tank T1
TFF T1
6
TFF T1
Flush Filter
7
TFF T1
Equilibrate
275
Column 2 T1
8
TFF T1
Filter
Base Case
17
9
TFF T1
Clean
10
Financial Analysis
TFF T1
Store
150
250
1000
Profit
Capital Cost
Production Costs
Both
14
19
Second
Fermentor
13
10
Small
Purification
7
750
500
500
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Facility
•
Facility Design
dependent upon
Process
– Planning for
future, how to
expand logically
•
Process Dependent
upon Facility
– Existing Facility
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Case Study
Large Greenfield Biotech Facility
•
15 Discrete Unit Operations
– Reactions
– Ultrafiltration and
chromatography
– Gas exchange
– Pasteurization
– Clean in Place
– Aseptic Filling
– Packaging
– Utility / High Purity Water
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Project Goals
•
•
•
•
•
•
200,000 Units /yr Production from Facility
Build fast
Build Process in Parallel to Facility
Minimize capital
Ease of operability
Ease of validation
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Initial Design
Plant initially designed without simulation effort
Performed feasibility studies, utilized past experiences
Approach
•
•
•
Start 1 batch per day
Start 250 L batch
Address future production capacity by sizing
vessels to hold 50% more volume than required for
250 L batch – i.e. 400 L for initial vessel
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Initial Design
•
Made logical sense from equipment sequence
– All the right equipment was there at a consistent
size
•
Smaller, less expensive equipment running more
frequently
•
Gives good equipment utilization – get some value
for your money
•
Use simulation to confirm
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Simulation to Confirm
•
Quick “reality check” of design showed
– High equipment utilization
– Limited “turnaround” time between batches
– Limited windows for maintenance
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Batch Process – Gantt Chart
DAY 13
14
15
HOUR 312
316
320
324
328
332
336
340
344
348
352
356
360
364
368
372
376
380
TIME 6 AM
10 AM 2 PM
6 PM
10 PM 2 AM
6 AM
10 AM 2 PM
6 PM
10 PM 2 AM
6 AM
10 AM 2 PM
6 PM
10 PM 2 AM
Setup Ba FCle
Setup Ba FCle
29% RBC Setup Ba FCle
Re
FDM
H
F
CIP
S
Re
FDM
H
F
CIP
S
Re FDMHF CIP S
31% POO
I
F
Wai
C
S
I
F
Wai
C
S
I F Wai C S
22% W AS
S
Cl
F
EI
R
R
Diafiltrati
CDiafiltra
CIP
C
SIP
F
FSSIP
Cl
F
EI
R
R
Diafiltrati
CDiafiltra
CIP
C
SIP
F
FSSIP
Cl
F
EI
RR Diafiltrati CDiafiltra CIP C SIP F FSS
94% W AS
Cl
F
EI
R
W
Diafiltrati
CDiafiltra
Wait
5.5
F
FS
Cl
F
EI
R
W
Diafiltrati
CDiafiltra
Wait
5.5
F
FS
Cl
F
EI
RW Diafiltrati CDiafiltra Wait 5.5
F FS
85% W AS
Cl F EI W Diafiltrati CDiafiltra Wait 5.5
F FS
Cl F EI W Diafiltrati CDiafiltra Wait 5.5
F FS
Cl F EI W Diafiltrati CDiafiltra Wait 5.5
F FS
85% LYSE
S
C
FR
Concentrati
M
TW
CIP
C
SIP
C
FR
Concentrati
M
TW
CIP
C
SIP
C
FR
Concentrati
M
TW
CIP
C S
60% CLAR
C
FW
Concentrati
FC
FS
C
FW
Concentrati
FC
FS
C
FW
Concentrati
FC
FS
42% CLAR
FWC FW S
FWC FW S
FWC FW S
18% CLAR
WTCIP 3 S
RCH Pasteurization 15 Hour
WTCIP 3 S
RCH Pasteurization 15 Hour
WTCIP 3 S
RCH Pasteur
92% PASTPasteurization 11.5 Hour
I FWTFlu W C SIP
I FWTFlu W C SIP
I FWTFlu W C SIP
32% VIRA
FInte FWC FRFlu Filtra AFC FInte FW SWCIP S
FInte FWC FRFlu Filtra AFC FInte FW SWCIP S
FInte FWC FRFlu Filtra AFC FInte FW SW
83% VIRA CIP S
FInte FC FWait Filtra WFC FInte FS
FInte FC FWait Filtra WFC FInte FS
FInte FC FWait Filtra WFC FInte FS
64% VIRA
CI
C FSIP WR Concentrati QADiafiltr DW Load 5.5
CI
C FSIP WR Concentrati QADiafiltr DW Load 5.5
CI
C FSIP WR Concentrati QADiafiltr
94% TRIS DW Load 5.5
WFW C FS
WFW C FS
WF
19% TRIS W C FS
C FWait
Concentrati ADiafiltr FC FS
C FWait
Concentrati ADiafiltr FC FS
C FWait
Concentrati ADiafiltr F
67% TRIS C FS
CO SIP
I FWLoad 5.5
CO SIP
I FWLoad 5.5
CO SIP
46% CHR I FWLoad 5.5
W CCWCCle Cle Stor F
CSe SE E E Load 5.5
W CCWCCle Cle Stor F
CSe SE E E Load 5.5
W CCWCCle Cle Stor F
CSe SE E
85% CHR E Load 5.5
W CIP S
WReceive 5.5 W AWLoad 5.5
W CIP S
WReceive 5.5 W AWLoad 5.5
W CIP S
77% CHR WReceive 5.5 W AWLoad 5.5
MC CMAWC
MW Ani C
MW Cati Wai C
MC CMAWC
MW Ani C
MW Cati Wai C
MC CMAWC
MW Ani C
MW C
60% BUFFCa Wai C
M
A
Wa
C
M
W
A
CM
CW
C
M
W
Cati
C
M
AWCM
A
Wa
C
M
W
A
CM
CW
C
M
W
Cati
C
M
AWCM
A
Wa
C
M
W
A
CM
CW
C
M
W
Cati
C
MAWC
60% BUFF
Wai
C
M
CM
AW
C
M
W
C
W
CSIP
M
A
Wait
C
M
CM
AW
C
M
W
C
W
CSIP
M
A
Wait
C
M
CM
AW
C
M
W
C
W
CSIP
MA W
56% BUFF
Wait
C
M
C
W
CM
AW
C
M
W
C
WCSIP
M
A
Wait
C
M
C
W
CM
AW
C
M
W
C
WCSIP
M
A
Wait
C
M
C
W
CM
AW
C
M
W
C
WCSIP
MA
61% BUFF
I FW Load 5.5
CO SIP
I FW Load 5.5
CO SIP
I FW Load 5.5
CO SIP
48% CHR
Se FS E W ELoad 5.5
Wa C C Clea Clea WStor
Se FS E W ELoad 5.5
Wa C C Clea Clea WStor
Se FS E W ELoad 5.5
Wa C C Clea Clea WS
90% CHR St
Wait
SC
Wait
4
FW
Receive
5.5
CADiaf
TCIP
S
FFC
FWait
SC
Wait
4
FW
Receive
5.5
CADiaf
TCIP
S
FFC
FWait
SC
Wait
4
FW
Receive
5.5
CADiaf TCIP S FFC F
98% W FI
C FWait 10.5 Hour
CADiaf Wait
FFC FS
C FWait 10.5 Hour
CADiaf Wait
FFC FS
C FWait 10.5 Hour
CADiaf Wait
FFC F
90% W FI S
N
CIP
CIP
C
N
CIP1
C
N
CIP
N
N
N
CIP
CIP
C
N
CIP1
C
N
CIP
N
N
N
CIP
CIP
C
N
CIP1
C
N
CIP
NN
58% CIP S
CCCCCCCN C CIP2 C CNCN CC
C NCCIP CCCC
CCCCCCCN C CIP2 C CNCN CC
C NCCIP CCCC
CCCCCCCN C CIP2 C CNCN CC
C NC
77% CIP SCIP CCCC
CI
N
CIP CIP
N Na N NN
CI
N
CIP CIP
N Na N NN
CI
N
CIP CIP
N N
50% CIP SNa N NN
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Equipment Utilization
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Hidden Constraints
•
•
•
Setup time
•
Precedence – cannot start a process activity until a
non-process activity is completed (QC testing
results)
•
•
Interference – piping or space limitations
Cleaning time
Interdependence – waiting for other equipment or
resources to be available
State – buffer expiration times, cleaning expiration
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Revised Approach
•
•
•
Start with objectives and build upon it
Identify hidden items
Challenge system – “What if”
– Cleaning time doubled
– Cleaning time stayed same, volume doubled
– Items not available when desired – buffer, raw
materials, equipment
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Revised Design
•
•
Start 1 batch every second day
•
•
Start 500 L batch
Pool final processing area to generate 1 batch
every 4 days
Minimal impact on Facility space
– Vessel volume size increased only by 1/3 to 1/2
– Vessel diameter increased by 6” in most cases
(1 ft on one)
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Initial Design – Gantt Chart
DAY 13
14
15
HOUR 312
316
320
324
328
332
336
340
344
348
352
356
360
364
368
372
376
380
TIME 6 AM
10 AM 2 PM
6 PM
10 PM 2 AM
6 AM
10 AM 2 PM
6 PM
10 PM 2 AM
6 AM
10 AM 2 PM
6 PM
10 PM 2 AM
Setup Ba FCle
Setup Ba FCle
29% RBC Setup Ba FCle
Re
FDM
H
F
CIP
S
Re
FDM
H
F
CIP
S
Re FDMHF CIP S
31% POO
I
F
Wai
C
S
I
F
Wai
C
S
I F Wai C S
22% W AS
S
Cl
F
EI
R
R
Diafiltrati
CDiafiltra
CIP
C
SIP
F
FSSIP
Cl
F
EI
R
R
Diafiltrati
CDiafiltra
CIP
C
SIP
F
FSSIP
Cl
F
EI
RR Diafiltrati CDiafiltra CIP C SIP F FSS
94% W AS
Cl
F
EI
R
W
Diafiltrati
CDiafiltra
Wait
5.5
F
FS
Cl
F
EI
R
W
Diafiltrati
CDiafiltra
Wait
5.5
F
FS
Cl
F
EI
RW Diafiltrati CDiafiltra Wait 5.5
F FS
85% W AS
Cl F EI W Diafiltrati CDiafiltra Wait 5.5
F FS
Cl F EI W Diafiltrati CDiafiltra Wait 5.5
F FS
Cl F EI W Diafiltrati CDiafiltra Wait 5.5
F FS
85% LYSE
S
C
FR
Concentrati
M
TW
CIP
C
SIP
C
FR
Concentrati
M
TW
CIP
C
SIP
C
FR
Concentrati
M
TW
CIP
C S
60% CLAR
C
FW
Concentrati
FC
FS
C
FW
Concentrati
FC
FS
C
FW
Concentrati
FC
FS
42% CLAR
FWC FW S
FWC FW S
FWC FW S
18% CLAR
WTCIP 3 S
RCH Pasteurization 15 Hour
WTCIP 3 S
RCH Pasteurization 15 Hour
WTCIP 3 S
RCH Pasteur
92% PASTPasteurization 11.5 Hour
I FWTFlu W C SIP
I FWTFlu W C SIP
I FWTFlu W C SIP
32% VIRA
FInte FWC FRFlu Filtra AFC FInte FW SWCIP S
FInte FWC FRFlu Filtra AFC FInte FW SWCIP S
FInte FWC FRFlu Filtra AFC FInte FW SW
83% VIRA CIP S
FInte FC FWait Filtra WFC FInte FS
FInte FC FWait Filtra WFC FInte FS
FInte FC FWait Filtra WFC FInte FS
64% VIRA
CI
C FSIP WR Concentrati QADiafiltr DW Load 5.5
CI
C FSIP WR Concentrati QADiafiltr DW Load 5.5
CI
C FSIP WR Concentrati QADiafiltr
94% TRIS DW Load 5.5
WFW C FS
WFW C FS
WF
19% TRIS W C FS
C FWait
Concentrati ADiafiltr FC FS
C FWait
Concentrati ADiafiltr FC FS
C FWait
Concentrati ADiafiltr F
67% TRIS C FS
CO SIP
I FWLoad 5.5
CO SIP
I FWLoad 5.5
CO SIP
46% CHR I FWLoad 5.5
W CCWCCle Cle Stor F
CSe SE E E Load 5.5
W CCWCCle Cle Stor F
CSe SE E E Load 5.5
W CCWCCle Cle Stor F
CSe SE E
85% CHR E Load 5.5
W CIP S
WReceive 5.5 W AWLoad 5.5
W CIP S
WReceive 5.5 W AWLoad 5.5
W CIP S
77% CHR WReceive 5.5 W AWLoad 5.5
MC CMAWC
MW Ani C
MW Cati Wai C
MC CMAWC
MW Ani C
MW Cati Wai C
MC CMAWC
MW Ani C
MW C
60% BUFFCa Wai C
M
A
Wa
C
M
W
A
CM
CW
C
M
W
Cati
C
M
AWCM
A
Wa
C
M
W
A
CM
CW
C
M
W
Cati
C
M
AWCM
A
Wa
C
M
W
A
CM
CW
C
M
W
Cati
C
MAWC
60% BUFF
Wai
C
M
CM
AW
C
M
W
C
W
CSIP
M
A
Wait
C
M
CM
AW
C
M
W
C
W
CSIP
M
A
Wait
C
M
CM
AW
C
M
W
C
W
CSIP
MA W
56% BUFF
Wait
C
M
C
W
CM
AW
C
M
W
C
WCSIP
M
A
Wait
C
M
C
W
CM
AW
C
M
W
C
WCSIP
M
A
Wait
C
M
C
W
CM
AW
C
M
W
C
WCSIP
MA
61% BUFF
I FW Load 5.5
CO SIP
I FW Load 5.5
CO SIP
I FW Load 5.5
CO SIP
48% CHR
Se FS E W ELoad 5.5
Wa C C Clea Clea WStor
Se FS E W ELoad 5.5
Wa C C Clea Clea WStor
Se FS E W ELoad 5.5
Wa C C Clea Clea WS
90% CHR St
Wait
SC
Wait
4
FW
Receive
5.5
CADiaf
TCIP
S
FFC
FWait
SC
Wait
4
FW
Receive
5.5
CADiaf
TCIP
S
FFC
FWait
SC
Wait
4
FW
Receive
5.5
CADiaf TCIP S FFC F
98% W FI
C FWait 10.5 Hour
CADiaf Wait
FFC FS
C FWait 10.5 Hour
CADiaf Wait
FFC FS
C FWait 10.5 Hour
CADiaf Wait
FFC F
90% W FI S
N
CIP
CIP
C
N
CIP1
C
N
CIP
N
N
N
CIP
CIP
C
N
CIP1
C
N
CIP
N
N
N
CIP
CIP
C
N
CIP1
C
N
CIP
NN
58% CIP S
CCCCCCCN C CIP2 C CNCN CC
C NCCIP CCCC
CCCCCCCN C CIP2 C CNCN CC
C NCCIP CCCC
CCCCCCCN C CIP2 C CNCN CC
C NC
77% CIP SCIP CCCC
CI
N
CIP CIP
N Na N NN
CI
N
CIP CIP
N Na N NN
CI
N
CIP CIP
N N
50% CIP SNa N NN
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Revised – Gantt Chart
DAY 13
14
15
HOUR 312
316
320
324
328
332
336
340
344
348
352
356
360
364
368
372
376
380
HOUR 6 AM 10 AM 2 PM 6 PM 10 PM 2 AM 6 AM 10 AM 2 PM 6 PM 10 PM 2 AM 6 AM 10 AM 2 PM 6 PM 10 PM 2 AM
S Bag
FC
11% RBC S Bag FC
S
Receiv
FDM
HF
CIP
WC
SIP
S
Receiv
FDMHF CIP WC SIP
26% POO
I F Wa C S
I F Wa C S
10% WAS
CDiafiltration CIP
W C SIP F FS
Cl F EI RSIP R PBS
CDiafiltration CIP
W C SIP
53% WASCl F EI RSIP R PBS
CDiafiltration Wait 7.5 Hours
F FS
Cl F EI RWait 3 PBS
CDiafiltration Wait 7.5 Hours
53% WASCl F EI RWait 3 PBS
PBS
CDiafiltration Wait 7.5 Hours
F FS
Cl F EI Wait
PBS
CDiafiltration Wait 7.5 Hours
53% LYSECl F EI Wait
C FR Concentrati MCH Pasteurization 12 Hours
TCI CI SIP
C FR Concentrati MCH Pasteuriz
55% CLAR
C FW Concentrati FC FS
C FW Concentrati FC FS
21% CLAR
FWa C FWS
FWa C FWS
10% CLAR
I
F
TF
C
SIP
11% VIRA
FInte F C FRSIP RF Filtration 5 ACIP
CI FC FInte FS
49% VIRA FS
FS
FInte
FC
FR
Wait
Filtration
5
Wait
5
FC FInte FS
49% VIRA
Load
6
Hours
CI
CI
C
FSIP
R
Concentrati
QADiafiltration
6 DW Load 6 Hours WCI Wait CI
60% TRIS
0% TRIS D
FC FS
6% TRIS D FS
C FWait
Concentrati WADiafiltration 6 FC FS
40% TRIS FS
I F Load 6 Hours CO SIP
23% CHR F Load 6 Hours CO SIP
S WEE Load 6 Hours W CWCCCle Cl WS
35% CHR E Load 6 Hours W CWCCCle Cl WS
W AWait 8.75 Hours
Load 6.5 Hours W CIP CI
SIP 3 Receive 6
W AWait 8.75 Hours
Load 6.5 Hours
67% CHR Receive 6
C
MA
C
M
AC
M
W
CC
M
C
C
MCati
C
M
C
CSIP
M
ACM
AC
MA
C
M
AC
M
W
CC
M
C
C
M
37% BUFF
AW
C
MACMAC
M
W
CM
W
CC
MC
CSIP
M
CM
AW
C
MACMAC
M
W
CM
W
CC
31% BUFF
I F Load 6.5 Hours CO SIP
I F Load 6.5 Hours
24% CHR
W
FS
W
E
EW
Load
6.5
Hours
Wa
C
W
C
Clea
Clea
W
S
W
FS
W
E
EWLoad 6.5 Hours
46% CHR
Na
C
CIP
C
C
N
CIP1
N
C
N
N
CI
Na
C
CIP
C
C
N
CIP1
N C N
32% CIP S
CC CC
CC CC
C C CN
C CI
NCIP2
N
CC CNC
CC CC
CC CC
33% CIP SCNC
CIP
C CI
C
CIP CI
CIP CIP
CIP C C C C CI
CI
C
C CI
C
CIP CI
CIP CIP
45% BUFF
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Equipment Utilization
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Getting More
•
•
What is required to increase capacity?
•
Only two additional process equipment were
needed to increase capacity 50%
Challenge process, buffer system and root utilities
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Revisit Simulation
•
•
•
Add 2nd Process Unit for 2 modules
•
Redundancy – Focus on critical portion of skid
Add 2 portable buffer tanks
All other Process Equipment utilized <75% with a
minimum 8 hr turnaround time
– 2nd pump rather than 2nd skid
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Batch Process – Gantt Chart
DAY 13
14
15
HOUR 312
316
320
324
328
332
336
340
344
348
352
356
360
364
368
372
376
380
HOUR 6 AM 10 AM 2 PM 6 PM 10 PM 2 AM 6 AM 10 AM 2 PM 6 PM 10 PM 2 AM 6 AM 10 AM 2 PM 6 PM 10 PM 2 AM
S Bag
FC
15% RBC S Bag FC
S
Receiv
FDM
HF
CIP
WC
SIP
S
Receiv
FDMHF CIP WC SIP
35% POO
I F Wa C S
I F Wa C S
14% WAS
CDiafiltration CIP
W C SIP F FS
Cl F EI RSIP R PBS
CDiafiltration CIP
W C SIP F FS
71% WASCl F EI RSIP R PBS
CDiafiltration Wait 7.5 Hours
F FS
Cl F EI RWait 3 PBS
CDiafiltration Wait 7.5 Hours
F FS
71% WASCl F EI RWait 3 PBS
PBS
CDiafiltration Wait 7.5 Hours
F FS
Cl F EI Wait
PBS
CDiafiltration Wait 7.5 Hours
F FS
71% LYSECl F EI Wait
C FR Concentrati MCH Pasteurization 12 Hours
TCI CI SIP
C FR Concentrati MCH Pasteurization 12 Hours
TCI CI
74% CLARSIP
C
FW
Concentrati
FC
FS
C
FW
Concentrati
FC
FS
28% CLAR
FWa C FWS
FWa C FWS
14% CLAR
I
FTF
CSIP
I F TF C SIP
15% VIRA
AW
CIP
CI
FC
FInte
FS
FInte
FC
FR
SIP
RF
Filtration
5
ACIP
W
CI
FC
FInte
FS
FInte
F
C
FRSIP
RF Filtra
65% VIRA
Wait
5.5
FC
FInte
FS
FInte
FC
FR
Wait
3.5
Filtration
5
Wait
6.25
FC
FInte
FS
FInte
FC
FR
Wait
Filtra
65% VIRA
Concentr
QADiafiltration
6
DW
W
Load
6
Hours
W
CI
Wait
C
C
FSIP
R
Concentrati
QADiafiltration
6
DW
W
Load
6
Hours
CI
C
C
FSIP
R Co
84% TRIS
0% TRIS D
FWa C FS
FWC FS
11% TRIS
C FWait 3 Concentrati WADiafiltration 6 FC FS
C FWait
Co
53% TRIS Concentr WADiafiltration 6 FC FS
I FWLoad 6 Hours CO SIP
I FW Load 6 Hours CO SIP
33% CHR
S WEE Load 6 Hours W CWCCCle Cl Wait S
SW WEE Load 6 Hours W CWCCCle Cl S
53% CHR
W
CIP
C
SIP
3 W Receive 6
W AWait 8.75 Hours
Load 6.5 Hou
47% CHR
SIP 3 WReceive 6
W AWait 10.5 Hours
Load 6.5 Hours W CIP CI
47% CHR
MWA C MAC
MW C C MC C
MWait Cati Wait CMC CSIP MC MAWC
MW A C MAC
MW C C MC C
M
66% BUFFW Cati WC MC Wait CSIP MC MAWC
M
W
C
Wait
CSIP
M
ACMAC
M
WACMAC
M
W
CM
W
C
C
M
Wait
C
Wai
CSIP
M
ACM
W
AC
M
W
ACMAC
M
W
CM
W
C
C
59% BUFF
I FWait Load 6.5 Hours CO SIP
I FW Load 6.5 Hou
37% CHR CO SIP
Wa
C
W
C
Clea
Clea
WS
W
FS
W
E
EWait
Load
6.5
Hours
Wa
C
Wait
C
Clea
Clea
W
S
W
FS
W
E EWLoad 6.5 Hou
61% CHR
C
CIP C C N
CIP1
N C N
N
CI
Na
C
CIP C C N
CIP1
N C N
N
CI
42% CIP SNa
NCCIP2 CC N CC CNC
CC CC
CC N CC
CCI
NCIP2
CC C N C C CNC
CC CC
CCN CC
C CI
44% CIP S
CIP
CIP CIP CI CI
CIP CI C
C
CI CI CI C
C
CIP CIP
CIP CIP CI CI CI CIP CI C
C
60% BUFF CI CI CI C C
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Equipment Utilization
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Challenging Buffer and Utilities
CIP Example
•
Initial Plan – 4 CIP
Skids
•
Increase to 5 after
Simulation
Hours of CIP Usage
200K
CIP Skid 1 CIP Skid 2 CIP Skid 3 CIP Skid 4 CIP Skid 5
Daily Avg
4
7
9
8
10
Daily Max
7
9
12
14
14
300K
CIP Skid 1 CIP Skid 2 CIP Skid 3 CIP Skid 4 CIP Skid 5
Daily Avg
6
10
12
11
13
17
15
Daily Max
7
10
15
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Options for Increased Capacity
•
•
•
Add additional equipment now
•
Without simulating, increased capacity would
require
Leave space and connections for future equipment
Specify equipment for expandability (pumps, filters)
– New facility
– Expansion to existing facility with shutdown of
existing operations
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Getting Approval
•
Real value info to technical team to convince upper
management to spend more money
Profit
Capital Cost
Production Costs
200K
ISPE Central Canada – September 29 2005
300 K
Hemosol
Alfa Laval
John Rydall Joe Weiss
Retrofit of Manufacturing
•
Flexible design elements readily enable the conversion of the
Hemolink facility for Commercial scale purification of Plasma
proteins using novel “Cascade” Technology.
•
Simulation of the new “Cascade” processes when overlaid on
the existing utility infrastructure and equipment has been used
to evaluate plant capacity and to support the initial design
approach in advance of the retrofit.
•
Currently examining “what if” scenarios with the goal towards
refining the design basis of the retrofit in order to achieve the
most efficient and optimal process implementation within the
facility
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Contract Manufacturing
•
Generic Processes and “What If” to challenge the
robustness of the facility
•
Assess the feasibility of conducting new processes
in the facility and their impact on other contracts
and/or Hemosol operations & utility infrastructure
•
Model client processes to confirm production from
facility – process, fill/finish, buffers, utilities
•
Approaches to campaigning and overall plant
scheduling
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Other Examples
•
•
Grass-Roots Facility - Saving Millions $$$
•
Critique of Existing Design - Expansion – Saving
60% of estimated costs, Millions $$$
•
Capacity Analysis of Existing Facility – Adding new
product into mix
•
Debottlenecking of Existing Facility – Identifying
“low lying fruit” and methods to go beyond
Debottlenecking of Existing Facility – Doubling
Capacity
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Case Study – New Product into
Mix
3 Products – Adding 4th – Expecting new line
PRODUCTION INFO
DESCRIPTION
Production Rate
(Vials/min)
Vial Size (mL)
Annual Production
Runs per year
Vials per run
Max Vials per Sterilization
Volume per run (L)
Batches per run
Sterilizations per run
PRODUCT 1
PRODUCT 2
PRODUCT 3
VIAL FILLED
VIAL FILLED PRODUCT - VIAL FILLED
PRODUCT NO
PRODUCT STERILIZED STERILIZER; STERILIZED
ASEPTIC
250
200
300
Weeks/yr
48
5
4,300,000
108
22
40,000
10
12,000,000
240
48
50,000
3
7,600,000
102
20
74,500
Days/wk
Days/yr
5
240
Runs/yr
Avg. Runs/day
450
1.9
20,000
200
1
2.0
ISPE Central Canada – September 29 2005
25,000
500
2
0
Hemosol
224
1
3.0
Alfa Laval
John Rydall Joe Weiss
Simulation Solutions
Can add 4th Product in multiple ways – most
economical is adding 2 large tanks
Large benefit drove QC to validate larger batch size
Case
Base
Option 1
Option 3
Option 2
Option 4
Original Operation
New Line
Work Weekend
Add Needed Equip
Batch Size & Add
Needed Equip
Products
3
4
4
Lines
2
3
2
Tanks
4
4+2
4
Days /
Week
5
5
7
4
2
4+2
5
Additional Equipment
None
New Line
None
2 Tanks, Filler, Stopperer,
Overcapper, Vial Washer,
Depyro Tunnel
4
2
4 + 2 large
5
2 Large Tanks
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
Capital Operating
Production
Cost
Cost
Increase Increase Increase
0
0
0
1 product
Large
25%
1 product
None
40%
1 product
Large
25%
1 product
Small
5%
John Rydall Joe Weiss
Case Study – Existing Production
Facility
•
Objective
– Double capacity
– No Facility Shutdown
– Complete in 6 Months
•
Anticipated Concerns
– High Purity Water
– CIP
– Waste
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Case Study – Existing Production
Facility
•
Multiple Layers of complexity
– Multiple Process/Product Areas
– Multiple Water qualities and temperature
•
Address Immediate, Mid-Range and LongRange plans
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Results for Short and Long Term
2.5
(4A) Add 2 New CIP Skids
(4A) Adjust Cleaning Recipe
(4B) SIP Line separate from
Tank
(4C) Decrease Testing Time
(4D) Add Portable UF cleaning
tanks
2.25
2
(3A) Add New WFI Still
(3B) Multi-batch buffer
preparation
(3B) Increased Bag Usage 1.5
Capacity
1.75
Combine Tank and Line
Cleaning
Media and Buffer work
around CIP
1.5
Implement CIP Manager
Use Buffer Bags for small
volume
1.25
1
0.75
(1) CIP
Bottleneck
1.3
1.2
1
(2) Increased
CIP
Bottleneck
2
(3A) WFI
Bottleneck
(3B) Buffer
Bottleneck
(4A) More CIP
Bottlenecks
(4B) SIP
Bottleneck
(4C) QA/QC
Turnaround
(4D) UF Cleaning
Bottleneck
0.5
1
2
3
4
5
Stage
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Simulation Value
•
Production Capacity Analysis
– Increase/Maximize existing product
– New product into facility / into mix
•
•
•
•
•
•
•
•
Technology comparison
Manpower evaluation
Scheduling
Economic evaluation
Equipment/Material movement – Traffic
Warehousing
Maintenance
Training
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Power Demand
1400
1200
1000
kWh
800
600
400
200
0
0
24
48
72
96 120 144 168 192 216 240 264 288 312 336 360 384 408 432 456 480 504 528 552 576 600 624 648 672 696
Time (hr)
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Power Demand – 2hr
1600
1400
1200
kWh
1000
800
600
400
200
0
0
24
48
72
96 120 144 168 192 216 240 264 288 312 336 360 384 408 432 456 480 504 528 552 576 600 624 648 672 696
Time (hr)
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Power Demand – 4 hr
2000
1800
1600
1400
kWh
1200
1000
800
600
400
200
0
0
24
48
72
96 120 144 168 192 216 240 264 288 312 336 360 384 408 432 456 480 504 528 552 576 600 624 648 672 696
Time (hr)
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Power Demand – 24 hr
2000
1800
1600
1400
kWh
1200
1000
800
600
400
200
0
0
24
48
72
96 120 144 168 192 216 240 264 288 312 336 360 384 408 432 456 480 504 528 552 576 600 624 648 672 696
Time (hr)
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
High Purity Water
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Impact of Increased Demand
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Overcoming Demand
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Overcoming Demand
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss
Thank you!
For additional information contact:
John R. Rydall
Joseph Weiss
(905) 286-6273
(215) 656-2546
jrydall@hemosol.com
joe.weiss@alfalaval.com
ISPE Central Canada – September 29 2005
Hemosol
Alfa Laval
John Rydall Joe Weiss