ISPE-CASA PRESENTS
“CLEAN & GREEN”
DEVELOPING A PROCESS MODEL FOR
SINGLE-USE TFF CASSETTES
By: Mark A. Perreault
CLEAN AND GREEN TECHNOLOGIES
FOR PURE WATER AND
PROCESS TECHNOLGIES
4/13/2009
ISPE Carolina South-Atlantic Chapter
1
Effects of Single Use Technology
Where has single-use technology effected
Bio-Processing?
Then…
4/13/2009
• Bioreactors
• Media Storage
• Aseptic Filtration
Now…
Effects of Single Use Technology
Single-use technology has made bioprocesses:
Cleaner
Safer
More Efficient
Single-use technology has enabled a typical
purification process to eliminate numerous
costly clean in place (CIP) operations
4/13/2009
ISPE Carolina South-Atlantic Chapter
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Considerations for Single Use TFF
Tangential Flow Filtration (TFF) is a very
common process step used during purification to
concentrate and diafilter process streams
When developing a process model for single use
TFF, consider its purpose, function, and scale
Only implement a single use process step if it
makes “good sense” and can be justified.
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Developing a Process Model for
Single Use TFF
Begin by identifying the TFF steps in your
purification process
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ISPE Carolina South-Atlantic Chapter
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Developing a Process Model for
Single Use TFF
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Developing a Process Model for
Single Use TFF
Several key parameters will quickly identify
which TFF steps are a good candidate for
single use and ones that are not
Consider the following:
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Developing a Process Model for
Single Use TFF
Comparison of System Design
Labor
Reusable TFF Process
Single Use TFF Process
Consumables
Reusable TFF Process
Single Use TFF Process
Economic Process Model Comparison
4/13/2009
ISPE Carolina South-Atlantic Chapter
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Developing a Process Model for
Single Use TFF
Comparison of System Design
Labor
Reusable TFF Process
Single Use TFF Process
Consumables
Reusable TFF Process
Single Use TFF Process
Economic Process Model Comparison
4/13/2009
ISPE Carolina South-Atlantic Chapter
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Developing a Process Model for
Single Use TFF
System Design
Single Use Options
UF / DF
prefilter
Retentate
Permeate
DF-buffer
Feed
Filtration Cassettes (only)
fluid reservoir
Cassette and Holder
Complete Single Use System
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ISPE Carolina South-Atlantic Chapter
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Developing a Process Model for
Single Use TFF
Examples of System Design
Reusable TFF System
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Single Use TFF System
ISPE Carolina South-Atlantic Chapter
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Developing a Process Model for
Single Use TFF
Comparison of System Design
Labor
Reusable TFF Process
Single Use TFF Process
Consumables
Reusable TFF Process
Single Use TFF Process
Economic Process Model Comparison
4/13/2009
ISPE Carolina South-Atlantic Chapter
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Developing a Process Model for
Single Use TFF
Labor required for a reusable TFF Process
Initial set-up and sanitization Reusable TFF Cassette Process
• Time and labor are consumed
Set-Up
2% 1% 3% flush
DI3% water
4% 3%
both before and after use
Sanitize
2% 2%
Flush
• Recourses are needed for
Normalized water permeability
(NWP)
measurement
NWP
cleaning
validation
Equilibration
Buffer Equilibration Process • A significant volume of purified
Clean
water is needed for CIP and
Flush
Process
flushing
NWP
• Membrane performance can
Store
Flush and clean
decrease after repeated use
50%
Storage
30%
4/13/2009
ISPE Carolina South-Atlantic Chapter
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Developing a Process Model for
Single Use TFF
Labor required for a Single Use TFF Process
Single-Use TFF Process
Initial set-up
• A greater portion of time and
resources can be devoted to
Equilibrate
processing
Process
• Both labor and system size are
minimized
Clean and/or dispose of remaining
• Reduced risksupporting
of cross
contamination
equipment
• Utility requirements are lower
Set-Up
80%
Equilibrate
Process
2%
8%
10%
Clean Equipment
• Greater manufacturing
flexibility is created
4/13/2009
ISPE Carolina South-Atlantic Chapter
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Developing a Process Model for
Single Use TFF
Comparison of System Design
Labor
Reusable TFF Process
Single Use TFF Process
Consumables
Reusable TFF Process
Single Use TFF Process
Economic Process Model Comparison
4/13/2009
ISPE Carolina South-Atlantic Chapter
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Developing a Process Model for
Single Use TFF
Consumables for a TFF Process
•
•
•
•
Purified Water – Added equipment costs and power
requirements
Equilibration Buffer – Pre-made buffers are expensive and
making buffers are labor intensive
Cleaning Solutions – Requires labor and equipment for
preparation of CIP solutions
Filtration Cassettes – Costs for initial investment of
reusable vs. reoccurring costs of single-use
4/13/2009
ISPE Carolina South-Atlantic Chapter
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Developing a Process Model for
Single Use TFF
Purified water requirements for a reusable TFF Process
5000
Initial DI Flush
Volume per run (Liters)
4500
Buffer Equil
4000
Cleaning Solution
3500
Final DI Flush
3000
2500
2000
1500
1000
500
0
0.1
1
5
10
20
50
Membrane Area (m2)
4/13/2009
ISPE Carolina South-Atlantic Chapter
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Developing a Process Model for
Single Use TFF
Purified water requirements for single-use TFF
5000
Initial DI Flush
Volume per run (Liters)
4500
Buffer Equil
4000
Cleaning Solution
3500
Final DI Flush
3000
2500
2000
1500
1000
500
0
0.1
1
5
10
20
50
Membrane Area (m2)
4/13/2009
ISPE Carolina South-Atlantic Chapter
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Developing a Process Model for
Single Use TFF
Water / Buffer Consumption Comparison
Volume per run (L/m2)
100
95
80
60
40
20
5
0
Reusable
Single-Use
Water / Buffer Consumption
4/13/2009
ISPE Carolina South-Atlantic Chapter
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Developing a Process Model for
Single Use TFF
Single-use TFF has a significant impact on TFF
process models
Cleaning solutions are eliminated
Water consumption is greatly reduced when
using single-use TFF
4/13/2009
ISPE Carolina South-Atlantic Chapter
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Developing a Process Model for
Single Use TFF
Consumables for a TFF Process
•
•
•
•
Purified Water – Added equipment costs and power
requirements
Equilibration Buffer – Pre-made buffers are expensive and
making buffers are labor intensive
Cleaning Solutions – Requires labor and equipment for
preparation of CIP solutions
Filtration Cassettes –Costs for initial investment of reusable
vs. reoccurring costs of single-use
4/13/2009
ISPE Carolina South-Atlantic Chapter
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Developing a Process Model for
Single Use TFF
Is there an economic benefit to using traditional cassettes as a
“single-use” product?
If not, can a feasible target cost of single-use cassettes be
determined?
One must consider major variables such as:
Equipment cost
Cleaning validation
Labor
Consumables
Reusable and single-use cassette cost can be weighed against the
percent savings of a single-use TFF process
4/13/2009
ISPE Carolina South-Atlantic Chapter
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Developing a Process Model for
Single Use TFF
What are the costs of reusable TFF cassettes?
Traditional reusable cassette costs are well
established.
Typical costs are as follows:
4/13/2009
ISPE Carolina South-Atlantic Chapter
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Developing a Process Model for
Single Use TFF
Filtration cassette costs for reusable TFF
$4,000
$3,500
$3,000
Supplier A
$2,500
Supplier B
$2,000
Supplier C
$1,500
Supplier D
$1,000
$500
$0
1
$ per sq meter surface area
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ISPE Carolina South-Atlantic Chapter
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Developing a Process Model for
Single Use TFF
Can one anticipate cassette costs for a single-use
TFF process that can trigger a “go” or “no go”
decision?
Consider the following:
Number of batches (or uses) per campaign
The average savings of using single-use cassettes per batch
The cost of the cassettes per batch
What is that anticipated target cost for single-use
TFF ?
4/13/2009
ISPE Carolina South-Atlantic Chapter
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Developing a Process Model for
Single Use TFF
90%
$3,600 per m2
80%
$3,000 per m2
Percent Savings
70%
$2,400 per m2
60%
$1,200 per m2
50%
$800 per m2
40%
30%
20%
10%
0%
0
5
10
15
20
25
30
35
40
45
Num ber of Batches
4/13/2009
ISPE Carolina South-Atlantic Chapter
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Developing a Process Model for
Single Use TFF
The target cost of a single-use TFF cassette
should be no greater than $800 / m2 based on this
model.
The cost of traditional reusable cassettes can
potentially limit the feasibility of single-use.
Is there an economic model that can predict
which processes are suited for single-use TFF?
4/13/2009
ISPE Carolina South-Atlantic Chapter
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Developing a Process Model for
Single Use TFF
Comparison of System Design
Labor
Reusable TFF Process
Single Use TFF Process
Consumables
Reusable TFF Process
Single Use TFF Process
Economic Process Model Comparison
4/13/2009
ISPE Carolina South-Atlantic Chapter
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Developing a Process Model for
Single Use TFF
Single-use TFF provides measurable benefits in many
circumstances, however it can potentially have economic
limitations depending on the scale and frequency of the
operation.
Two key factors affect the economy of single use TFF are:
Membrane area of the operation
The number of cycles the membrane is reused
The following graph shows the relationship between the number
of annual process cycles and the economic benefit (percent
savings) associated with single-use TFF at several different
process scales.
4/13/2009
ISPE Carolina South-Atlantic Chapter
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Developing a Process Model for
Single Use TFF
Single Use Economic Model
90%
Area: 0.1m2
80%
Area: 0.5m2
Area: 5.0m2
70%
Area: 10m2
Percent Savings
Area: 20m2
60%
50%
40%
30%
20%
10%
0%
0
5
10
15
20
25
30
35
40
Number of Batches
Number of batches are based on an annual cycle
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ISPE Carolina South-Atlantic Chapter
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Developing a Process Model for
Single Use TFF
The general trend shows single-use TFF technology is
most beneficial at smaller scales, i.e. less than 5m2.
As the scale grows to 10m2, this model predicts the
break even point occurs at approximately 20 reuse
cycles.
Larger scale operations benefit when the number of
annual process cycles is fewer than 20 reuse cycles.
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ISPE Carolina South-Atlantic Chapter
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Developing a Process Model for
Single Use TFF
Model accounts for:
System Design & Fabrication
Validation
CIP Cycles
Labor & Overhead Costs
Consumables
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ISPE Carolina South-Atlantic Chapter
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A Case Study for Single Use TFF
A case specific analysis can be generated factoring these five
parameters.
A 50ft2 (5m2) concentration and diafiltration process was
modeled.
Primary process steps were analyzed for the level of support
required from the standpoint of labor and the facility.
The following graph compares the sum of labor, facility,
water, and consumable costs associated with a reusable
TFF process vs. a single use one.
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A Case Study for Single Use TFF
Reusable vs. Single-Use Process Cost / Batch
Labor Costs
$30,000
Store
$25,000
NWP
Cost (USD)
Labor rate includes overhead
costs of a typical GMP
BioPharm process facility
A greater portion of time and
resources can be devoted to
processing
Greater manufacturing
flexibility is created
Flush
$20,000
Clean
Process
$15,000
Equilibration
$10,000
NWP
Flush
$5,000
Sanitize
Set-Up
$0
Reusable TFF
1
Single-Use TFF
2
Process Type
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ISPE Carolina South-Atlantic Chapter
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A Case Study for Single Use TFF
Water Cost per Batch
Re-Usable
Water / Buffer Costs
Water / buffer costs include
equipment, monitoring,
preparation, and disposal
Purified water system size
can be greatly reduced with
single-use TFF
Disposal is also minimized
Single Use
$2,500
$1,995
$2,000
$1,500
$1,000
$500
$105
$0
1
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ISPE Carolina South-Atlantic Chapter
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A Case Study for Single Use TFF
Run # vs. Cassette Cost / Batch
Consumable Costs
Re-Usable
$18,000
$16,000
Cassette Cost per Run
Consumable costs are
based on current TFF
cassette prices
Re-Usable cassette cost
occurs once and is then
divided over the total
number of uses
Single Use cassette cost
occurs once for each run
Single Use
$20,000
$14,000
$12,000
$10,000
$8,000
$6,000
$4,000
$2,000
$0
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20
Run Number
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ISPE Carolina South-Atlantic Chapter
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A Case Study for Single Use TFF
Re-Usable
Single Use
Run #
Cost / run
Total Cost
Run #
Cost / run
Total Cost
Overhead & Labor
$28,000
$560,000
Overhead & Labor
$19,600
$392,000
Water Usage
$1,995
$39,900
Water Usage
$105
$2,100
Consumables
$900
$18,000
Consumables
$4,000
$80,000
TOTAL COST
$30,895
$617,900
$23,705
$474,100
Total Cost per Campaign
Total Campaign Cost
Re-Usable
Single Use
$600,000
$500,000
Total Cost
One campaign is defined by
20 individual process
batches
Total surface area was fixed
at 5m2 for each process
A sum of labor w/overhead,
water usage, and
consumables constitute the
total campaign cost
$700,000
$400,000
$300,000
$200,000
$100,000
$0
1
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ISPE Carolina South-Atlantic Chapter
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A Case Study for Single Use TFF
Facility requirements were specified and an overhead rate was
determined based on the service required for each process step.
Labor rates were determined in a similar manner; management,
operators, and quality personnel were all factored in on a weighted
basis.
Although operating costs vary from site to site, the savings associated
with single use is measurable.
Operating costs for a reusable TFF process is $30,895 per run as
compared to the cost of a single-use process of $23,705 per run.
Approximately $7,200 USD is saved per run (or approximately 30%).
The total savings of just this one TFF process is approximately
$143,000 per campaign, assuming a total of 20 discrete batches.
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ISPE Carolina South-Atlantic Chapter
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Single Use TFF - Summary
Single-Use TFF eliminates the need to flush with costly purified
water or measure water permeability rates, saving time and
resources.
Pre-Sanitized cassettes are installed, equilibrated with buffer, and
used in processing.
Development work, scale up and processing can be conducted
nearly 50% faster without the need for membrane cleaning and
measurement or water flux recovery.
Cassette performance is more consistent from run to run as each
process occurs using a new membrane.
Cross-contamination is minimized with single-use cassettes.
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ISPE Carolina South-Atlantic Chapter
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Single Use TFF - Conclusions
Single-Use TFF provides the greatest benefit at small to
moderate scales
Contract manufacturing suites are ideal candidates for Single-Use
TFF
Many intangible benefits are also realized
Cross-Contamination
Batch to batch reproducibility
Manufacturing Flexibility
Single-Use TFF provides both environmental and
economic savings over traditional Reusable TFF
4/13/2009
ISPE Carolina South-Atlantic Chapter
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Thank you for your attention.
ISPE-CASA PRESENTS
“CLEAN & GREEN”
DEVELOPING A PROCESS MODEL FOR
SINGLE-USE TFF CASSETTES
By: Mark A. Perreault
4/13/2009
ISPE Carolina South-Atlantic Chapter
41