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Engin Ayturk, Ph.D.Principal R&D EngineerPall Life SciencesBioPharm Applications R&D
This presentation is the Confidential work product of Pall Corporation and no portion of this presentation may be copied, published, performed, or redistributed without the express written authority of a Pall corporate officer.
© 2012 Pall Corporation.
A Process and Economic Analytical Approach to Single-Use TFF
2© 2012 Pall Corporation
Outline
Introduction and motivations Objectives Case study outline Process definition Model inputs and assumptions Detailed process overview
Cost of Goods (CoGs) breakdown Sensitivity and comparison analysis
3© 2012 Pall Corporation
Introduction & MotivationsWhy single-use in TFF? Provides reductions in:
System preparation Downtime in the
production area Risk of batch or cross
contamination Validation time and costs
4© 2012 Pall Corporation
Introduction & MotivationsWhy single-use in TFF? Provides reductions in:
System preparation Downtime in the
production area Risk of batch or cross
contamination Validation time and costs
Who can use single-use in TFF?
CMO’s Multi-product facilities Production of clinical or small
batches Typical applications
Proteins Recombinant molecules Vaccines Potent biological & cytotoxic
drugs
5© 2012 Pall Corporation
Pall Allegro Technical Solutions Single-use TFF Standard System
Features: Automated ½” tubing 1000 L/h feed flow 0.5 - 2.5 m2 area 4 bar operating
pressure
* Other systems sizes are also available
6© 2012 Pall Corporation
Pall Allegro Technical Solutions Single-use TFF Standard System Flow Path
Key Attributes: Good engineering design Ease of use Ease of access to components Gamma irradiated manifolds Choice of pre-calibrated sensors
7© 2012 Pall Corporation
Objectives
Conduct a thorough Cost of Goods (CoGs) analysis of single-use TFF unit operation
Quantify major economical benefits Evaluate the impact of key process
parameters Benchmark against conventional re-use TFF
8© 2012 Pall Corporation 8© 2012 Pall Corporation
Case Study: Process Definition and Overview
Process Input Re-use TFF Cassettes and Single-use TFF Cassettes
CFEED 5 g/LVFEED 250 L
Process UF1: 10X (Flux = 60 LMH)* Diafiltration: 5 Diavolumes UF2: 3.5X (Flux = 20 LMH)*
Buffers PBS Formulation BufferCassette Type / Area 2.5 m2
Process Time 4-5 hours Max. # of Re-Use 10 (Re-use TFF) and 1 (SUTFF)
No. of Batches / Year 20Yield 95%
* Flux data based on IgG
9© 2012 Pall Corporation
QFeed
QP
F P
FP
FP
QRet
QFeed
QP
F PF P
FP
FP
FP FP
QRet
Process Economics Case Study:Re-use vs. Single-use TFF Unit Operation
Conventional Re-use TFF(Fed-batch)
Conventional Re-use TFF(Fed-batch)
Stainless Steel Systemand
Vessels
Single-use TFF (SUTFF)(Fed-batch)
Single-use TFF (SUTFF)(Fed-batch)
QFeed
QP
F P
FP
QRet
FP
QFeed
QP
F PF P
FP FP
QRet
FP
FP
Allegro SUTFF System with Disposable Bags
andSingle-use Flow Path
10© 2012 Pall Corporation 10© 2012 Pall Corporation
Detailed Process Overview“Pre-use Conditioning, Processing and Post-use Conditioning”
Single-use TFF
Pre-use Conditioning
Pre-use Conditioning
Processing
Processing
InstallationInstallation
WFI Flush(20 L/m2)
WFI Flush(20 L/m2)
Buffer Conditioning
(10 L/m2)
Buffer Conditioning
(10 L/m2)
Concentration(10X)
Concentration(10X)
Diafiltration(5 DVs)
Diafiltration(5 DVs)
FinalConcentration
(3.5X)
FinalConcentration
(3.5X)
Product RecoveryProduct Recovery
Re-use TFF Pre-use
Conditioning Pre-use
Conditioning Post-use
Conditioning Post-use
Conditioning
Processing
Processing
InstallationInstallation
Buffer Conditioning
(10 L/m2)
Buffer Conditioning
(10 L/m2)
Sanitization(20 L/m2)
Sanitization(20 L/m2)
WFI Flush(100 L/m2)WFI Flush(100 L/m2)
WFI Flush(20 L/m2)
WFI Flush(20 L/m2)
NWPNWP
Post-cleaning Flush
(50 L/m2)
Post-cleaning Flush
(50 L/m2)
Storage(10 L/m2)Storage(10 L/m2)
Cleaning(CIP)
Cleaning(CIP)
NWPNWP
Concentration(10X)
Concentration(10X)
Diafiltration(5 DVs)
Diafiltration(5 DVs)
FinalConcentration
(3.5X)
FinalConcentration
(3.5X)
Product RecoveryProduct Recovery
11© 2012 Pall Corporation
BioSolve® Model
“BioSolve is an Excel-based Cost of Goods (CoG) model by BioPharm Services Limited, which provides user-configurable process sequences, detailed manufacturing cost calculations”, and allows new technologies to be analyzed easily…
CapitalCapital MaterialsMaterials ConsumablesConsumables LabourLabour OtherOther
MediaBufferDirect RMBought WFICIPQC Tests
MediaBufferDirect RMBought WFICIPQC Tests
Resins/MABagsFiltersOther
Resins/MABagsFiltersOther
ProcessQualityIndirect
ProcessQualityIndirect
InsuranceWaste MgmtMaintenanceUtilities
InsuranceWaste MgmtMaintenanceUtilities
EquipmentCoWetc.
EquipmentCoWetc.
CoGsCoGs
* Other CoGs category include facility operating costs
12© 2012 Pall Corporation 12© 2012 Pall Corporation
Annual CoGs Breakdown 20 Batches per Year
In addition: 94% less water usage (m3/batch) 416% more plastic waste (kg/batch)
* Other CoGs category include facility operating costs
CapitalCapital MaterialsMaterials ConsumablesConsumables LabourLabour OtherOther
MediaBufferDirect RMBought WFICIPQC Tests
MediaBufferDirect RMBought WFICIPQC Tests
Resins/MABagsFiltersOther
Resins/MABagsFiltersOther
ProcessQualityIndirect
ProcessQualityIndirect
InsuranceWaste MgmtMaintenanceUtilities
InsuranceWaste MgmtMaintenanceUtilities
EquipmentCoWetc.
EquipmentCoWetc.
CoGsCoGs
Annual CoGs for Re-use vs. Single-use
-27%
-65%
-4%
+1018%
-60%
-14%
Annual CoG (US$)
Capital
Materials
Consumables
Total Labour
Other
US$
Re-use TFFSingle-use TFF
13© 2012 Pall Corporation 13© 2012 Pall Corporation
Estimation of Total Capital
Total Capital is the sum of equipment capital, cost of works, other capital and internal capital, which is applied in CoGs calculations as an annual charge, distributed over a finance period of eight (8) years, with an interest rate of 12% and future value of 10%.
* % of Equipment Capital** % of Equipment Capital + CoWs
Equipment CapitalGeneral Equipment
“Support & Utilities”(i.e., Floor scale, refrigerator, freezer, autoclave, laminar flow
hood, compressed air, CIP skids, WFI & PW storage vessels, waste collection tanks, etc.)
General Equipment “Support & Utilities”
(i.e., Floor scale, refrigerator, freezer, autoclave, laminar flow hood, compressed air, CIP skids, WFI & PW storage
vessels, waste collection tanks, etc.)
Process Equipment(i.e., Bioreactors, Chromatography and UF skids,
vessels, columns pumps, etc.)
Process Equipment(i.e., Bioreactors, Chromatography and UF skids,
vessels, columns pumps, etc.)
Cost of Works*(CoWs)
Cost of Works*(CoWs)
Internal Capital**Internal Capital**
Other Capital**Other
Capital**
14© 2012 Pall Corporation 14© 2012 Pall Corporation
Process Equipment Process Equipment Capital for Re-use TFF is 2.4X
higher than Single-use TFF Due to high UF skid costs and additional SS vessels needed
Re-use TFF
9%
9%
9%
5% 5%
9%
49%
5%
UF Skid Product Hold VesselBuffer Prep Vessel Buffer Hold VesselBuffer Prep Vessel Buffer Hold VesselBuffer Prep Vessel Buffer Hold Vessel
Single-use TFF
14%
73%
2%
0.5%11%
0.1%
UF SkidBuffer Prep Mixing System SupportBuffer Prep Container SupportBuffer Prep TrolleyBuffer Prep Mixing System SupportBuffer Prep Container Support
15© 2012 Pall Corporation 15© 2012 Pall Corporation
Utility Sizing
Noticeable reduction in water usage w/ Single-use TFF.
WFI and PW Usage per Batch
795L
1939L
657L
0L
207L
0L 0L 0L0
400
800
1200
1600
2000
Process Process Cleaning Cleaning
WFI PW WFI PW
Volu
me
[L/B
atch
]
Re-use TFFSingle-use TFF
16© 2012 Pall Corporation 16© 2012 Pall Corporation
Utility Sizing
Noticeable reduction in water usage w/ Single-use TFF Utility sizing noticeably impacts the
sizing & selection of general equipment needed for support & utilities
WFI and PW Usage per Batch
795L
1939L
657L
0L
207L
0L 0L 0L0
400
800
1200
1600
2000
Process Process Cleaning Cleaning
WFI PW WFI PW
Volu
me
[L/B
atch
]
Re-use TFFSingle-use TFF
WFI & PW Generation Rates & Storage Tanks
2575
258 362
3622
22623
20521
0
500
1000
1500
2000
2500
3000
3500
4000
WFIGeneration
Rate
WFIStorage
TankVolume
PWGeneration
Rate
PW StorageTank
Volume
[L/h] [L] [L/h] [L]
WFI
/PW
Gen
erat
ion
Rat
e [L
/hr]
&
WFI
/PW
Tan
k Si
ze [L
]
Re-use TFF Single-use TFF
17© 2012 Pall Corporation© 2012 Pall Corporation
Material Prep Volumes and Cost AllocationRe-use TFF
75L
25L
132L
PBSNaOHFormulation Buffer
Single-use TFF
0L25L
132L
PBSNaOHFormulation Buffer
18© 2012 Pall Corporation 18© 2012 Pall Corporation
Consumables Contribution per Batch
Re-use TFF1%
87%
6%
6%
Re-Use TFF CassetteSS Vessel FilterSS Vessel FilterSS Vessel Filter
Single-use TFF
1%7%
3%
3%51%
35%
SUTFF CassetteSU FlowpathSolution Mixer Bag SystemHold BagSolution Mixer Bag SystemHold Bag
19© 2012 Pall Corporation
Re-use TFF"Allocation of direct labor hours"
53%
30%
17%
Direct HoursSolution PrepCleaning
Single-use TFF"Allocation of direct labor hours"
52%
48%
Direct HoursSolution PrepCleaning
19© 2012 Pall Corporation
Labor
More than 50% labor savings Impact: Increased productivity Better resource allocation
Process/ProductionProcess/Production
IndirectIndirect
Direct Man HoursDirect Man Hours
Solution PrepSolution Prep
CleaningCleaning
QA (50%)QA (50%)
QC (30%)QC (30%)
Logistics (8%)Logistics (8%)
Engineering (15%)Engineering (15%)
Other (15%)Other (15%)
QualityQuality
16.6 hours
7.1 hours
20© 2012 Pall Corporation 20© 2012 Pall Corporation
Sensitivity Analysis: # of Batches per Year
At a batch size of 250 L, the SUTFF option is most cost effective over re-use TFF when the number of batches per year 50.
(Batch Volume = 250L)
41%
36%
32%
27%
19%
15%
7%
-14%
44%
23%
-20%
-10%
0%
10%
20%
30%
40%
50%
1 5 10 15 20 25 30 40 50 100
Number of Batches per Year [-]
% S
UTF
F Sa
ving
s pe
r Bat
ch o
ver R
e-us
e TF
F
21© 2012 Pall Corporation 21© 2012 Pall Corporation
Sensitivity Analysis: Batch Volume
For 20 batches per year, the SUTFF option is most cost effective over re-use TFF at batch volumes 1500 L.
(20 Batches per year)
27%
22%
15%
10%
3%
-7%
9%
29%
-10%
-5%
0%
5%
10%
15%
20%
25%
30%
35%50 25
0
500
750
1000
1250
1500
2000
Batch Volume [L]
% S
UTF
F Sa
ving
s pe
r Bat
ch o
ver R
e-us
e TF
F
22© 2012 Pall Corporation
Summary and Conclusions
Single-use TFF systems Single-use flow paths
Eliminates risk of batch or cross contamination Eliminates cleaning requirements Reduces validation time and costs Accelerates process time
Fully automated Ease of use Control and monitor processes automatically
Good engineering design System reliability, control and ease of use in manufacture
Process economics Significant savings in capital, materials, labor and facility operating
costs Increases productivity and allows better resource allocation
23© 2012 Pall Corporation
Thank You!