A Process and Economic Analytical Approach to …...Quantify major economical benefits Evaluate the...

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


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


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


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


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


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


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


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)


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)



FinalConcentration

(3.5X)

FinalConcentration

(3.5X)

Product RecoveryProduct Recovery


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


Resins/MABagsFiltersOther


ProcessQualityIndirect


InsuranceWaste MgmtMaintenanceUtilities


EquipmentCoWetc.

EquipmentCoWetc.

CoGsCoGs

* Other CoGs category include facility operating costs


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









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


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**


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


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

]



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

]


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


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


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


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


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


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


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


Thank You!

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