Novasep Process: TangenX Tangential Flow Filtration Products Strategies for Single Use Tangential Flow Filtration In Biopharmaceutical Applications Michael LaBreck Global Product Manager TangenX TFF Products Novasep Process: TangenX Tangential Flow Filtration Products

SiusTM Single Use TFF Cassettes

SiusTM and SiusTM-LS Overview SiusTM family of single-use cassettes Purpose built for single-use Ready to Use - Reduced prep time Delivered in 0.2M NaOH – Pre-sanitized Cassette design for Development, Clinical, and Process Scale SiusTM-LS 0.01 –0.1 m² surface area SiusTM 0.5 –2.5 m² surface area

Contact Angle Measurement TangenX Membrane Properties Modified Polyether Sulfone (mPES) membranes currently available ProStream: 1kD, 3kD, 5kD, 10kD, 30kD, 50kD, 100kD, 300kD Neutrally Balanced Charge / Low Protein Binding HyStream: 5kD, 10kD, 30kD, 50kD, 100kD, 300kD, 0.1µm, 0.2µm, 0.45µm, 0.65µm Hydrophilic - Minimal fouling with hydrophobic molecules / Low Protein Binding Contact Angle Measurement (water at 20oC) HyStream Membrane Selectivity Curves for: ProStream Membranes HyStream Membranes

Rejection Characteristics (UF Membranes) 1,000 10,000 100,000 Molecular Weight 100% Percent Rejection Novasep Process: TangenX Tangential Flow Filtration Products 5

Rejection Characteristics (UF Membranes) 1,000 10,000 100,000 Molecular Weight 100% Percent Rejection Novasep Process: TangenX Tangential Flow Filtration Products 6

Rejection Characteristics (UF Membranes) 1,000 10,000 100,000 Molecular Weight 100% Percent Rejection Novasep Process: TangenX Tangential Flow Filtration Products 7

Pore Size Distribution (UF Membranes) 10KD Novasep Process: TangenX Tangential Flow Filtration Products 8

Pore Size Distribution (UF Membranes) Competitor pore size distribution TangenX pore size distribution 10kD 10kD Novasep Process: TangenX Tangential Flow Filtration Products 9

IBC Applications for Biopharmaceuticals La Jolla, CA June 1-3 2009 Novasep Process: TangenX Tangential Flow Filtration Products

Single Use TFF Applications Labor Consumables Workflow

Single Use TFF Applications Labor Consumables Workflow

Required Steps for TFF process RE-USABLE TFF Set Up Sanitize Flush NWP Equilibrate Process Clean Storage Time

Required Steps for TFF process RE-USABLE TFF Set Up Sanitize Flush NWP Equilibrate Process Clean Storage Time Process = 6 hrs

Required Steps for TFF process Set Up Sanitize Flush NWP Equilibrate Process Clean Storage RE-USABLE TFF Time Process = 6 hrs Total Time = 12 hrs

Required Steps for TFF process SINGLE USE TFF Process= 6 hrs Set Up Equilibrate Process Time

Required Steps for TFF process SINGLE USE TFF Process= 6 hrs Set Up Equilibrate Process Total Time = 7.0 hrs

Time Savings versus Single Use Cassettes Time Allocation Reusable TFF Process A significant amount of time is spent preparing and cleaning reusable cassettes Time is used more efficiently when using single-use cassettes Water usage and utilities are conserved Time Allocation Single Use TFF Process

Single Use TFF Applications Labor Consumables Workflow

Developing a Model for Single Use TFF Consumables Include: Purified Water Buffers Cleaning Solutions Filtration Cassettes

Economy of Single Use TFF 75% Less Buffer / WFI Required 230 60 50 100 150 200 250 Buffer/WFI Usage (L/sq. meter) Re-use Single Use

Developing a Model for Single Use TFF Consumables Include: Purified Water Buffers Cleaning Solutions Filtration Cassettes

Single Use – Economics Average = $4,800 / meter2 Reusable Cassette Suppliers $0 $500 $1,000 $1,500 $2,000 $2,500 $3,000 $3,500 $4,000 $4,500 1 $ per sq meter surface area Supplier A Supplier B Supplier C Supplier D Average = $4,800 / meter2

$ per sq meter surface area Single Use – Economics Other Supplier Reusable TFF $4,800 per meter2 TangenX SiusTM Single Use TFF $930 per meter2 $4,800 $930 $0 $500 $1,000 $1,500 $2,000 $2,500 $3,000 $3,500 $4,000 $4,500 1 $ per sq meter surface area Re-use Single use 80% Less per TFF cassette

SiusTM and SiusTM-LS Overview Membrane surface areas available 100 cm², 200 cm², 0.1 m²: Process development 0.5 m², 1.5 m², 2.5 m²: Pilot / Process SiusTM-LS 0.01 –0.1 m² surface area SiusTM 0.5 –2.5 m² surface area

NovaSetTM Reusable TFF Cassettes Direct Scalability – From Single Use to Reusable Same channel geometry (ΔP and crossflow rate) Same membrane chemistry (Prostream and Hystream)

Single Use TFF Applications Labor Consumables Workflow

Other Benefits to Single Use TFF Reduces validation requirements Process flexibility Reduces risk of cross-contamination Consistent membrane performance run to run Removes process bottlenecks – Improves workflow

SiusTM and SiusTM-LS Summary Pre-sanitized, 100% Integrity Tested Equilibrate and ready-to-use Reduce Labor by 50% Reduce Buffer / WFI by 75% Full range of formats and pore sizes

SiusTM Cassette Holders & Disposable Flow Path Inserts

Disposable Flow Path Inserts Filter Plate Inserts Disposable Flowpath

Disposable Flow Path Inserts Filter Plate Inserts (TFP75-SE16) 0.5 to 5.0 meter2 (up to 49 LPM) Disposable Pre-sanitized USP Class VI Polypropylene 1” TC (4) ports Low cost SS Holder

Disposable Flow Path Inserts TSPDI-VXBC: 10 m² up to 30 m² capacity TFP99-SP20 Filter Plate Insert (150 LPM)

Disposable Flow Path Inserts Filter Plate Inserts – LS (TFPLS-SA08) 0.01 m2 to 0.1 m2 x 5 Disposable Pre-sanitized USP Class VI Polypropylene 3/4” mini TC or luer lock Low cost SS Holder

Novasep Process: TangenX Tangential Flow Filtration Products Single Use TFF: Case Study Novasep Process: TangenX Tangential Flow Filtration Products

Novasep Process: TangenX Tangential Flow Filtration Products Michael Xenelis, EMD Serono Biotech Center IBC Bioprocess International Conference October 16, 2009 Novasep Process: TangenX Tangential Flow Filtration Products

Novasep Process: TangenX Tangential Flow Filtration Products

Total Process Time = 13.1 Hours Novasep Process: TangenX Tangential Flow Filtration Products

Novasep Process: TangenX Tangential Flow Filtration Products

Novasep Process: TangenX Tangential Flow Filtration Products

Novasep Process: TangenX Tangential Flow Filtration Products Single Use TFF: Case Study Novasep Process: TangenX Tangential Flow Filtration Products

Single Use TFF Case Study Single Use TFF vs. Reusable TFF Recombinant Protein 500L Batch Size 10X Concentration / 5 volume Diafiltration Process Flux = 100 LMH Process Time = 4 Hours Membrane Area = 2.5 Sq. Meter

Single Use TFF Case Study Single Use TFF vs. Reusable TFF Economic Model 20 runs per year Membrane costs Labor and Overhead (validation) WFI and Buffers

Single Use TFF Case Study Membrane Costs Run # vs. Cassette Cost / Run $0 $1,000 $2,000 $3,000 $4,000 $5,000 $6,000 $7,000 $8,000 $9,000 $10,000 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Run Number Cassette Cost per Run Re-Usable Single Use

Single Use TFF Case Study Labor and Overhead Labor QA / QC Validation Facilities – HVAC, Clean Room

Single Use TFF Case Study Labor and Overhead Labor and Overhead Rate $1,000/hr hours $ Set-Up 0.5 $500 Sanitize Flush NWP Equilibration 0.25 $250 0.3 Process 4.0 $4,000 Clean 2.5 $2,500 1.0 $1,000 Store 10.25 $10,250 5.75 $5,750 Reusable Single Use $0 $2,000 $4,000 $6,000 $8,000 $10,000 $12,000 Reusable vs. Single-Use Process Cost 1 2 Process Type Cost (USD) Store NWP Flush Clean Process Equili. Sanitize Set-Up

Single Use TFF Case Study Single Use TFF vs. Reusable TFF Buffer Costs WFI Buffer chemicals Consumables – filters, bags Labor QA/QC Validation

Single Use TFF Case Study Buffer Costs Buffer Cost per Campaign $13,800 $3,600 $0 $2,000 $4,000 $6,000 $8,000 $10,000 $12,000 $14,000 $16,000 Re-Usable Single Use Buffer Cost (USD) Buffer Cost $1.20 per liter Process Area 2.5 per m2 Number of Runs 20 per campaign Cost per run Total Cost Re-Usable $690 $13,800 Single Use $180 $3,600 Note: * Buffer cost includes system, maintainance, buffers, raw materials, monitoring, and disposal

Single Use TFF Case Study: Summary Cost / run Total Cost Overhead & Labor $10,250 $205,000 $5,750 $115,000 Buffer Usage $690 $13,800 $180 $3,600 Consumables $500 $10,000 $2,000 $40,000 TOTAL COST $11,440 $228,800 $7,930 $158,600 Total Savings $70,200 Re-Usable Single Use Total Cost per Campaign $0 $50,000 $100,000 $150,000 $200,000 $250,000 1 Total Cost Re-Usable Single Use

Single Use TFF Case Study: Summary 45% Increase in Productivity Process Time 10.25 5.75 2 4 6 8 10 12 Hours Reusable Single Use

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