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CUNO Filter Systems for Bioprocess and Biological Separations

Applications Cell Culture and Fermentation Protein Purification Plasma Fractionation Sterile Filtration of Biologicals Utilities, Plant Services and Bulk Chemical Filtration

CUNO is a leader in advanced depth filter systems and membrane-based separations, offering a range of products for all stages of biopharmaceutical and biological processing from bench-top to pilot-scale to manufacturing scale operations.

Cover photo courtesy of BioEngineering AG, Switzerland.

Contents

Scientific Applications Support Services (SASS) CUNO . . . A World Leader in Fluid Purification Bioprocessing and Biological Filter Applications 2 3 4 5 6 6 6 7 7 8 9 10 10 11 11 12 12 13 14 15

u Cell Culture and Fermentation Processes u Downstream Processing

Cell Separation Zeta Plus® for Cell Separation u Post Cell Separation Operations Concentration and Purification u Human Plasma-Derived Biologicals Blood Fractionation u Sterile Filling of Biological Products Utilities, Plant Services and Bulk Chemical Filtration u Water Filtration u Bulk Chemical and Solvent Filtration u Air and Gas Filtration Specialty Applications

u Removal of Endotoxin by

Positively-Charged Filters

u Chromatography Column Protection u Removal of Contaminating DNA

with Zeta Plus Filters CUNO Products for Biological Manufacturing and Bioprocessing

u Prefiltration and Clarification 15 u Zeta Plus Generation 2 Filter Systems 16 u Zeta Plus Generation 2 Cartridge Systems 17 u ZetaCarbon® Cartridge Systems 18 u Zeta Plus Applications in Bioseparations 19 u The Zeta Plus Advantage in Cell Separation 20 u Zeta Plus Scale-up for Cell Separation 21 ® XL: Featuring MaxMediaTM Construction u PolyPro u PolyNetTM PB Filter Cartridges u CUNO Membrane Cartridge Filtration

22 23 24 SterASSURETM Cartridge and Capsule Filters 24 TM PB Cartridge and Capsule Filters 25 LifeASSURE Microfluor ® II Filters 26 27 29 29 for Extended Filter Life

CUNO Filter Housings and Engineered Systems CUNO Incorporated - Over 90 Years of Solutions Quality Management & ISO Standards

When the Question is Quality, the Answer is CUNO.

Genetically-engineered biopharmaceuticals, plasma-derived biologicals, cell culture media and sera, monoclonal antibodies, vaccines and biologically-based diagnostics... Some of the world's most valuable products. Products that demand the ultimate in purity and quality. That's why, biopharmaceutical companies and biological manufacturers everywhere turn to CUNO for cost-effective solutions to a wide range of processing challenges­from the clarification of cell culture-derived proteins to the purification of plasma-derived biologicals. They've discovered that CUNO filter systems consistently provide the requisite purity for the most demanding applications. CUNO filtration products offer safety, efficacy and superiority. With over 200 patents worldwide, CUNO offers the most advanced and innovative products available for biological separations. Discover CUNO's innovative solutions for the purification of bioprocess-derived proteins and biologicals.

Scientific Applications Support Services (SASS)

The cornerstone of CUNO's philosophy is service to customers, not only in product quality and prompt delivery, but also in validation, application support and in the sharing of scientific information. CUNO's Scientific Applications Support Services works closely with customers to solve difficult filtration challenges and to recommend the most efficient, economical filter systems. SASS specialists can perform on-site testing and utilize filtration applications expertise to partner with customers. CUNO resolves filtration problems promptly and efficiently in a cost-effective, confidential manner with a commercial support group consisting of CUNO's in-house customer service staff, application specialists, and engineering services. CUNO's broad distributor base and sales offices provide worldwide customer service, local inventory, and field support in virtually every major center of manufacturing for the refining industry.

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CUNO . . . A World Leader in Fluid Purification

CUNO is a U.S. based multinational, high technology company with over 1300 employees worldwide and manufacturing facilities in the United States, France, Japan, Australia and Brazil. Many of CUNO's manufacturing sites have ISO 9001 registered quality systems. Global manufacturing sites together with trained stocking distributors and state-of-the-art laboratory support bring quality solutions to challenging bioprocess and biological separations.

CUNO's world-class manufacturing plants are located throughout the world assuring a consistent supply of

l l l

advanced filtration products to biopharmaceutical companies and biological

l l

manufacturers worldwide.

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CUNO has maintained its leadership in fluid purification by continually providing superior products and technical support. CUNO filtration systems are designed and manufactured to the most stringent industry standards. This assures the reliability of CUNO systems that manufacturers have come to expect.

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Bioprocessing and Biological Filter Applications

Bioprocessing refers to the production of biologically active therapeutic and diagnostic proteins that are expressed by mammalian or bacterial cells. A series of unit operations isolate and purify products of fermentation. A simplified schematic showing the various unit operations is shown in Figure 1.

Figure 1

CUNO offers a complete range of filtration products for each of these demanding unit operations. CUNO filter systems consistently deliver cost effective, high efficiency separations which meet or exceed operating criteria.

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Cell Culture and Fermentation Processes

Air and liquid nutrient feed streams are clarified and sterile-filtered to eliminate particulate and microbiological contamination from the fermenter. Serum and culture media feeds are sterile filtered with Zetapor membrane cartridges to remove contaminating microorganisms. Microfluor II sterile hydrophobic filters provide sterile filtration of inlet fermentation air. Manufacturers of rDNA proteins use Microfluor II for sterile filtration of bioreactor exhaust gas insuring that microorganisms do not exit the bioreactor environment. Table 1 lists recommended CUNO filters for cell culture and fermentation.

Figure 2

Table 1 - Recommended CUNO Filters for Cell Culture and Fermentation Processes

Request Filter Datasheets for Product Ordering Guides and Specifications

Filter Number 1 2 3 4 5 6 7

Filter Application Steam for Cleaning and Sterilizing Equipment Prefiltration of Air to Sterile Filters (oil-free) Sterile Filtration of Fermenter Inlet Air Sparging Air Prefiltration of Fermenter Exhaust Gas Sterile Filtration of Fermenter Exhaust Gas (off-gas) Prefiltration of Feeds (growth media, nutrients, make-up water, raw materials) Sterile Filtration of Feeds (growth media, nutrients, make-up water) Holding Tank Vent

Recommended CUNO Filter Poro-Klean® porous metal Polypro XL Microfluor II Poro-Klean porous metal Polypro XL Microfluor II Zeta Plus 60SP PolyNet PB LifeASSURE PB SterASSURE Microfluor II

Rating 5 micron 1.2 micron 0.2 micron 5 micron 1.2 micron 0.2 micron 0.5, 1.0 micron 0.5-70 micron 0.2, 0.45 micron 0.1, 0.2 micron 0.2 micron

Filter Datasheet # LITPK001 LITPXLEL LITCMR2 LITPK001 LITPXLEL LITCMR2 LITZP.S01 LITCPN2 LITCLAPB1 LITZRSTR1 LITCMR2

8 9

5

"Downstream processing can account for as much as 70% of a product's manufacturing cost" 1

Downstream Processing

Cell Separation

The objective of this phase of downstream processing, cell separation, is to recover the product from the fermentation broth (harvest fluid), while maximizing yield (Figure 3). Initial clarification steps separate the biomass from the desired product in solution. In some cases, the desired product is intracellular and cell disruption techniques must first be employed. Table 2 below lists recommended CUNO filters for cell separation operations. For more information on the utilization of Zeta Plus depth filters for clarification of cell culture fluids, request article reprint LITTDCS.1496 - Clarification of Animal Cell Culture Process Fluids Using Depth Microfiltration 2.

4

Bioreactor

Cell Separation

Harvest Vessel

3

Cell Suspension

Figure 3

Stage 1

Stage 2

Harvest Fluid

Table 2 - Recommended CUNO Filters for Downstream Processing/Cell Separation Phase

Request Filter Datasheets for Product Ordering Guides and Specifications

Filter Number 1 2 3 4

Filter Application Cell Separation Stage 1 Cell Separation/DNA Reduction Stage 2 Sterile Filtration of Clarified Harvest Fluid Harvest Vessel Tank Vent

Recommended CUNO Filter Zeta Plus 05, 10SP Maximizer 10M02, 30M03 Zeta Plus 60, 90SP Maximizer 60M03, 90M05 SterASSURE Microfluor II

Rating 3 micron 0.5 micron 0.2 micron 0.2 micron

Filter Datasheet # LITZP.SO1 LITCZPMAX1 LITZP.SO1 LITCZPMAX1 LITZRSTR1 LITCMR2

Zeta Plus for Cell Separation

Zeta Plus depth filtration provides effective, economical cell separation for removing cells, cell debris, endotoxin and contaminating host cell DNA. Zeta Plus filters provide higher yields and enhanced purity of filtrates when compared to centrifuges and eliminate handling of solids and pastes. The significant advantages of CUNO Zeta Plus when compared to technologies such as centrifugation, tangential flow filtration (TFF) and plate and frame presses are listed in Table 12 on page 20.

1

K.L. Carson, Purification Begins Early in a Cost-Effective Strategy for Bioprocessing, Genetic Engineering News, Vol. 14, Issue 6, March 15, 1994, pp 12-19 D. Wang, R. Singhvi, C. Schorr, et al. BioPharm, Vol. 9, No. 4, April 1996, pp. 35-41

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Post Cell Separation Operations

Concentration and Purification

Purification steps are highly dependent on the nature of the product. Chromatographic columns should be protected with LifeASSURE PB or SterASSURE filters to reduce contaminant load and extend column life. Chromatography buffers are also membrane filtered assuring optimal purity. Specially developed Zeta Plus Delipid and Delipid Plus Media can be utilized to selectively adsorb lipids which foul and block chromatographic columns. Zeta Plus VRTM Series viral reduction depth filters provide validatable log reduction of contaminating viruses from recombinant biopharmaceutical proteins and monoclonal antibody products. Table 3 below lists recommended CUNO filters for concentration and purification of valued products.

Figure 4

Table 3 - Recommended CUNO Filters for Downstream Processing-Concentration and Purification

Request Filter Datasheets for Product Ordering Guides and Specifications

Filter Number 1 2 3 4 5 6 7

Filter Application Pre-UF Filtration Prefiltration Lipid Reduction Viral Reduction Sterile Filtration (optional) Holding Tank Sterile Vent Final Sterile Filtration

Recommended CUNO Filter LifeASSURE PB Polypro XL Zeta Plus Delipid or Zeta Plus Delipid Plus Zeta Plus VR Series VR07 LifeASSURE PB SterASSURE Microfluor II SterASSURE

Rating 0.2 micron 0.6 micron 0.6 micron 0.2 micron 0.2, 0.45 micron 0.2 micron 0.2 micron 0.2 micron

Filter Datasheet # LITCLAPB1 LITPXLEL LITZPDE1 LITZPVR LITCLAPB1 LITZRSTR1 LITCMR2 LITZRSTR1

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Human Plasma-Derived Biologicals "The role of electrokinetics is of paramount importance Blood Fractionation in the clarification or Human blood and plasma contain many proteins, the extraction and purification of which are of great medical importance. The development of production scale stabilization of plasma processes to fractionate plasma into components of therapeutic value has led to a fractions because it is the process mainly responsible surge in the use of blood products. Major plasma derivatives include: u albumin for removal of submicron 1 and colloid particles" u immunoglobulins (IgG, IgA)

u coagulation factors (Factor VIII antihaemophilic factor [AHF], fibrinogen)

Fractionation procedures derived from the Cohn process are the most widely used for the production of albumin, immunoglobulins, and other proteins found in plasma. Zeta Plus filters provide electrokinetic enhancement of the filtration processes in the Cohn methodology. Special grades of Zeta Plus, Delipid and Delipid Plus, aid in the processing of plasma fractions by removing lipoproteins, cholesterol, and triglycerides that lead to product instability and tend to block downstream filters. Low extractable Zeta Plus filters (LA/SA/CA formulation) assure ultra-low levels of aluminum and other ionic extractables. Zeta Plus VR Series viral reduction depth filters remove significant levels of viruses from plasma-derived proteins, providing an added measure of end product safety. Zeta Plus cartridge systems play an important role in the clarification of plasma-derived protein products in virtually every blood fractionation plant around the world. Figure 5 indicates the filtration stages where Zeta Plus systems are utilized. Recommended grades of Zeta Plus are indicated in Table 4.

Figure 5

Table 4 - Recommended CUNO Filters for Blood Fractionation

Request Filter Datasheets for Product Ordering Guides and Specifications

Filter Number 1 2 3 4 5 6 7 8 9 10

Filter Application Prefiltration (post-thaw) Post-Precipitate I + II Clarification Pre-Fraction II + III Precipitate Clarification Pre-Immunoglobulin Clarification Pre-HPPF Clarification Pre-Albumin Clarification Final Albumin Clarification Albumin Rework Clarification Clarification and Lipid Removal Viral Reduction

Recommended CUNO Filter Zeta Plus 01AP Grade Zeta Plus 60LA Grade Zeta Plus 90LA Grade Zeta Plus 90LA Grade Zeta Plus 90LA Grade Zeta Plus 60LA Grade Zeta Plus 90LA Grade Zeta Plus 90LA Grade Zeta Plus Delipid/Delipid Plus VR06

Rating 20 micron 0.6 micron 0.2 micron 0.2 micron 0.2 micron 0.6 micron 0.2 micron 0.2 micron 0.6 micron 0.2 micron

Filter Datasheet # LITZP.A01 LITZP.LA2 LITZP.LA2 LITZP.LA2 LITZP.LA2 LITZP.LA2 LITZP.LA2 LITZP.LA2 LITZPDE1 LITZPVR

1

8

J. Curling, Methods in Plasma Fractionation, Academic Press, New York, Harcourt Brace, 1980, pp. 246

Sterile Filling of Biological Products

Sterilizing-grade membrane filter cartridges ensure sterility of the final parenteral product just prior to filling operations. High flow Zetapor membrane cartridges provide a sterile fluid stream and the potential for significant pyrogen reduction. CUNO prefilters such as PolyPro XL provide high contaminant holding capacity while protecting downstream sterile filters. With very low extractable levels, Zetapor membranes are non-particle shedding and are integrity testable. Microfluor II sterilizing hydrophobic tank vent cartridges maintain a sterile environment in product holding tanks. Table 5 below recommends CUNO filters for Sterile Filling Operations.

Figure 6

Table 5 - Recommended CUNO Filters for Sterile Filling

Request Filter Datasheets for Product Ordering Guides and Specifications

Filter Number 1 2 3 4 5 6 7 8 9

Filter Application Sterile N2 Blanket WFI Filtration (optional) Holding Tank Prefilter Holding Tank Sterile Filter Sterile Tank Vent Particulate Trap Filter Filling Machine Sterile Filter WFI for Vial Washer (optional) Air/N2 for Vial Cleaning

Recommended CUNO Filter Microfluor II SterASSURE LifeASSURE PB Zetapor 020SP Microfluor II Poro-Klean SterASSURE SterASSURE Microfluor II

Rating 0.2 micron 0.2 micron 0.2 micron 0.2 micron 0.2 micron 5 micron 0.2 micron 0.2 micron 0.2 micron

Filter Datasheet # LITCMR2 LITZRSTR1 LITCLAPB1 LITCZR020SP LITCMR2 LITPK001 LITZRSTR1 LITZRSTR1 LITCMR2

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Utilities, Plant Services and Bulk Chemical Filtration

Filtration is used for utility and plant services such as water, chemicals, solvents, air/nitrogen and other process gases, including steam.

Water Filtration

There are different standards for water quality in a biological manufacturing facility. The most widely recognized are Purified Water (PW) and Water for Injection (WFI).

u USP Water for Injection (WFI) - for product formulation, equipment

and container cleaning, WFI steam production

u USP Purified Water - for equipment and container cleaning, fermenter

make-up water (sterile filtered), clean steam production CUNO offers a comprehensive range of filter options including charge-modified media for efficient removal of contaminants much smaller than the filter's rating. In high purity water systems (Figure 7), LifeASSURE PB prefilters and SterASSURE or Zetapor membrane filters are recommended for reduction of pyrogens, colloidal matter and other negatively charged contaminants. See page 12 for more information on the use of positively charged CUNO filters for reduction of endotoxin levels. Recommended CUNO filter cartridges for a typical biopharmaceutical water system are listed in Table 6.

Figure 7

Table 6 - Recommended CUNO Filters for Process Water

Request Filter Datasheets for Product Ordering Guides and Specifications

Filter Number 1 2 3 4 5 6

Filter Application Removal of Silica Particles Carbon Fine Removal Resin Trap Filter D.I. Bacterial Removal Sterile Tank Vent Sterile Filtration­Point-of-Use

Recommended CUNO Filter PolyNet PB PolyNet PB PolyNet PB PolyPro XL LifeASSURE PB Microfluor II SterASSURE Zetapor 020SP

Rating 50 micron 20 micron 5 micron 0.6 micron 0.2 micron 0.2 micron 0.2 micron 0.2 micron

Filter Datasheet # LITCPN2 LITCPN2 LITCPN2 LITPXLEL LITCLAPB1 LITCMR2 LITZRSTR1 LITCZR020SP

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Bulk Chemical and Solvent Filtration

Chemicals and solvents used in biological manufacturing include alcohol, acetone, methylene chloride, and numerous other aggressive materials (Figure 8). Antibiotics produced through large scale fermentation utilize solvents in the extraction phase and the solvent/antibiotic mix. Recommended CUNO filters for chemical and solvent filtration are shown in Table 7.

Figure 8

Table 7 - Recommended CUNO Filters for Chemicals/Solvents

Request Filter Datasheets for Product Ordering Guides and Specifications

Filter Number 1 2 3 4 5

Filter Application Coarse Prefiltration Fine Prefiltration Tank Vent Membrane Prefilter Final Sterile Filter

Recommended CUNO Filter PolyNet PB PolyNet PB Microfluor II PolyPro XL Zetapor 020SP SterASSURE

Rating 20 micron 2 - 10 micron 0.2 micron 0.6 micron 0.2 micron 0.2 micron

Filter Datasheet # LITCPN2 LITCPN2 LITCMR2 LITPXLEL LITCZR020SP LITZRSTR1

Air and Gas Filtration

Air and gas systems requiring filtration include sterile filtration of inlet fermenter air, pressure sources for tank-to-tank transfers and cooling mediums for holding tanks after sterilization. For sterile manufacturing processes, gasses coming into contact with the product are always sterile filtered. For example, nitrogen used as a purge or blanketing gas is sterile filtered. Microfluor II 0.2 micron filters provide reliable sterile filtration of air and gas in bioprocess manufacturing environments. An example of sterile air filtration is shown in Figure 2 on page 5, as filter number 3 where inlet air is sterile-filtered to eliminate airborne contaminants from entering a fermenter or bioreactor.

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Specialty Applications

Removal of Endotoxin by Positively-Charged Filters

Lipopolysaccharide (LPS) or endotoxin is derived from the cell wall of gram negative bacteria. Because LPS is so highly pyrogenic, its removal from parenteral solutions is important. Filtration using either an ultrafiltration membrane or a depth filter is a popular means of depyrogenating biological solutions. Both Zetapor and Zeta Plus filters have been shown to remove endotoxin from aqueous solutions. Waterson1 examined the ability of Figure 9 - Comparison of upstream and downstream endotoxin 3 levels when using Zeta Plus 90ZA filter media 90ZA Zeta Plus filters to remove endotoxin from a purified water stream. Cartridge filters with nineteen square feet of surface area were installed after the ion Endotoxin Units Per ml Differential Pressure 60 30 exchange bed of a working system. The inlet pyrogen levels varied because at times the water source was fresh 50 25 Upstream Endotoxin Level city water and at other times it was water from recirculaDownstream Endotoxin Level 40 20 Differential Pressure tion among storage tanks. The endotoxin levels were 30 15 measured using the Limulus Amoebocyte Lysate (LAL) 20 10 gel clot assay. During its effective mechanical life, the filter removed endotoxins to undetectable levels. In 5 10 nearly every sample tested, filtrate LAL values were 0 0 below the sensitivity limit of the LAL gel clot test assay 0 20 40 60 80 100 120 140 (0.125 EU/mL). Even at the end of its useful mechanical Throughput Volume,Thousands of Gallons life, Zeta Plus provided fully adequate pyrogen reduction. The data are presented in Figure 9. The ability of Zetapor membrane filters to remove endotoxin from various solutions has been studied by Gerba and Hou2. Saline (0.9%), dextrose (5%) and distilled water were contaminated with varying concentrations of purified Escherichia coli lipopolysaccharide. The solution was passed through a 3.9cm2 filter, and the endotoxin concentration of the filtrate was determined by using the LAL gel clot assay. Endotoxin was efficiently removed by the charge modified nylon filters with a slightly reduced removal in the presence of salt. The data presented in Table 8 highlight the enhanced endotoxin removal of the charge modified nylon membranes when compared to other medium such as uncharged nylon or cellulose nitrate.

Table 8 - Removal of Endotoxin by Membrane Filters

Filter

Solution

Input Endotoxin Concentration (pg/ml) 5,000 10,000

Endotoxin concentration in filtrate (pg/ml) after passage of (ml) 50 100 500 200 500 <50 2,000 8,000 18,000 2,000 500 1,000 <50 4,000 8,000 18,000 2,000 500 1,000 <50 ND* 8,000 18,000 2,000

Charged Nylon

0.9% Saline

5% Dextrose 10,000 in Distilled Water 20,000 Uncharged Nylon Cellulose Nitrate 0.9% Saline 0.9% NaCL Distilled Water 14,000 18,000 2,000

Each solution was contaminated with the indicated concentration of E. coli endotoxin and passed through a 3.9cm2 filter. Results are averages of three experiments. *ND - not done because of filter clogging.

1

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Robert Waterson, Novel Depth Filtration Technologies: Strategies for Process Development, Pharmaceutical Engineering, Vol. 10, Issue 5, Sept./Oct. 1990, pp 22-29 2 C. Gerba and K. Hou, Endotoxin Removal by Charge-Modified Filters, Applied and Environmental Microbiology, Vol. 50, Issue 6, Dec. 1985, pp 1375-1377

Chromatography Column Protection

The final step in purifying a genetically engineered protein is often liquid chromatography. Specialized resins that involve separation mechanisms such as ion exchange or affinity chromatography offer excellent resolution and product recovery. However, such columns are expensive and efforts to maintain their longevity are paramount. CUNO offers several options for column protection: LifeASSURE, SterASSURE, PolyPro XL and Delipid filters. Each of these filters offers unique benefits to meet specific separation needs.

Benefits: u Significantly extends a column's

service life

u Enhanced chromatographic

performance

u Fewer regeneration cycles for

improved productivity

Figure 10

LifeASSURE PB Filters

CUNO LifeASSURE PB filters provide exceptional bioburden and particulate control as well as high resistance to sodium hydroxide (caustic) regeneration and sanitization solutions. LifeASSSURE PB filters incorporate CUNO's patented FlexNTM Nylon 6,6 multi-zone membrane construction. This unique membrane forming method results in a single membrane layer consisting of zones with varying porosity. The upstream zone contains larger pores acting as a prefilter capturing larger particles and bacteria, while the tighter, downstream zone provides retention of smaller particles and bacteria. This multizone structure results in greater contaminant capacity while maintaining fast flow rates. This combination provides the end user with the security and reliability of consistently high bacteria removal along with the enhanced economies of longer lasting, faster flowing filter assemblies.

SterASSURE Filters

CUNO SterASSURE 0.2 and 0.1 micron rated, sterilizing grade filters are manufactured using two layers of multi-zone FlexN Nylon 6,6 membrane. The FlexN membrane provides exceptionally long filter life and secure microorganism retention. Additionally, this filter is validated to provide complete retention of Brevundimonas diminuta.

PolyPro XL Filters

CUNO PolyPro XL all polypropylene filters offer broad chemical compatibility for more aggressive fluids. The polypropylene filter medium offers exceptionally high flow rates due to its special MaxMedia pleating construction. PolyPro XL filters are available in a full range of particulate removal ratings to 0.2 micron.

Delipid Filters

CUNO Zeta Plus Delipid filters are cellulose based depth filters which contain a lipid adsorbent filter aid. Fermentation broths often contain lipid components and cell debris which can foul chromatography columns. Delipid filters are designed to provide optimum protection of chromatography resins.

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Removal of Contaminating DNA with Zeta Plus Filters

Manufacturers of biopharmaceuticals generated from recombinant DNA or hybridomas utilize the electrokinetic performance of Zeta Plus filter systems to remove residual DNA impurities. The presence of host-cell DNA or viral DNA in parenteral solutions is considered to be potentially unsafe. The Food and Drug Administration in its documentation considers that a sensitivity level of 10 pg of residual DNA per parenteral dose represents a safety level achievable in processing operations. As an additional benefit, the removal of DNA at an early stage in the purification process, such as the cell separation stage, lengthens the life and enhances the performance of chromatography columns used in the later stages of purification.

DNA Challenge of Zeta Plus Filters

CUNO Zeta Plus 90SP filter media was challenged with DNA at two different pH levels­pH 7.4 where the media has a positive charge and pH 9.0 where the charge is eliminated­to determine the roles of electrokinetic attraction and mechanical entrapment in the retention of DNA by Zeta Plus.

u 47-mm filter discs from various lots were challenged with a

100-mL solution of calf thymus DNA. Filtrate was collected and DNA concentration was determined following binding with a photofluorescent dye

u Retention of DNA on Zeta Plus was correlated with electrokinetic

charge capacity which can vary with pH. The correlation was determined by the filter's ability to retain the negatively-charged Metanil Yellow dye The results of one study are shown in Table 9.

Table 9 - DNA Challenge Test Results for Zeta Plus 90SP Media

Filter Lot # 24022 22342 24107

Percent Capture of Calf Thymus DNA @ pH 7.4 9.0 58% 50% 66% 19% 0% 21%

Metanil Yellow Dye Capacity (mg/g) @ pH 7.4 9.0 0.93 0.68 1.0 0.2 0.18 0.21

The study concluded that Zeta Plus depth filter media removes DNA from solution by a combination of mechanisms, but primarily by electrokinetic attraction. At low pH levels where the media exhibits high electrokinetic capacity, a substantial amount of DNA can be removed at the "front end" of a cell separation operation. For more information on retention of DNA, request technical article reprint, LITTDC2 - The Role of Charge in the Retention of DNA by Charged CelluloseBased Depth Filters 1.

1

N. Dorsey, J. Eschrich, G. Cyr, BioPharm, Vol. 10, No. 1, January 1997

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CUNO Products for Biological Manufacturing and Bioprocessing

CUNO offers a comprehensive range of filtration products­from high efficiency depth filters for clarification and prefiltration to sterilizing grade final membrane filters­as well as a full line of sanitary stainless steel filter housings designed and manufactured specifically for bioprocessing and biological production. Products for these applications include:

u Zeta Plus Depth Filter Systems u PolyPro XL Pleated Media Cartridges u PolyNet PB Depth Filter Cartridges u LifeASSURE Nylon FlexN Membrane Cartridges and Capsules u SterASSURE Nylon FlexN Membrane Sterilizing Cartridges and Capsules u Microfluor II PTFE Membrane Cartridges and Capsules u Sanitary Design Filter Housings and Skid-Mounted Systems

Prefiltration and Clarification

Few companies equal CUNO's experience and product range for challenging prefiltration and clarification applications. In bioprocess operations, CUNO products are used to clarify turbid biological solutions, including mammalian cell culture harvest fluids, microbial fermentation broths and fermentation feeds such as serum and media.

Figure 11

CUNO prefilters provide high particulate removal and reduced bioburden, reducing total filtration costs by removing the bulk of contaminants at the prefilter stage and extending the life of final sterile membrane filters (Figure 11).

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Zeta Plus

Generation

Filter Systems

Zeta Plus is a family of advanced cellulose-based depth filtration media designed to retain contaminants by both mechanical straining and electrokinetic adsorption. For over three decades, CUNO has manufactured Zeta Plus multicell cartridge filtration systems which combine high efficiency separations with unmatched filter life in a totally enclosed environment. Zeta Plus systems are used worldwide in bioprocessing applications, providing reliable and cost effective filtration.

. . . Introducing the Next Generation . . .

Today, innovations in cartridge design, expanded media choices and a broader range of filter housings make Zeta Plus Generation 2 even more reliable and cost effective.

Figure 12 Zeta Plus Performance

100 90 80 70

The

Generation

Features:

u Advanced durable cartridges designed to withstand repeated

steam sterilization and arduous processing conditions.

Electrokinetic Effect

Combined Mechanical and Electrical Removal

u A variety of cartridge sizes and configurations to grow with

process needs and meet any flow rate requirement.

Mechanical Removal

Percent Removal

60 50 40 30 20 10 0 0.2 0.4 0.6 0.8 1.0 1.2

u New sanitary housings with improved sealing systems,

built-in accessories and easy to use closures.

Mechanical Straining Effect

u A choice of depth filtration media for a broad range of

bioprocessing applications.

Particle Size (MIcrons)

What is Zeta Plus?

Zeta Plus is a family of patented filtration media composed of industry-accepted filter aids embedded in a cellulose fiber matrix. During the manufacturing process, molecules carrying a positive charge are chemically bonded to the matrix components permanently forming an interconnected, rigid filter sheet with positively-charged electrokinetic capture sites. The resulting porous filter structure is a tortuous network of charge-enhanced flow channels capable of removing hazes and retaining bacteria, particulates, colloidal debris and submicronic contaminants to a level which mechanical screening alone cannot achieve (Figure 12). The graded density construction and the charge-enhanced internal adsorptive capacity of Zeta Plus provide high-efficiency submicron filtration to outperform pleated prefilters and competitive depth filters.

Figure 13 - Shown above is a scanning electron photomicrograph of the internal adsorptive capacity of Zeta Plus filter media. Note the electrokinetic capture of the rod shaped bacteria.

How Zeta Plus Works

In solution, cells and cellular debris, endotoxin, contaminating DNA, and viruses carry a negative charge. CUNO's proprietary application of positive zeta potential to Zeta Plus filter media creates a filter matrix that enhances the capture and retention of all negatively charged colloidal materials for more efficient filtration (Figure 13).

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Zeta Plus

Generation

Cartridge Systems

Since its introduction, Zeta Plus has been the industry standard in depth filtration for bioseparations. CUNO has consistently raised depth filtration to higher levels of quality and performance with such technological breakthroughs as low extractable media, 16-inch diameter cartridges, Zeta Plus capsules and media specifically designed for bioseparations.

The

Generation

Features Include:

u Scaleability from laboratory capsules to pilot-scale cartridges to full production

systems, to meet any flow requirements. Cartridge sizes in 8-inch, 12-inch and 16-inch diameter offering up to 37 ft2 of surface area in a single cartridge

u Disposable Zeta Plus BioCap 30, 1000, and 2000 capsules for small volume filtration

or scale-up evaluations

u Filter media for today's bioseparation requirements including lipid removal,

DNA removal and depyrogenation

u Housing designs with ultrafine Ra (Roughness Average) surface finishes to

minimize microbial adhesion

u Complete sanitary systems including piping, valves, optional feed loops

and integral CIP capability

u Robust cartridge design to ensure integrity in severe environments u Installation Qualification Test Procedure for testing in-situ to ensure proper cartridge

installation and system integrity (request LITTDIQ for more information)

u Drug Master Files at the FDA describing component raw materials,

suppliers and testing procedures for Zeta Plus media and cartridges

u Specialized cartridge designs with increased cell-to-cell spacing for body feed filtration

Zeta Plus Cartridge Construction

To construct a high-area Zeta Plus cartridge, two Zeta Plus sheets are formed into an envelope-like cell that is stacked with similar cells. Generation 2 cartridges use patented stiff cell separators to improve flow and media utilization and enhance filter life. Improved "tensioning" provides the ultimate in cartridge integrity under demanding process conditions.

The extensive range of proprietary filter media formulations and porosities are optimized for biological and bioprocessing separations. Specialized cartridge designs with increased cell-to-cell spacing are available for body feed filtration.

Positive spring-loaded sealing system provides optimal sealing compression to prevent filter bypass even under the most arduous process conditions. Patented edge seal design for durable cell construction maintains integrity under the most demanding process conditions. Pretensioned cartridge construction ensures integrity in severe environments including in-situ steam and hot water sanitization.

Patented stiff-cell separator maximizes cartridge flow and extends service life to provide lower total filtration costs.

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ZetaCarbon Cartridge Systems

ZetaCarbon Medium: The Efficient Way to Decolorize Your Process Liquids

ZetaCarbon medium incorporates the latest technology to decolorize and remove contaminants from your process streams. ZetaCarbon cartridges and sheets eliminate the concerns of using powdered carbon. In today's manufacturing processes, efficiency, yield, quality and consistency are critical as well as operating in a safe environment for operators. Bulk carbon can also be a limiting step in many operations preventing enhanced yields and increased production batches. ZetaCarbon medium addresses all of these concerns.

Table 10 - Advantages of ZetaCarbon Compared To Bulk Activated Carbon

Bulk Activated Carbon Carbon Dust Health Issues: Safety: Cleanliness Lung disease Adsorbs oxygen Fire risk

ZetaCarbon Advantage Totally-enclosed filtration systems can be sterilized, provide operator safety, and eliminate loss of expensive product. Less fire risk and almost no carbon dust Clean product. After initial flush of the cartridge, with minimal release of carbon fines in the filtered solution

Production Process: Time consuming and Costly Rarely 100% clean­batch to batch contamination Downstream carryover Long due to contact time and preparation time, and removal time Relies on diffusion of contaminants to reach active site Additions of filter aid required to remove carbon A filtration step is required to remove the carbon carry over to solvent recovery plants

Process Times

Decreased process time because of constant flow rate filtration and efficiency. No product rework because of consistent performance Activated carbon is fixed and the flow is forced through the matrix which increases efficiency A single step is used as decolorization is combined with the filtration step. Reduced costs in solvent recovery

Carbon Powder Process Steps

ZetaCarbon Cartridge System Advantages:

u Cartridge system reduces filter change-out time and operating costs u Small "footprint" systems reduce floor space requirements u Easy validation for cleaning and sterilization methods

The Logical Choice

ZetaCarbon cartridge systems add up to significant savings for biological and biopharmaceutical manufacturers with a complete range of totally-enclosed, sanitary cartridge housings. Systems are available for all stages of process development from bench-top to pilot-scale to full manufacturing scale. For additional information on CUNO ZetaCarbon Cartridge Systems, request LITCZC1. 18

Zeta Plus Applications in Bioseparations

Biopharmaceutical companies employ Zeta Plus filter systems to remove cells, cell debris, endotoxin, residual DNA, and viruses from biological products. Zeta Plus cartridge systems provide single pass, low shear clarification of fermenter harvest fluids. They have been scaled up from small bench and pilot scale fermentations to manufacturing scale processes of over 10,000 liters in a GMP environment. Figure 14 depicts Zeta Plus grades and the associated removal range. Zeta Plus media choices are listed in Table 11.

Figure 14 Filter Grades

For bioprocess applications, Zeta Plus choices include media optimized for:

u Significant lipid reduction

upstream of chromatography columns

u Log reduction of viruses u Protection of downstream

processes including sterile filters, ultrafiltration and chromatography systems

u Removal of cells and cell debris

from bioreactor harvest fluids (Cell Separation)

u Clarification of cell lysates u Removal of contaminating

host cell DNA

u Purification of sera and

cell culture media feeds

u Decolorization u Prefiltration of fermentation

feed streams

u Reduction of bacterial

endotoxins (pyrogens)

u Clarification of plasma-derived

biologicals (blood fractionation)

u Clarification of toxoid broths

for vaccine manufacturing

Table 11 - Zeta Plus Generation 2 Filter Media

Media Type SP LP LA/SA/CA DELIPID/ DELIPID PLUS ZETACARBON ZA VR MAXIMIZER

Applications Most bioprocessing and biological applications, including cell separation, DNA and pyrogen reduction Optimized for sensitive LAL test procedures (low LAL reactivity) and pyrogen reduction Media with extremely low extractable levels (ultra-low aluminum ion extractables) Lipid reduction from protein solutions and blood fractions Decolorization and removal of trace organics Long term pyrogen reduction from high-purity water systems Enhanced log reduction of viruses from blood-plasma derivative proteins and recombinant proteins Extended throughput of biological and bioprocess fluids

Grades Available 05, 10, 30, 60, 90 SP 30, 60, 90 LP 10, 30, 60, 90 LA/SA/CA DEL1, DELP R12S, R32S, R52S 60, 90 ZA VR01, 02, 03, 04, 05, 06, 07 10M02, 30M03, 60M03, 90M05, 90M08, 120M08

19

The Zeta Plus Advantage in Cell Separation

Zeta Plus cartridge systems offer significant advantages over competitive technologies and offerings. Table 12 lists general desired process parameters comparing Zeta Plus systems with tangential flow, centrifugation, and plate and frame filter presses. Note that only Zeta Plus can satisfy the broad range of requirements.

Table 12 - Zeta Plus Cartridge System Advantages Compared to Centrifugation, Tangential Flow Filtration and Plate and Frame Filter Presses Desirable Process Parameter Objective Zeta Plus Cartridge System Tangential Flow (TFF) Cassette System Centrifugation Plate & Frame Filter Press

Linear process scale-up Clean-in-place (CIP) and Steam-in-place (SIP) capability Safe operation

Predictable performance, reproducibility of process for GMP, flexibility of use Minimal downtime, reduced labor, reduced risk of contamination No high speed moving parts, no electrical requirements, no noise / vibration Compliance with GMP mechanical simplicity , Minimal downtime / maintenance Optimal product yield Excellent system economics Minimal operator exposure to process fluid, no external contamination

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4

4 4 4 4 4 4 4 4

4

4

Ease of validation Operator-friendly/minimal labor High product recovery Low capital /operating costs Totally-enclosed system

Simple disposal of used filter media User-friendly, no cross-contamination, ideal for multi-product plants High separation efficiency Efficient removal of cells / cellular debris, effective pretreatment for further downstream processing Reduced adhesion of contaminants to surfaces, easy-to-clean (CIP) Relieves load on downstream processes, regulatory compliance, end product safety Gentle treatment of sensitive cells, minimizes generation of cell debris

4 4 4

4 4 4

Sanitary surface finish for product contact parts "Front-end" DNA, endotoxin, and virus reduction Negligible effects on shear sensitive cell lines

Compact equipment/small footprint Maximizes valuable facility floor space Rapid processing time Integrity-testable Mobile systems Short downtime between runs, short residence time of cells in the system Defect-free system, proper installation of filter cartridges Moveable skid-mounted systems

4 4 4

Clearly, a totally enclosed, low shear Zeta Plus system with CIP and SIP capabilities offers a wide range of benefits over more capital intensive systems such as centrifugation and tangential flow filtration. Totally enclosed, low capital cost Zeta Plus systems outperform plate and frame filter presses with ease of change-out, sterilization and much lower space requirements.

20

Zeta Plus Scale-up For Cell Separation Scale-up With Zeta Plus

Generation

From the Laboratory

Figure 15 - Zeta Plus Disposable BioCap Capsules are ideal for laboratory testing and product development.

It's as Simple as a Straight Line...

CUNO offers a comprehensive range of Zeta Plus products which are well suited for small scale testing and scale-up operations, including 47mm, 90mm Zeta Plus discs and totally-disposable Zeta Plus BioCap capsules. Shown in Figures 15, 16 and 17 are a range of Zeta Plus products available for scale-up from the lab bench to pilot plant to full manufacturing scale operations. For more information on disposable BioCap assemblies, request LITZPBC1.

à à

To Pilot Production

To Full Production

Case Study­Ease of Scale-up

Figure 16 - 8ZPIP sanitary housings and plug-in cartridges, with surface areas from 1 ft2 to 3.5 ft2 are well suited for pilot-scale process development.

Scale-up with Zeta Plus from laboratory testing to full production is simple, linear and predictable. In one case study, a major U.S. pharmaceutical company developed a laboratory (bench-top) method to produce a therapeutic protein (from a CHO cell line) using Zeta Plus 90mm discs for cell separation. The transition from 90mm discs to 16-inch diameter cartridges was simple and accurate.

Laboratory Parameters: u Conventional laboratory bioreactor u Cell suspension volume: 1 liter u Cell density at harvest day:

2 X 106 cells/mL (viable)

u Complete cell separation was achieved

with a two stage Zeta Plus system: 10SP 90mm disc followed by 90SP 90mm disc

Process Parameters: u Conventional agitated bioreactor u Cell suspension volume: 1200 liters u Cell density at harvest day:

Figure 17 - Zeta Plus 12ZP and 16ZP sanitary housings using 12" and 16" cartridges, with surface areas up to 37.5 ft2 for a single cartridge, are designed to meet any manufacturing scale requirement.

2 X 106 cells/mL (viable)

u The scaled-up Zeta Plus system for

cell separation at the process level: 10SP 16" cartridges followed by 90SP 16" cartridges The scaled-up, 1200 liter batch size was processed in 60 minutes with excellent filtrate quality and optimal product recovery. The scale-up to the 1200 liter level was simple, linear and predictable. 21

PolyPro XL

CUNO's PolyPro XL filter cartridge represents a major advance in pleated polypropylene filter design and performance. MaxMedia construction1 combines:

u Up to 50% more filter media (surface area) than competitive filters u Graded-density media for optimum contaminant holding u New cartridge design for increased flow and reduced pressure drop.

The result is a filter cartridge that lasts longer, performs better, and saves money.

Figure 18

The MaxMedia Advantage

Surface area dictates just how long a filter will last and how it will perform. However, increasing surface area without considering the flow path between the media's pleats could result in flow restrictions and early media blinding. To provide the optimum between surface area and performance, CUNO has ensured that the pleating process and media support materials work together to provide enhanced flow characteristics and longer service life.

PolyPro XL Features:

u MaxMedia construction provides higher product throughputs,

extraordinarily long service life, and lower total filtration operating costs.

u Absolute-rated filter performance results in consistent

and reproducible contaminant removal.

Figure 19 - Shown is the unique pleat geometry offered by the PolyPro XL MaxMedia technology that provides greater contaminant removal capability and maximum filter life.

u Graded-density, multi-layer filter media selectively entraps

contaminant throughout the filter media to maximize filter life.

u Backflushable, rugged polypropylene cartridge construction

extends service life and is compatible with a wide range of solvents and cleaning solutions, including dilute caustic.

Graded-Density­The Key to Longer Life

The PolyPro XL filter's graded-density media structure removes particles sequentially by size­the larger particles by the more open, outer medium and the smaller particles by the tighter, inner medium. The outer medium acts as a prefilter, while the inner provides the absolute removal specified by the cartridge rating. This construction effectively spreads the contaminant through the depth of the filter media resulting in extremely high contaminant capacity with lower pressure drop for longer service life.

Chemical Compatibility

Polypropylene construction provides chemical compatibility in many demanding process fluid applications. Compatibility is influenced by process operating conditions; in critical applications, cartridges should be tested under actual conditions to ensure correct selection. For more information, please ask for CUNO literature number LITPXLEL

1

22

U.S. Patent Numbers 5,882,288; 6,048,298

PolyNet PB

PolyNet PB filter cartridges are CUNO's latest advance in depth filtration technology. The all polypropylene filter is constructed using a patent pending process that utilizes flow enhancing filter media and an innovative flow pattern. The result is an absoluterated filter with vastly superior on-stream life that provides more cost effective filtration than conventional melt-blown filter technologies. PolyNet PB filter cartridges are particularly well suited for demanding biological and pharmaceutical filtration applications.

PolyNet PB Advantages u Superior service life­as much as 4 times greater

Figure 20

dirt holding capacity than competitive filters

u All polypropylene depth filter cartridges for

broad chemical and temperature compatibility

u Ratings from 0.5-70 microns to suit a wide range of applications u Absolute-rated performance for consistent filtration quality u Exhibits superior particle retention under increasing differential pressure

PolyNet PB Construction

CUNO designed the PolyNet PB cartridge to provide significantly superior service life while maintaining a consistent filtration efficiency. PolyNet PB filters achieve this through an innovative cartridge design that allows uniform distribution of fluid flow and contaminant throughout the entire depth of the cartridge. PolyNet PB filter construction combines a unique polypropylene media with fluid distribution netting to form multiple layers. Critically positioned media flow channels allow greater movement of fluid from layer to layer. Three distinct media sections, made from multiple media/netting layers, are combined to form the filter cartridge. The outer and middle sections contain multiple layers of interleaved filter media and fluid distribution netting. Within each media layer a portion of the fluid travels through the media while the balance of the fluid is delivered directly to the next distribution layer through the flow channels. The fluid distribution netting provides longitudinal and latitudinal flow paths to evenly distribute fluid flow across the surface of each successive media layer. For more information, please ask for CUNO literature number LITCPN2

23

CUNO Membrane Cartridge Filtration

CUNO offers a variety of proprietary membrane filter products for the purification of biological fluids involving applications requiring hydrophilic filters (such as aqueous-based products) and those requiring hydrophobic filters (such as sterile air, gas streams, nitrogen and aggressive solvents). CUNO's line of membrane cartridge filtration products includes SterASSURE, Zetapor, LifeASSURE PB and Microfluor II cartridge filters.

SterASSURE Cartridge and Capsule Filters

Capsule

SterASSURE filter cartridges and capsules are CUNO's latest advance in membrane filter technology. Encompassing two leading-edge processes, FlexN membrane manufacture and Advanced Pleat Technology1 design, the SterASSURE series of filters offers absolute bacteria retention, as well as exceptionally long service life. Designed with pleated Nylon 6,6 membrane in an all-polypropylene cartridge construction, SterASSURE filters are ideally suited for a wide range of sterilizing applications in the pharmaceutical, biological, and bioprocess industries. SterASSURE filters are available in 0.2 and 0.1 micron ratings. Both filter grades are validated for absolute retention of B. diminuta, and 0.1 micron rated SterASSURE filters provide mycoplasma retention.

FlexN Membrane Technology

SterASSURE filters incorporate CUNO's advanced FlexN membrane technology2. It allows unmatched flexibility in creating a multi-zone membrane that offers the maximum in contaminant holding capacity while maintaining high retention efficiency. The SEM photograph (Figure 22) shows that the SterASSURE membrane consists of an "open" zone and a "tighter" zone. In effect, the open zone acts as a prefilter by capturing larger particles and colloids while the tighter zone provides the retention of smaller contaminants.

Table 13 - SterASSURE Membrane Filter Features and Benefits

Mini Cartridge

Features Multi-zone, FlexN Nylon membrane

Benefits Maximum membrane protection Increased contaminant capacity Extended service life Lower total filtration costs Faster flow rates and smaller filter assemblies Lower total filtration costs Ensures product quality Ensures performance to specification and proper installation Superior retention of microorganisms Safe for product contact

Advanced Pleat Technology design for extremely high surface area

Standard Cartridge

100% Integrity tested at factory Integrity testable by the user True membrane construction Passes USP Biological Reactivity Tests for Class VI Plastics

1 1

24

U.S. Patent Number 6,315,132 U.S. Patent Numbers 6,090,441; 6,264,044; 6,280,791

LifeASSURE PB Cartridge and Capsule Filters

LifeASSURE PB filters contain a single layer of the same FlexN Nylon 6,6 filter medium as used in SterASSURE sterilizing grade filters. Designed with pleated Nylon 6,6 membrane in an all-polypropylene cartridge construction, LifeASSURE PB filters are ideally suited for a wide range of prefiltration and clarification applications in the pharmaceutical, biological, and bioprocess industries.

Optimal System Performance

Figure 22

Used as a prefilter, LifeASSURE PB filters protect and significantly extend the service life of CUNO's sterilizing grade SterASSURE final filter, as well as other membrane filters. LifeASSURE PB filters will:

u increase final filter life substantially, often by 10 times or more, u decrease filter change-outs, greatly reducing filter costs, and u provide superior microorganism reduction

Optimized for Use with SterASSURE and Zetapor SP Sterilizing Grade filters

LifeASSURE PB filters are designed for use with SterASSURE and Zetapor SP sterilizing grade final filters. The combination of prefilter and final filter, all with the same materials of construction, offers minimal system extractables. The unique FlexN construction advantage provides higher system flow rates than competitive prefilter-final filter systems.

Figure 23 - Throughput Comparison (in percent) Table 14 - Comparative Prefilter­Final Filter Pressure Drop at a Specific Flow Rate

Prefilter LifeASSURE PB, 0.45µm LifeASSURE PB, 0.20µm Milligard

®1

Final Filter SterASSURE 0.2 SterASSURE 0.2 Durapore 0.2

®

Combined Differential Pressure @ 3 GPM (Water Flow) 4.15 4.75 5.0 7.4

CWSS 0.6

Pall HDC

®2

Pall Ultipor NF 0.2

®

1Milligard and Durapore are registered trademarks of Millipore Corporation 2HDC and Ultipor are registered trademarks of Pall Corporation

Optimized for Service Life and Effluent Quality

As the data in Figure 23 demonstrates, LifeASSURE PB filters are designed to provide both enhanced service life and performance. When compared to competitive products, LifeASSURE PB filters allow the user to select equivalent effluent quality with vastly superior life, or improve the effluent quality with reduced, yet competitively superior, service life. Either way, the result is the same, LifeASSURE PB filters allow significantly more throughput than the competitive filters and provide up to double the service life.

25

Microfluor II Critical Sterilizing Grade PTFE Cartridge and Capsule Membrane Filters

Microfluor II PTFE membrane filters offer the ultimate in microorganism retention for air and gas streams without sacrificing air flow capacity. For critical applications where sterilization of air and gas streams or aggressive liquids is required, Microfluor II is validated for complete retention of B. diminuta based on liquid challenge following American Society of Testing and Materials (ASTM) methodology at a minimum challenge level of 107 CFU/cm2 of filter area. In addition, Microfluor II filters are validated for retention of Phi X-174 bacteriophage based on aerosol testing. Microfluor II membrane filters provide reliable sterilizing performance and extremely high air flow rates. High airflow per filter assembly ensures the most economical and highest performing solution possible for tank vent filtration and fermentation air sterilization possible. Microfluor II filters employ a patent pending construction consisting of PTFE membrane and specially selected polypropylene support layers that combined provide higher airflow rates than competitive PTFE membrane filters.

Figure 24 - CUNO designs and manufactures large multiple cartridge housings optimized for high flow sterile inlet air into fermenters. These housings, with installed Microfluor II cartridges, replace technologically inferior glass wool packed towers.

Cartridge and Capsule Configurations to Meet Any Process Requirement

Microfluor II membrane filters are available in 5 to 40-inch cartridges, 2.5 and 5-inch Mini Cartridges and 2.5, 5, 10, 20 and 30-inch capsules. With the exceptionally high Microfluor II flow rates, smaller and more economical assemblies can provide the same airflow as larger, more-costly competitive PTFE filters.

Table 15 - CUNO Microfluor II

Feature Hydrophobic PTFE membrane Liquid validation of B. diminuta retention High air flow with low pressure drop 21 CFR materials of construction and drug master file listing

Figure 25

Benefit Membrane will not become blocked with moisture Reliable sterilizing performance in wet or dry conditions Higher air flow for fermenter aeration and economical vent filter assemblies Eases validation and regulatory submissions

Microfluor II Applications

Microfluor II filters are optimized for applications requiring air or gas flow. The hydrophobic PTFE filter membrane prevents wetting with aqueous liquids or moisture that can block free airflow. Some applications, however, may require filtration of aggressive fluids such as acids or bases. Depending on compatibility, Microfluor II can be used to provide sterile filtration of these fluids by prewetting the membrane with a low surface tension fluid such as alcohol. Applications include sterile:

u Venting of process tanks u Filtration of process air and aseptic filling lines u Filtration for lyophilizer vacuum breaks u Filtration for autoclave vents u Filtration of fermentation inlet and exhaust air u Filtration of aggressive liquids

For additional information on CUNO Microfluor II, request LITCMR2 26

CUNO Filter Housings and Engineered Systems

CUNO offers an extensive range of cartridge filter housings to meet any process flow requirement. Designed for the production environment, CUNO sanitary design cartridge housings handle the most critical clarification and sterile filtration applications in bioprocess manufacturing.

Process Flow Rates from 1 GPM to 2000 GPM

CUNO filter housings can meet virtually any process flow requirement found in biological manufacturing. From the laboratory bench to pilot plant to full production scale, CUNO sanitary filter housings are available for varying batch volume sizes and flow rates.

Materials of Construction

CUNO sanitary cartridge housings are manufactured from 316L stainless steel for maximum corrosion resistance. Housings are provided with a mirror-polish or an optional electropolished 10Ra surface finish that minimizes bacterial adhesion and maximizes cleanability.

Safety

CUNO housings are designed and tested to assure safe operation in demanding production environments. Housings can be provided that meet safety code requirements of all countries around the world, including ASME-code stamped vessels.

27

Figure 26 - A sanitary design filtration system with Zetapor and Zeta Plus housings for 15,000 L cell broth clarification is shown.

User-Friendly Design

CUNO sanitary filter housings are designed with the end-user in mind permitting rapid installation and removal of filter cartridges. Fast-action swing bolts and quick release clamps reduce downtime and minimize labor. Housings have easy-to-clean vents, drains and sanitary connections.

Engineered Systems

For enhanced mobility, CUNO provides cart or skid mounted systems for processspecific requirements. CUNO mobile filtration units can be provided with pumps, gauges, piping and optional feed loops. CUNO also provides sanitary housings with integral spray ball assemblies for clean-in-place (CIP) and steam-in-place (SIP) operations. A cartridge lifting device, ZetaGrip, is available for lifting 12 and 16-inch cartridges, enabling easy and safe removal of Zeta Plus cartridges.

28

CUNO Incorporated Over 90 Years of Solutions

When looking for bioprocessing filtration solutions, the industry has turned to CUNO for performance. CUNO has achieved a leadership position by striving to be the best supplier of high quality products designed to provide cost effective solutions. Some filter manufacturers offer a limited range or a single filter option. CUNO, however, understands that each application is unique and there is always an alternative. CUNO has both the experience and the breadth of products to provide quality improvements and dramatic cost savings for the customer.

Quality Management & ISO Standards

CUNO has maintained its leadership in fluid filtration and purification by continually providing superior products and technical support. CUNO filtration systems are designed and manufactured to the most stringent industry standards to assure the reliability of CUNO systems that our customers have come to expect.

CUNO has established a global quality management program which encompasses all facets of its operations. An essential part of the CUNO program is the creation of multi-function teams whose combined expertise is devoted to continuous improvement of processes, procedures, and quality systems. In addition, the CUNO system ensures the active support and participation of senior management. CUNO is fully committed to the tenets of the quality management program and provides a support system for the quality process. The majority of CUNO manufacturing plants are ISO 9001 registered. At CUNO, Quality is defined by the never-ending pursuit for continuous improvement in products, services, and personnel.

29

Fluid Purification

n Innovative Depth Filter

Service Worldwide

Technology and Final Sterilizing Membrane Filters

n Electrokinetic Filtration

CUNO Incorporated

400 Research Parkway Meriden, CT 06450, U.S.A. 203/237-5541 800/243-6894 Fax 203/238-8977 & 203/238-8716

Technology for Removal of Contaminating DNA, Endotoxins, and Viruses

n Full Line of High Quality

CUNO Pacific Pty., Ltd.

140 Sunnyholt Road Blacktown, N.S.W. 2148 Australia

Stainless Steel Sanitary Filter Housings

n Advanced Scientific

CUNO Filtration Asia Pte. Ltd.

18 Tuas Link 1 (3rd Floor) Singapore 638597

Applications Support Services (SASS)

n CUNO Quality,

CUNO K.K.

Hodogaya Station Building 6F 1 - 7 Iwai-cho, Hodagaya-Ku Yokohama 240 Japan

CUNO Latina Ltda

Rua Amf do Brasil 251 18120 Mairinque - Sp Brazil

CUNO Service, CUNO Reliability

CUNO Limited

21 Woking Business Park Albert Drive Woking Surrey GU21 5JY United Kingdom

Visit us @ www.cuno.com

Your Local CUNO Distributor:

© CUNO Incorporated, 2002 ALL RIGHTS RESERVED

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