Validation Guide For Cobetter DLHPVND Series Hydrophilic Filters - en V8.3 202005

Validation Guide
Cobetter DLHPVND Series Filters

Pharmaceutical grade hydrophilic PVDF membrane
Contents
I. Introduction .........................................................................................................................................................1
II. Product Specifications ........................................................................................................................................2
1. Catalogue Numbers Description .................................................................................................................2
2. Specifications .................................................................................................................................................3
III. Performance Verification....................................................................................................................................6
1. Bacteria Challenge Test and Correlation with Non-Destructive Integrity Test ........................................6
2. Hydraulic Stress............................................................................................................................................10
3. Water Flow Rate ...........................................................................................................................................19
4. Thermal Resistance .....................................................................................................................................23
5. Chemical Compatibility ...............................................................................................................................31
6. Extractables (NVR) .......................................................................................................................................33
7. Total Organic Carbon (TOC) and Conductivity ..........................................................................................34
8. Particle Shedding ........................................................................................................................................40
9. Non-fiber Releasing ....................................................................................................................................44
10. Bacterial Endotoxins Test ............................................................................................................................46
11. USP <87> Biological Reactivity Test, In Vitro ..............................................................................................48
12. USP <88> Class VI Biological Reactivity Test, In Vivo ................................................................................49
13. FDA 21 CFR Indirect Food Additive .............................................................................................................50
i
I. Introduction
This Validation Guide provides information of Cobetter DLHPVND series filters, including test methods,
performance and specifications related to pharmaceutical manufacturing process. This guide is designed
as a reference for end user to validate Cobetter DLHPVND series filters to meet requirements of regulatory
authorities within the pharmaceutical industry.
Cobetter DLHPVND series sterilizing-grade filters contain 0.1 m or 0.22 m hydrophilic polyvinylidene
fluoride (PVDF) membrane with an upstream PVDF membrane as prefilter, which are designed for sterile
filtration in pharmaceutical applications. Cobetter DLHPVND series bioburden reduction filters contain
double-layer hydrophilic polyvinylidene fluoride (PVDF) membranes which are designed for bioburden
reduction and particle control in pharmaceutical applications.
Quality Assurance
Cobetter establishes and continuously maintains the company’s quality assurance system in accordance
with the requirements of ISO® 9001:2015 quality management system and cGMP. Products are manufac-
tured under strict quality system to ensure stable and reliable quality.
Raw Material Control

Cobetter has established a rigorous supplier selection and periodic evaluation system. The core materials
are selected from internationally renowned raw material suppliers and manage the suppliers hierarchi-
cally. Injection molding pellets, support layers, O-rings and other materials or components are inspected
according to the company's internal control standards to ensure the quality of raw materials is stable
and reliable.
Quality and Environment Management

The entire manufacturing process of the Cobetter filter from raw material storage to product packaging
is completed in the ISO Class 8 clean area, which ensures the cleanliness of the product and prevents
pollution. The air purification system is confirmed and maintained regularly to ensure that the cleanliness
of environment continuously meets the requirements of ISO Class 8. The suspended particles, sedimen-
tation bacteria, temperature, humidity and differential pressure are monitored periodically to provide for
a highly controlled clean environment.
Lot Release and Traceability

The sterilizing grade Cobetter filter requires 100% integrity testing before delivery. The test methods
include bubble point, diffusion flow and water intrusion. The specific test method can be found in the
integrity test section of the quality certificate.
The product lot number and serial number of Cobetter filter are engraved on the cartridge cage.
Customers can also find the corresponding product lot number in the product label and quality certif-
icate. The product can be traced from the whole process of raw materials, equipment, manufacturing
process through the lot number and serial number.
1
Validation Guide Cobetter DLHPVND Series Hydrophilic Filters
II. Product Specifications

1. Catalogue Numbers Description
Cobetter DLHPVND Series Cartridge Filters
DLHPVND P
Cartridge Type Pore Size Cartridge Adapter Type Cartridge Length O-ring Material
Blank - 69 mm 2210 - 0.22+0.1 m DOE - Double open end 05 - 5-inch S - Silicone
2222 - 0.22+0.22 m with flat gasket 10 - 10-inch E - EPDM
4522 - 0.45+0.22 m HTF - 222 / Fin 20 - 20-inch V - Fluoroelastomer
4545 - 0.45+0.45 m HSF - 226 / Fin 30 - 30-inch P - FEP/PFA encap-
6545 - 0.65+0.45 m HTCG - 222 / Flat 40 - 40-inch sulated O-rings
HSCG - 226 / Flat
Adapter Schematic
DOE HTF HSF HTCG HSCG
Cobetter WSF Capsule Filter with DLHPVND 0.22+0.22 μm Membrane
WSF 0 5 DLHPVND 2 2 2 2 P
Capsule Type Capsule Size Membrane Type Pore Size

WSF - Cobetter WSF series 05 - 5 inch DLHPVND - Cobetter DLHPVND 2222 - 0.22+0.22 m
capsule filters membrane
Bricap®1 T20 Capsule Filter with Cobetter DLHPVND 0.45+0.22 μm Membrane
T 2 0 S S DLHPVND 4 5 2 2 A 1 P
Capsule Size Pore Size Quantity per package

T20 - Bricap® T20 4522 - 0.45 +0.22 m 1 - 1 / pkg.
Inlet, Outlet & Gauge Port Type Sterilization

S - 38 mm (1 1/2") Sanitary Flange A - Autoclavable
K - 14 mm (9/16") Sanitary Flange
N - without Gauge Port
1 Bricap is trademark of Cobetter capsule filter.
2
2. Specifications (Per 10-inch Cartridge)
Cobetter DLHPVND Series Sterilizing-grade Cartridge Filters
Filter DLHPVND 0.22+0.1 μm DLHPVND 0.22+0.22 μm DLHPVND 0.45+0.22 μm

Length 254.0 mm (10 in.)
Diameter 69.0 mm (2.7 in.)
Materials of Construction
Filter membrane Hydrophilic polyvinylidene fluoride (PVDF)
Supports Polypropylene
Core, cage, end caps Polypropylene
Adapter internal support PBT
O-rings Silicone, EPDM, Fluoroelastomer
Pore Size 0.22+0.1 m 0.22+0.22 m 0.45+0.22 m
Effective Filtration Area (EFA) 2 2

0.58 m (6.2 ft )
Maximum Operating Pressure 6.9 bar (100 psi) at 25 °C

4.0 bar (58 psi) at 60 °C
2.4 bar (35 psi) at 80 °C
Maximum Differential Pressure
Forward 6.9 bar (100 psi) at 25 °C
4.0 bar (58 psi) at 60 °C
2.4 bar (35 psi) at 80 °C
Reverse 3.0 bar (44 psi) at 25 °C
1.0 bar (15 psi) at 80 °C
Water Bubble Point at 20 °C ≥ 4.8 bar (70 psi) , air ≥ 3.2 bar (46 psi) , air ≥ 3.2 bar (46 psi) , air
Air Diffusion at 20 °C, water wet ≤ 20 mL/min at 3.86 bar (56 psi) ≤ 18 mL/min at 2.8 bar (41 psi) N/A
Bacterial Retention Retention of 107 cfu/cm2 Brevundimonas diminuta (ATCC® 19146) according to ASTM F838.
Sterilization
Steam in Place Can be steam sterilized for 30 minutes at 135 °C in forward direction (< 0.3 bar, 5 psi) with
100 cycles and in reverse direction (< 0.1 bar, 1.5 psi) with 50 cycles.
Autoclave Can be autoclaved 400 cycles for 30 minutes at 130 °C.
TOC / Conductivity at 25 °C Autoclaved filter effluent meets the USP <643> for Total Organic Carbon and USP <645> for
Water Conductivity per WFI requirements after a UPW flush of 40 L.
Particle Shedding Autoclaved filter effluent meets the requirements in USP <788> for large volume injections.
Non-Fiber Releasing Component materials meet the criteria for a “Non-fiber-releasing filter” as defined in 21 CFR
210.3 (b) (6).
Bacterial Endotoxin Aqueous extraction of autoclaved filter contains < 0.25 EU/mL as determined by Limulus
Amebocyte Lysate (LAL), USP <85>.
USP <87> Cytotoxicity Meet the requirement of USP <87> In Vitro Biological Reactivity Test.
USP <88> Biological Reactivity Meet the criteria of the USP <88> Biological Reactivity Test for Class VI-121 °C plastics.
Indirect Food Additive All component materials meet the FDA Indirect Food Additive requirements cited in 21 CFR
177–182.
Quality Assurance These products are manufactured in a facility which adheres to ISO® 9001:2015 Practices.
3
Cobetter DLHPVND 0.45+0.45 μm Cartridge Filter
Filter DLHPVND 0.45+0.45 μm

Pore Size 0.45+0.45 m
Effective Filtration Area (EFA) 0.58 m2 (6.2 ft2)

4.0 bar (58 psi) at 60 °C
2.4 bar (35 psi) at 80 °C
4.0 bar (58 psi) at 60 °C
2.4 bar (35 psi) at 80 °C
1.0 bar (15 psi) at 80 °C
Water Bubble Point at 20 °C ≥ 1.2 bar (17 psi) , air
Sterilization
210.3 (b) (6).
177–182.
4
Filter DLHPVND 0.65+0.45 μm

Pore Size 0.65+0.45 m
Effective Filtration Area (EFA) 0.58 m2 (6.2 ft2)

4.0 bar (58 psi) at 60 °C
2.4 bar (35 psi) at 80 °C
4.0 bar (58 psi) at 60 °C
2.4 bar (35 psi) at 80 °C
1.0 bar (15 psi) at 80 °C
Water Bubble Point at 20 °C ≥ 1.2 bar (17 psi) , air
Sterilization
210.3 (b) (6).
177–182.
5
III. Performance Verification

1. Bacteria Challenge Test and Correlation with Non-Destructive Integrity Test
The USP < 1229.4 > defines “A sterilizing-grade filter is one that is capable of retaining a minimum
1×107 cfu of B. diminuta (ATCC® 19146) per square centimeter of effective filter area when tested in
accordance with ASTM® F838-05 (2013), Standard Test Method for Determining Bacterial Retention of
Membrane Filters Utilized for Liquid Filtration .”
A liquid bacteria challenge test (BCT) was performed to confirm that Cobetter DLHPVND sterilizing grade
cartridge filters can completely retain a minimum concentration of 107 cfu/cm2 (EFA) Brevundimonas
diminuta (ATCC® 19146) and meet the criteria for sterilizing grade performance as defined in ASTM
methodology.
Since the bacteria challenge test is a destructive method, it must be correlated with a non-destructive
integrity test. The FDA guideline states, “After a filtration process is properly validated for a given product,
process and filter, it is important to assure that identical filter replacement (membrane or cartridge) used
in production runs will perform in the same manner. One way of achieving this is to correlate filter perfor-
mance data with filter integrity testing data. Normally, integrity testing of the filter is performed after
the filter unit is assembled and sterilized prior to use. More importantly, however, such testing should be
conducted after the filter is used in order to detect any filter leaks of perforations that may have occurred
during the filtration.”
The final membrane of Cobetter DLHPVND 0.22+0.22 m cartridge filter is identical to the Cobetter
DLHPVND 0.45+0.22 m cartridge filter. The bacterial challenge test in this validation was performed
using Cobetter DLHPVND 0.45+0.22 m cartridge filter that represents the worst condition.
6
Summary of Method
Cobetter DLHPVND 0.45+0.22 m cartridge filters were wetted with water and steamed at 135 °C for
30 minutes prior to testing. The cartridge filters were subjected to integrity test and then challenged with
Brevundimonas diminuta (ATCC® 19146) of the challenge level over 1×107 cfu/cm2 in accordance with
ASTM F838 at a pressure of 2 bar.
After the bacteria challenge test, the control analysis filter and challenge analysis filters are incubated
on Tryptic Soy Agar (TSA) plates at 30 °C to determine if there are any challenge bacteria passing through
the tested filter. The analysis is conducted according to ASTM methodology.
Bacterial Challenge Test Schematic
Purified Water Pressure

Gauge
Valve
Valve
Control Drain
Analysis Filter
Pressure
Valve Gauge
Sterilizing-grade Test Filter
Prefilter
Valve
Bacteria
Suspension Valve
Challenge Drain
Steam Pump Analysis Filter
7
Results
Challenge Level
Lot Number Bubble Point (bar) (cfu/10-inch) Filtrate Sterility LRV/cm2
A022917B15 4.379 1.94 × 1011 Sterile 7.52
11
A024768210 4.327 1.46 × 10 Sterile 7.40
A023737C15 4.263 1.94 × 1011 Sterile 7.52

11
A022827B10 4.254 1.05 × 10 Sterile 7.26
A024118109 4.244 1.94 × 1011 Sterile 7.52

10
A023797C18 4.243 7.36 × 10 Sterile 7.10
A023787C18 4.040 9.76 × 1010 Sterile 7.23

10
A022287A14 4.023 7.57 × 10 Sterile 7.12
A023707C16 3.959 7.26 × 1010 Sterile 7.10

11
A022277A14 3.937 1.20 × 10 Sterile 7.32
A024788210 3.918 1.10 × 1011 Sterile 7.28

11
A023757C18 3.874 1.05 × 10 Sterile 7.26
A022927B15 3.713 1.83 × 1011 Sterile 7.50

10
A023777C15 3.671 7.26 × 10 Sterile 7.10
A022277A14 3.666 9.76 × 1010 Sterile 7.23

11
A022927C15 3.646 1.10 × 10 Sterile 7.28
A022927C15 3.62 1.46 × 1011 Sterile 7.40

10
A022927B15 3.603 7.57 × 10 Sterile 7.12
A023918103 3.507 1.46 × 1011 Sterile 7.40

10
A023737C15 3.481 8.47 × 10 Sterile 7.16
A022287A14 3.479 1.20 × 1011 Sterile 7.32

11
A024098109 3.478 1.83 × 10 Sterile 7.50
A024778210 3.471 9.67 × 1010 Sterile 7.22

11
A023717C16 3.460 1.05 × 10 Sterile 7.26
A023627C13 3.422 9.67 × 1010 Sterile 7.22

11
A023627C13 3.306 1.83 × 10 Sterile 7.50
A022237A13 3.184 8.47 × 1010 Sterile 7.16

10
A023797C18 3.110 7.36 × 10 Sterile 7.10
A023757C18 3.100 7.36 × 1010 Sterile 7.10

10
A023807C19 2.999 7.26 × 10 Sterile 7.10
A023727C15 2.910 8.47 × 1010 Sterile 7.16

11
A024108109 2.789 1.20 × 10 Sterile 7.32
A022927C15 2.785 7.57 × 1010 Sterile 7.12

10
A024788210 2.703 9.67 × 10 Non sterile <7
A024108109 2.676 9.76 × 1010 Non sterile <7

11
A023958105 2.671 1.10 × 10 Non sterile <7
8
Conclusion
Correlation of the ASTM Bacteria Challenge Tests

with Non-Destructive Integrity Test
6.0
Bubble Point (bar)
psi
80
Sterile
5.0
Non sterile
Sterile Threshold
4.0 60
Bubble Point Spec
3.0
40
2.0
20
1.0
0.0 0
Lot No.
According to the results of the bacterial challenge test, Cobetter DLHPVND 0.45+0.22 m cartridge filters
can completely retain a minimum concentration of 107 cfu/cm2 Brevundimonas diminuta (ATCC® 19146)
with a sterile filtrate when the bubble point of tested filters is greater than 2.785 bar. Taking into account
the safety factor, the bubble point specification for Cobetter DLHPVND 0.45+0.22 m cartridge filter is set
to:
≥ 3.2 bar (46 psi) in water at 20 °C.
9
2. Hydraulic Stress
The maximum operating pressure and maximum differential pressure of the filter element at a specific
temperature depend on its pressure resistance. The hydraulic stress test is to confirm the pressure resis-
tance of the filter at a specific temperature under the worst-case simulated conditions.
The mechanical and structural features of the filter determine the high risk of reverse-use of the filter
causing structural damage. It is not recommended to use the filter in reverse direction in the actual
production process. The reverse test conditions in this validation test are only the worst-case simulation
of the instantaneous reverse pressure difference that may occur in the actual production process, and
cannot be used as the basis for the reverse use of the filter.
Hydraulic Stress Test Schematic
Pressure
Gauge
Thermometer Valve
Pressure
Valve Gauge
Liquid Storage Tank Pump Test Filter

(Built-in temperature control device)
10
2.1. Hydraulic Stress Test at 25 °C
Summary of Method
Cobetter DLHPVND series cartridge filters were wetted with water and steamed at 135 °C for 30 minutes
prior to testing. The filters were wetted with water and then integrity tested.
The filters were plugged with test dust to increase the differential pressure across the upstream and
downstream of the filter. A hydraulic stress of 6.9 bar was applied to the filters at 25 °C for 30 minutes in the
forward direction with 10 cycles. Then a differential pressure of 3.0 bar was applied to the filters at 25 °C
for 10 minutes in the reverse direction with 3 cycles.
The filter integrity test was carried out to find any changes during the hydraulic stress test.
Prior to Hydraulic Stress Post Hydraulic Stress

Bubble Point Diffusion @ 3.86 bar Bubble Point Diffusion @ 3.86 bar
Lot Number (bar) (mL/min) (bar) (mL/min)
A025878420 5.948 12.9 5.730 13.0
A022317A14 5.705 13.2 5.611 13.7
A022227A12 6.165 16.0 6.435 16.3

A025228308 3.982 6.5 3.845 6.6
A024598206 4.145 9.5 4.084 9.6
A024948226 3.961 9.4 3.897 9.7
11
Bubble Point (bar)
Lot Number Prior to Hydraulic Stress Post Hydraulic Stress
DLHPVND 0.45+0.22 m cartridge filter
A022927C15 3.831 3.805
A024118109 3.717 3.811
A023958105 3.821 3.805
A027118717 2.068 2.107
A026928705 1.951 1.829
A027128717 2.156 2.126
A172909301 2.224 2.181
A171528C14 2.285 2.231
A170458928 2.399 2.308
Conclusion
Cobetter DLHPVND series cartridge filters maintain integrity after a series of hydraulic stress tests at
25 °C described above.
12
Summary of Method
downstream of the filter. A hydraulic stress of 4.0 bar was applied to the filters at 60 °C for 30 minutes in
the forward direction with 6 cycles.

A025878420 6.090 13.6 6.301 13.4
A022317A14 5.808 15.0 5.923 15.0
A022227A12 6.108 14.4 6.054 14.0

A025228308 3.952 7.0 4.195 6.9
A024598206 3.972 8.3 3.885 8.4
A024948226 4.029 8.9 4.068 9.0
13
Bubble Point (bar)
A022927C15 3.722 3.819
A024118109 3.870 3.981
A023958105 3.963 3.855
A027118717 1.840 1.903
A026928705 2.104 2.076
A027128717 1.812 1.984
A172909301 2.254 2.321
A171528C14 2.203 2.198
A170458928 2.494 2.494
Conclusion
14
Summary of Method
downstream of the filter. A hydraulic stress of 2.4 bar was applied to the filters at 80 °C for 30 minutes in
the forward direction with 4 cycles. Then a differential pressure of 1.0 bar was applied to the filters at 80 °C
for 10 minutes in the reverse direction with 3 cycles.

A025878420 5.874 13.4 5.848 13.5
A022317A14 5.860 15.3 5.756 14.7
A022227A12 6.290 14.3 6.467 14.2

A025228308 3.901 5.9 3.761 6.0
A024598206 4.248 8.6 4.324 8.3
A024948226 4.081 8.5 3.957 8.7
15
Bubble Point (bar)
A022927C15 3.713 3.761
A024118109 3.816 3.986
A023958105 3.972 3.902
A027118717 1.904 1.801
A026928705 2.091 1.985
A027128717 1.821 1.799
A172909301 2.145 2.135
A171528C14 2.153 2.153
A170458928 2.229 2.241
Conclusion
16
Summary of Method
Cobetter DLHPVND series cartridge filters were plugged with test dust to increase the differential pressure
across the upstream and downstream of the filter, and integrity tested. Then the filters were wetted with
water and steamed at 135 °C for 30 minutes with a differential pressure of 0.35 bar.

A025878420 6.032 13.1 6.184 13.4
A022317A14 5.858 14.6 5.899 14.0
A022227A12 6.077 15.8 6.255 15.3

A025228308 3.915 5.7 3.882 5.8
A024598206 4.087 8.9 4.123 8.9
A024948226 3.977 8.6 3.831 8.7
17
Bubble Point (bar)
A022927C15 3.877 3.969
A024118109 3.759 3.833
A023958105 3.893 3.750
A027118717 2.065 2.044
A026928705 2.189 2.191
A027128717 1.846 1.841
A172909301 2.111 2.147
A171528C14 2.119 2.064
A170458928 2.493 2.518
Conclusion
Cobetter DLHPVND series cartridge filters maintain integrity after a hydraulic stress test at 135 °C
described above.
18
3. Water Flow Rate
Cobetter DLHPVND series cartridge filters were wetted with water and steamed at 135 °C for 30 minutes.
Cobetter WSF capsule filters with DLHPVND 0.22+0.22 m membrane were wetted with water and
autoclaved at 130 °C for 30 minutes. Cobetter Bricap T20 capsule filters with DLHPVND 0.45+0.22 m
membrane were wetted with water and autoclaved at 126 °C for 60 minutes. The filters were wetted with
water and then integrity tested. The required differential pressure for the test is acquired by adjusting the
inlet valve of the filter. After achieving a constant differential pressure, the flow rate and water tempera-
ture were recorded. All the results of filters were corrected to a water temperature of 20 °C. The graph was
plotted after the pressure drop were measured from the filters at various water flow rates.
Water Flow Rate Test Schematic
Pressure
Gauge
Purified Water
Test Filter
Thermometer
Valve Flow Meter
Pump Drain
Cobetter DLHPVND 0.22+0.1 μm
Water Flow Rate — Cobetter DLHPVND 0.22+0.1 μm Cartridge Filter

(DLHPVND2210HSF**SP)
GPM
0 3 6 9 12
2.5
Differential Pressure (bar)
psi
35
30
2.0
10 inch
20 inch 25
30 inch
1.5
20
1.0 15
10
0.5
5
0.0 0
0 10 20 30 40 50
Water Flow Rate @ 20 °C (L/min)
19

GPM
0 5 10 15 20
1.5
psi
20
1.2
10 inch
20 inch 15
30 inch
0.9
10
0.6
5
0.3
0.0 0
0 10 20 30 40 50 60 70 80
Water Flow Rate — Cobetter WSF Capsule Filter with DLHPVND 0.22+0.22 μm Membrane
(WSF05DLHPVND2222P)
GPM
0 3 6 9 12
2.0
25 psi
1.5 5 inch
20
1.0 15
10
0.5
5
0.0 0
0 10 20 30 40 50
20
Water Flow Rate — Cobetter DLHPVND 0.45+0.22 m Cartridge Filter

GPM
0 5 10 15 20
1.5
psi
20
1.2
10 inch
20 inch 15
30 inch
0.9
10
0.6
5
0.3
0.0 0
0 10 20 30 40 50 60 70 80
Water Flow Rate —Bricap T20 Capsule Filter with Cobetter DLHPVND 0.45+0.22 μm Membrane
(T20SSNDLHPVND4522A1P)
GPM
0 5 10 15
0.5
psi
7.0
6.0
0.4 SS
5.0
0.3
4.0
0.2 3.0
2.0
0.1
1.0
0.0 0.0
0 10 20 30 40 50 60
21

(DLHPVND4545HSF10SP)
GPM
0 5 10 15 20
0.5
psi
7.0
6.0
0.4 10 inch
5.0
0.3
4.0
0.2 3.0
2.0
0.1
1.0
0.0 0.0
0 10 20 30 40 50 60 70 80

GPM
0 5 10 15 20
0.60
psi
8
10 inch
0.45 20 inch
30 inch 6
0.30
4
0.15 2
0.00 0
0 10 20 30 40 50 60 70 80 90
22
4. Thermal Resistance
Cobetter DLHPVND series cartridge filters can be either steamed in place (SIP) or autoclaved. Since
multiple sterilization cycles may be required in actual use, the influences of the sterilization on the perfor-
mances of Cobetter DLHPVND series cartridge filters were examined. As a result, recommendations and
limits for multiple sterilization are given below.
Cobetter DLHPVND cartridge filters were wetted with water and subjected to integrity test prior to testing.
Cobetter DLHPVND cartridge filters were wetted with water and installed in the steam steriliza-
tion device in the forward direction. The steam valve and downstream valve were slowly adjusted
to increase the temperature to 135 °C as the same time ensuring the differential pressure across
the upstream and downstream of the filter less than 0.3 bar. The cartridge filters were steam
sterilized at a constant temperature of 135 °C for 30 minutes. After a 30-minute steam steriliza-
tion, closed the steam valve and slowly adjusted the downstream valve to release steam pressure.
The steam sterilization device was cooled by dry compressed air or natural cooling. Continu-
ally monitored the differential pressure across the upstream and downstream of the filter within
0.3 bar during the whole process of temperature rise, sterilization and cooling. The sequence
was repeated until the 100 SIP sterilization cycles had been achieved for each filter. Cobetter
LHPVND cartridge filters were wetted with water and installed in the steam sterilization device
in the reverse direction. The cartridge filters were steam sterilized at 135 °C for 30 minutes with
50 cycles in the reverse direction under the differential pressure less than 0.1 bar.
Cobetter DLHPVND cartridge filters were water wetted and wraped with tinfoil or cleansteam bag. The
cartridge filters were autoclaved 400 cycles at 130 °C for 30 minutes.
The filters were validated by integrity test to analyze and evaluate the influences of multiple sterilization.
Schematic of Steam-in-Place
Steam Pressure Pressure

Gauge Gauge
Valve Thermometer
Pressure Valve Pressure Valve

Gauge Gauge
Prefilter Test Filter
23
4.1. Cobetter DLHPVND 0.22+0.1 μm Cartridge Filter

Steam in Place
Prior to Sterilization After 150 SIP Cycles

A022247A13 5.992 12.9 6.158 13.5
A022227A12 5.832 14.5 6.058 15.4
A022297A14 6.044 15.3 6.213 16.1
Effect on Bubble Point

—— Cobetter DLHPVND 0.22+0.1 μm Cartridge Filter
8.0
Bubble Point (bar)
psi
100
6.0
75
4.0
50
2.0 25
Prior to Sterilization
0.0 0 After 150 SIP Cycles

A022247A13 A022227A12 A022297A14
Effect on Diffusion
20
Diffusion @ 3.86 bar ( mL/min)
15
10
5
0 After 150 SIP Cycles

A022247A13 A022227A12 A022297A14
24
Autoclave
Prior to Sterilization After 400 Autoclave Cycles

A022247A13 5.876 12.3 6.137 13.2
A022227A12 5.860 12.9 6.149 13.8
A022297A14 6.159 14.1 6.346 15.4

8.0
Bubble Point (bar)
psi
100
6.0
75
4.0
50
2.0 25
0.0 0 After 400 Autoclave Cycles

A022247A13 A022227A12 A022297A14
Effect on Diffusion
20
Diffusion @ 3.86 bar ( mL/min)
15
10
5
0 After 400 Autoclave Cycles

A022247A13 A022227A12 A022297A14
25

Steam in Place
Prior to Sterilization After 150 SIP Cycles

A022987B17 3.865 7.8 3.961 8.4
A023597C08 4.191 7.8 4.221 8.8
A024088109 3.995 8.4 4.138 9.1

6.0
Bubble Point (bar)
psi
80
4.5
60
3.0 40
1.5 20

A022987B17 A023597C08 A024088109
Effect on Diffusion
12.0
Diffusion @ 2.8 bar (mL/min)
9.0
6.0
3.0
0.0 After 150 SIP Cycles

A022987B17 A023597C08 A024088109
26
Autoclave
Prior to Sterilization After 400 Autoclave Cycles

A022987B17 3.920 7.6 4.085 8.4
A023597C08 4.051 8.2 4.215 9.0
A024088109 4.130 8.4 4.284 9.1

6.0
Bubble Point (bar)
psi
80
4.5
60
3.0 40
1.5 20

A022987B17 A023597C08 A024088109
Effect on Diffusion
12.0
Diffusion @ 2.8 bar (mL/min)
9.0
6.0
3.0
0.0 After 400 Autoclave Cycles

A022987B17 A023597C08 A024088109
27
Bubble Point (bar)
Lot Number Prior to Sterilization After Multiple Steam Cycles
After 150 SIP cycles
A022827B10 3.929 4.016
A022287A14 3.834 4.111
A023737C15 3.758 3.875
After 400 autoclave cycles
A022827B10 3.865 4.031
A022287A14 3.787 4.085
A023737C15 3.812 3.949

6.0
Bubble Point (bar)
psi
80
4.5
60
3.0 40
1.5 20

A022827B10 A022287A14 A023737C15

6.0
Bubble Point (bar)
psi
80
4.5
60
3.0 40
1.5 20

A022827B10 A022287A14 A023737C15
28
Bubble Point (bar)
A027118717 1.911 1.954
A026928705 2.079 2.164
A027128717 1.959 2.111
A027118717 2.017 2.104
A026928705 1.917 1.974
A027128717 1.836 1.883

2.8 40
Bubble Point (bar)
2.1 psi
30
1.4 20
0.7 10

A027118717 A026928705 A027128717

2.8 40
Bubble Point (bar)
psi
2.1 30
1.4 20
0.7 10

A027118717 A026928705 A027128717
29
Bubble Point (bar)
A172909301 2.237 2.410
A171528C14 2.108 2.306
A170458928 2.391 2.582
A172909301 2.272 2.522
A171528C14 2.117 2.322
A170458928 2.410 2.700

4.0
Bubble Point (bar)
psi
3.0 45
2.0 30
1.0 15

A172909301 A171528C14 A170458928

4.0
Bubble Point (bar)
psi
3.0 45
2.0 30
1.0 15

A172909301 A171528C14 A170458928
Conclusion
The results indicate that the integrity test of the Cobetter DLHPVND series cartridge filters is not affected
by the recommended sterilization methods.
30
5. Chemical Compatibility
Summary of Method
The evaluation of chemical compatibility for Cobetter DLHPVND series cartridge filters was determined
using a 48-hour static soak in the test solvent at 25 °C.
Results
Cartridge O-rings
Solvent Element Silicone EPDM Fluoroelastomer

Acetic Acid, glacial R L L N
Acetic Acid, 90% R R — N
Acetic Acid, 30% R R — L
Acetic Acid, 10% R R — L
Hydrochloric Acid, conc. 35% N N N N
Hydrochloric Acid, 20% L N N L
Hydrochloric Acid, 3.3% — R N R
Nitric Acid, conc. 67% N N N R
Nitric Acid, 27% N N L R
Sulfuric Acid, conc. 96% N N — R
Sulfuric Acid, 16% — N — R
Ammonium Hydroxide, 3N, 5.7% — R — R
Ammonium Hydroxide, 6N, 11.4% N R — R
Potassium Hydroxide, 15% N N R R
Sodium Hydroxide, 3N, 11% N L R R
Sodium Hydroxide, 22% N L R R
Amyl Alcohol R N R R
Benzyl Alcohol R L — R
Butanol R L R R
Ethanol R L R R
Isopropanol R L R R
Methanol R R R N
Ethylene Glycol R R — R
Glycerol R R — R
Propylene Glycol R R — R
Ethylether R N — N
Tetrahydrofuran N N N N
Tetrahydrofuran, 50% (v-v) — — — N
Acetone N N R N
Cyclohexanone N N L N
Methyl Ethyl Ketone (MEK) N N R N
Methyl Isobutyl Ketone (MIBK) N N R N
31
Cartridge O-rings
Solvent Element Silicone EPDM Fluoroelastomer

Amyl Acetate R N R N
Butyl Acetate L N R N
Cellusolve Acetate L R — N
Ethyl Acetate R N R N
Isopropyl Acetate R N R N
Methyl Acetate N N R N
Carbon Tetrachloride L N N R
Chloroform L N N R
Ethylene Dichloride N — — —
Methylene Chloride N N N N
Tetrachloroethylene R — — —
Trichloroethane N N N R
Benzene L N N R
Toluene L N N R
Xylene L N N R
Cottonseed R R — R
Peanut R R — R
Formaldehyde, 37% R L R N
Formaldehyde, 4% R R — R
Hexan L N — R
Acetonitrile L N R N
Dimethyl Formamide (DMF) N N N N
Dimethyl Sulfoxide (DMSO) N — — —
Kerosene R N N R
Pyridine N N N N
Petroleum Spirits N N N R
Hydrogen Peroxide R R R R
Ozone N N L N
Phenol N N R R
Legend:
R - Compatible
L - Limited compatibility
N - Incompatible
— - No data
Conclusion
The chemical compatibility results under laboratory conditions are for reference only. It is recommended
to verify the compatibility of the product with the filter under actual process conditions before use.
32
6. Extractables (NVR)
The purpose of this test was to determine the quantity of material that can be extracted from Cobetter
DLHPVND 0.45+0.22 m cartridge filter using purified water.
Summary of Method
Cobetter DLHPVND 0.45+0.22 m cartridge filters were autoclaved at 130 °C for 30 minutes prior to
testing. The quantity of gravimetric extractables for filters were determined using a 24-hour static soak
in purified water of 1.5 L at ambient room temperature. Part of the extract solution of 750 mL was evapo-
rated to dryness using a rotary evaporator and then dried to constant weight. At the same time, using
purified water as a blank control for NVR tests.
Results
Lot Number NVR (mg/10-inch)
A17987031268 96.8
A17023032739 98.2
A17991031313 102.6
Conclusion
The extractable level of the Cobetter DLHPVND 0.45+0.22 m cartridge filter under laboratory conditions
is for reference only. It is recommended to test under actual process conditions.
33
7. Total Organic Carbon (TOC) and Conductivity

The extractables in the filter can be reduced by flushing with water. The filter effluent was tested online
for conductivity and total organic carbon (TOC) under different flush volumes of ultra-pure water. The
recommended pre-flush volume is given when the TOC and conductivity of effluent meet the WFI specifi-
cation.
Summary of Method
Cobetter DLHPVND series cartridge filters were autoclaved at 130 °C for 30 minutes prior to testing. The
filters were flushed with ultra-pure water which meets the WFI specification of TOC less than 500 ppb and
conductivity less than 1.3 S/cm at 25 °C. The filter effluent was tested online for conductivity and total
organic carbon (TOC).
Depending on the online measurement of conductivity, the maximum conductivity is based on USP <645>
Stage 1 — Temperature and Conductivity Requirements table.
Stage 1 — Temperature and Conductivity Requirements

Temperature (°C) Conductivity Requirement (μS/cm) Temperature (°C) Conductivity Requirement (μS/cm)
10 0.9 25 1.3
15 1.0 30 1.4
20 1.1 35 1.5
TOC and Conductivity Test Schematic
To Ultra-pure Water
Test Filter
Valve TOC Analyzers Conductivity Meter
Pump Drain
Recommended Pre-flush Volume
DLHPVND DLHPVND DLHPVND DLHPVND DLHPVND

Filter Type
0.22+0.1 m 0.22+0.22 m 0.45+0.22 m 0.45+0.45 m 0.65+0.45 m
Pre-flush Volume (L) 40 40 40 70 50
34
TOC — Cobetter DLHPVND 0.22+0.1 μm Cartridge Filter
5.0
TOC (ppm)
4.0 Lot# A025878420

Lot# A025268308
Lot# A022307A14
3.0 USP <643> WFI Specification
2.0
1.0
0.0
0 4 8 12 16 20 24 28 32 36 40 44
Flush Volume (L)
Conductivity — Cobetter DLHPVND 0.22+0.1 μm Cartridge Filter
7.5
Conductivity @ 25 °C (μS/cm)
6.0 Lot# A025878420

Lot# A025268308
Lot# A022307A14
3.0
1.5
0.0
0 4 8 12 16 20 24 28 32 36 40 44
Flush Volume (L)
35
TOC — Cobetter DLHPVND 0.22+0.22 m Cartridge Filter
5.0
TOC (ppm)
4.0 Lot# A024608206

Lot# A026158509
Lot# A024948226
2.0
1.0
0.0
0 4 8 12 16 20 24 28 32 36 40 44
Flush Volume (L)
3.0
2.4 Lot# A024608206

Lot# A026158509
Lot# A024948226
1.2
0.6
0.0
0 4 8 12 16 20 24 28 32 36 40 44
Flush Volume (L)
36
TOC — Cobetter DLHPVND 0.45+0.22 m Cartridge Filter
5.0
TOC (ppm)
4.0 Lot# A024098109

Lot# A023958105
Lot# A023757C18
2.0
1.0
0.0
0 4 8 12 16 20 24 28 32 36 40 44
Flush Volume (L)
Conductivity — Cobetter DLHPVND 0.45+0.22 m Cartridge Filter
5.0
4.0 Lot# A024098109

Lot# A023958105
Lot# A023757C18
2.0
1.0
0.0
0 4 8 12 16 20 24 28 32 36 40 44
Flush Volume (L)
37
3.5
TOC (ppm)
2.8 Lot# A027118717

Lot# A026928705
Lot# A027128717
1.4
0.7
0.0
0 8 16 24 32 40 48 56 64 72 80
Flush Volume (L)
3.0
2.4 Lot# A027118717

Lot# A026928705
Lot# A027128717
1.2
0.6
0.0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68
Flush Volume (L)
38
5.0
TOC (ppm)
4.0 Lot# A172909301

Lot# A171528C14
Lot# A170458928
2.0
1.0
0.0
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Flush Volume (L)
2.5
Lot# A172909301
2.0 Lot# A171528C14
Lot# A170458928
USP <645> WFI Specification
1.5
1.0
0.5
0.0
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Flush Volume (L)
Conclusion
The effluent of Cobetter DLHPVND series cartridge filters meets the USP <643> for Total Organic Carbon
and USP <645> for Water Conductivity per WFI requirements after a water flush of recommended
pre-flush volume.
39
8. Particle Shedding
Summary of Method
Cobetter DLHPVND series cartridge filters were autoclaved at 130 °C for 30 minutes prior to testing.
The test devices and connected tubing were pre-flushed until the system condition meets the testing
requirements. The filters were flushed with prefiltered purified water at a flow rate of 1 L/min for a total of
20 L. The filter effluent was analyzed by following USP <788> Method 1 (light obscuration particle count
test) for particle shedding.
Particle Shedding Test Schematic
To Purified Water
Particle Counter
Valve Valve
Pump Prefilter Test Filter Drain
Particle Requirements for Large Volume Parenterals in USP <788>
Particle Size (μm) Requirements
≥ 10 ≤ 25 particles/mL
≥ 25 ≤ 3 particles/mL
40
Particle Count — Cobetter DLHPVND 0.22+0.1 m Cartridge Filter
25.7 3.2
Particles (≥ 10 μm) Count (Particles /mL)

25.0 3.0
2.1 ≥ 10 m Lot# A025878420 ≥ 25 m Lot# A025878420 0.6

≥ 10 m Lot# A025268308 ≥ 25 m Lot# A025268308
≥ 10 m Lot# A022307A14 ≥ 25 m Lot# A022307A14
1.4 USP <788> Specification for Large Volume Parenterals 0.4
0.7 0.2
0.0 0.0
0 2 4 6 8 10 12 14 16 18 20
Flush Volume (L)
Particle Count — Cobetter DLHPVND 0.22+0.22 μm Cartridge Filter
26.2 3.2

25.0 3.0
3.6 ≥ 10 m Lot# A024608206 ≥ 25 m Lot# A024608206 0.6

≥ 10 m Lot# A026158509 ≥ 25 m Lot# A026158509
≥ 10 m Lot# A024948226 ≥ 25 m Lot# A024948226
1.2 0.2
0.0 0.0
0 2 4 6 8 10 12 14 16 18 20
Flush Volume (L)
41
Particle Count — Cobetter DLHPVND 0.45+0.22 μm Cartridge Filter
26.2 3.2

25.0 3.0
3.6 ≥ 10 m Lot# A024098109 ≥ 25 m Lot# A024098109 0.6

≥ 10 m Lot# A023958105 ≥ 25 m Lot# A023958105
≥ 10 m Lot# A023757C18 ≥ 25 m Lot# A023757C18
1.2 0.2
0.0 0.0
0 2 4 6 8 10 12 14 16 18 20
Flush Volume (L)
25.3 3.2

25.0 3.0
0.9 ≥ 10 m Lot# A027118717 ≥ 25 m Lot# A027118717 0.6

≥ 10 m Lot# A026928705 ≥ 25 m Lot# A026928705
≥ 10 m Lot# A027128717 ≥ 25 m Lot# A027128717
0.3 0.2
0.0 0.0
0 2 4 6 8 10 12 14 16 18 20
Flush Volume (L)
42
25.6 3.2

25.0 3.0
1.8 ≥ 10 m Lot# A172909301 ≥ 25 m Lot# A172909301 0.6

≥ 10 m Lot# A171528C14 ≥ 25 m Lot# A171528C14
≥ 10 m Lot# A170458928 ≥ 25 m Lot# A170458928
0.6 0.2
0.0 0.0
0 2 4 6 8 10 12 14 16 18 20
Flush Volume (L)
Conclusion
The particle count of autoclaved Cobetter DLHPVND series cartridge filters effluent meets the require-
ments in USP <788> for large volume parenterals.
43
9. Non-fiber Releasing
Filters for liquid filtration used in the manufacture, processing, or packaging of injectable drug products
intended for human use shall not release fibers into such products that is being filtered.
“Non-fiber Releasing Filter ” and “Fiber “ are defined in 21 CFR 210.3 (b) (6). “Non-fiber-releasing filter
means any filter, which after any appropriate pretreatment such as washing or flushing, will not release
fibers into the component or drug product that is being filtered.” “Fiber means any particulate contami-
nant with a length at least three times greater than its width.”
Summary of Method
Cobetter DLHPVND series cartridge filters were autoclaved at 130 °C for 30 minutes prior to testing. The
filter was flushed with prefiltered purified water at a flow rate of 1 L/min for a total of 10 L. The filter
effluent was filtered through 0.8 µm black gridded disc filter to collect any fibers released from the filters.
The disc filter was examined under 50x microscope for presence of any fibers.
Non-fiber Releasing Test Schematic
To P ur ified Wat er
Valve Valve
Pump Prefilter Test Filter Fiber Collection Filter Drain
44
Results
Lot Number Number of Fibers in Effluent
Cobetter DLHPVND 0.22+0.1 m cartridge filter
A025878420 0
A025268308 0
A022307A14 0
A024608206 0
A026158509 0
A024948226 0
A024098109 0
A023958105 0
A023757C18 0
A027118717 0
A026928705 0
A027128717 0
A172909301 0
A171528C14 0
A170458928 0
Conclusion
Cobetter DLHPVND series cartridge filters meet the criteria for a “Non-fiber-releasing filter” as defined in
21 CFR 210.3 (b) (6).
45
10. Bacterial Endotoxins Test

Bacterial endotoxins test for Cobetter DLHPVND cartridge filters was performed according to current
USP <85> BACTERIAL ENDOTOXINS TEST . The Bacterial Endotoxins Test (BET ) is a test to detect or quantify
endotoxins from Gram-negative bacteria using amoebocyte lysate from the horseshoe crab (Limulus
polyphemus or Tachypleus tridentatus ).
Summary of Method
Cobetter DLHPVND series cartridge filters were installed in non-pyrogenic stainless steel housing then
filled with endotoxin free water (Water for BET ) and static soaking for 1 hour at ambient room tempera-
ture. Samples were then taken and evaluated using the Limulus Amebocyte Lysate (LAL) gel clot test with
a sensitivity of 0.25 EU/mL ( = 0.25 EU/mL).
Preparation of solutions
Endotoxin Solution to Which

/
Solution Concentration Endotoxin Is Added Number of Replicates
A Sample solution None / Sample Solution 2
B Positive product control 2 / Sample Solution 2
C Positive control 2 / Water for BET 2
D Negative control None / Water for BET 2
Prepare Solution A and the positive product control Solution B using Sample solution. The positive control
Solutions B and C contain the Standard Endotoxin Solution at a concentration corresponding to twice the
labeled lysate sensitivity. The negative control Solution D consists of Water for BET .
Incubate the reaction mixture at 37 ± 1 °C for 60 ± 2 minutes, avoiding vibration. To test the integrity of
the gel, take each tube in turn directly from the incubator, and invert it through about 180° in one smooth
motion. If a firm gel has formed that remains in place upon inversion, record the result as positive.
A result is negative if an intact gel is not formed. The test is considered valid when both replicates of
Solutions B and C are positive and those of Solution D are negative. When a negative result is found for
both replicates of Solution A , the preparation under test complies with the test. When a positive result is
found for both replicates of Solution A , the preparation under test does not comply with the test.
46
Results
Lysate Sensitivity Solution Result

(EU/mL) Lot Number A B C D (EU/mL)
DLHPVND 0.22+0.1 m cartridge filter
0.25 A025878420 ——

++ ++ ——

< 0.25
0.25 A025268308 ——

++ < 0.25
0.25 A022307A14 ——

++ < 0.25
0.25 A024608206 ——

++ ++ ——

< 0.25
0.25 A026158509 ——

++ < 0.25
0.25 A024948226 ——

++ < 0.25
0.25 A024098109 ——

++ ++ ——

< 0.25
0.25 A023958105 ——

++ < 0.25
0.25 A023757C18 ——

++ < 0.25
0.25 A027118717 ——

++ ++ ——

< 0.25
0.25 A026928705 ——

++ < 0.25
0.25 A027128717 ——

++ < 0.25
0.25 A027118717 ——

++ ++ ——

< 0.25
0.25 A026928705 ——

++ < 0.25
0.25 A027128717 ——

++ < 0.25
Legend: ' + ' —— A firm gel has formed that remains in place upon inversion, Positive.
'—' —— An intact gel is not formed, Negative.
Conclusion
The aqueous extraction of Cobetter DLHPVND series cartridge filters contains < 0.25 EU/mL as determined
by Limulus Amebocyte Lysate (LAL), meeting the requirements of USP monographs for Sterile Water for
Injection .
47
11. USP <87> Biological Reactivity Test, In Vitro

USP <87> Biological Reactivity Test, In Vitro is designed to determine the biological reactivity of mamma-
lian cell cultures following contact with the elastomeric plastics and other polymeric materials with direct
or indirect patient contact or of specific extracts prepared from the materials under test.
Conclusion
The component materials of Cobetter DLHPVND series filters meet the requirement of USP <87> Biological
Reactivity Test, In Vitro .
48
12. USP <88> Class VI Biological Reactivity Test, In Vivo
USP <88> Biological Reactivity Test, In Vivo is designed to determine the biological response of animals to
elastomerics, plastics, and other polymeric material with direct or indirect patient contact, or by the injec-
tion of specific extracts prepared from the material under tes.
USP <88> Class VI-121 °C Biological Reactivity Tests were performed on all components of Cobetter
DLHPVND series cartridge filters to estimate the biosafety. The tests were conducted in an accredited,
independent laboratory following Good Laboratory Practices.
Summary of Method
The current USP<88> Class VI-121 °C Plastics tests, including the following tests:
Procedure Animal Test Material
Systemic Injection Test Mouse

• Extract of Sample in Sodium Chloride Injection
Intracutaneous Test Rabbit or Guinea Pig • Extract of Sample in 1 in 20 Solution of Alcohol
in Sodium Chloride Injection
• Extract of Sample in Polyethylene Glycol 400
• Extract of Sample in Vegetable Oil
Implantation Test Rabbit Implant strips of Sample
Conclusion
The component materials of Cobetter DLHPVND series filters meet the criteria of the USP <88> Biological
Reactivity Test for Class VI-121 °C plastics.
49
13. FDA 21 CFR Indirect Food Additive

The raw materials used to manufacture Cobetter DLHPVND series filters were confirmed to be fully
compliant with the Federal Food, Drug and Cosmetic Act and applicable food additive regulations.
Results
Component Materials FDA 21 CFR Reference
Membranes Polyvinylidene fluoride 177.2510
Supports Polypropylene 177.1520
Core, cage, end caps Polypropylene 177.1520
Capsule Housing Polypropylene 177.1520
O-rings Silicone 177.2600
O-rings EPDM 177.2600
O-rings FEP/PFA encapsulated 177.1550

Fluoroelastomer
50
Sales and Technical Assistance
86-571-87704359 (English)
86-571-87704270 (Japanese)
86-571-87704256
sales@cobetterfilter.com
Cobetter Filtration Equipment Co., Ltd

19/F Block B, Huanyu Business Center, No.626, Kejiguan Road,
Binjiang District, Hangzhou, 310052, China
Daqiao Industry Park, Heshang Town,
Xiaoshan District, Hangzhou, 311265, China
http://www.cobetterfiltration.com Version 8.3 2020 | Specifications subject to change without notice.

Validation Guide For Cobetter DLHPVND Series Hydrophilic Filters - en V8.3 202005

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Validation Guide For Cobetter DLHPVND Series Hydrophilic Filters - en V8.3 202005

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Validation Guide

Cobetter DLHPVND Series Filters

II. Product Specifications ........................................................................................................................................2

1. Catalogue Numbers Description .................................................................................................................2

III. Performance Verification....................................................................................................................................6

3. Water Flow Rate ...........................................................................................................................................19

4. Thermal Resistance .....................................................................................................................................23

5. Chemical Compatibility ...............................................................................................................................31

6. Extractables (NVR) .......................................................................................................................................33

7. Total Organic Carbon (TOC) and Conductivity ..........................................................................................34

8. Particle Shedding ........................................................................................................................................40

9. Non-fiber Releasing ....................................................................................................................................44

10. Bacterial Endotoxins Test ............................................................................................................................46

11. USP <87> Biological Reactivity Test, In Vitro ..............................................................................................48

12. USP <88> Class VI Biological Reactivity Test, In Vivo ................................................................................49

13. FDA 21 CFR Indirect Food Additive .............................................................................................................50

Raw Material Control

Quality and Environment Management

Lot Release and Traceability

II. Product Specifications

DOE HTF HSF HTCG HSCG

Cobetter WSF Capsule Filter with DLHPVND 0.22+0.22 μm Membrane

Capsule Type Capsule Size Membrane Type Pore Size

Bricap®1 T20 Capsule Filter with Cobetter DLHPVND 0.45+0.22 μm Membrane

Capsule Size Pore Size Quantity per package

Inlet, Outlet & Gauge Port Type Sterilization

1 Bricap is trademark of Cobetter capsule ﬁlter.

Filter DLHPVND 0.22+0.1 μm DLHPVND 0.22+0.22 μm DLHPVND 0.45+0.22 μm

Diameter 69.0 mm (2.7 in.)

Effective Filtration Area (EFA) 2 2

Maximum Operating Pressure 6.9 bar (100 psi) at 25 °C

Cobetter DLHPVND 0.45+0.45 μm Cartridge Filter

Filter DLHPVND 0.45+0.45 μm

Diameter 69.0 mm (2.7 in.)

Effective Filtration Area (EFA) 0.58 m2 (6.2 ft2)

Maximum Operating Pressure 6.9 bar (100 psi) at 25 °C

Filter DLHPVND 0.65+0.45 μm

Diameter 69.0 mm (2.7 in.)

Effective Filtration Area (EFA) 0.58 m2 (6.2 ft2)

Maximum Operating Pressure 6.9 bar (100 psi) at 25 °C

III. Performance Verification

Bacterial Challenge Test Schematic

Puriﬁed Water Pressure

A023737C15 4.263 1.94 × 1011 Sterile 7.52

A024118109 4.244 1.94 × 1011 Sterile 7.52

A023787C18 4.040 9.76 × 1010 Sterile 7.23

A023707C16 3.959 7.26 × 1010 Sterile 7.10

A024788210 3.918 1.10 × 1011 Sterile 7.28

A022927B15 3.713 1.83 × 1011 Sterile 7.50

A022277A14 3.666 9.76 × 1010 Sterile 7.23

A022927C15 3.62 1.46 × 1011 Sterile 7.40

A023918103 3.507 1.46 × 1011 Sterile 7.40

A022287A14 3.479 1.20 × 1011 Sterile 7.32

A024778210 3.471 9.67 × 1010 Sterile 7.22

A023627C13 3.422 9.67 × 1010 Sterile 7.22

A022237A13 3.184 8.47 × 1010 Sterile 7.16

A023757C18 3.100 7.36 × 1010 Sterile 7.10

A023727C15 2.910 8.47 × 1010 Sterile 7.16

A022927C15 2.785 7.57 × 1010 Sterile 7.12

A024108109 2.676 9.76 × 1010 Non sterile <7

Correlation of the ASTM Bacteria Challenge Tests

≥ 3.2 bar (46 psi) in water at 20 °C.

Hydraulic Stress Test Schematic

DLHPVND 0.45+0.22 m cartridge ﬁlter

DLHPVND 0.45+0.45 m cartridge ﬁlter

DLHPVND 0.65+0.45 m cartridge ﬁlter

DLHPVND 0.45+0.22 m cartridge ﬁlter

DLHPVND 0.45+0.45 m cartridge ﬁlter

DLHPVND 0.65+0.45 m cartridge ﬁlter

DLHPVND 0.45+0.22 m cartridge ﬁlter

DLHPVND 0.45+0.45 m cartridge ﬁlter

DLHPVND 0.65+0.45 m cartridge ﬁlter