Validation Guide For Cobetter Safesure AFM Series Hydrophobic Filters - en V2.5 202101

Validation Guide
Cobetter Safesure™ AFM Filters

Sterilizing-grade hydrophobic PTFE membrane
Contents
I. Introduction .........................................................................................................................................................1
II. Product Specifications ........................................................................................................................................2
1. Catalogue Numbers Description .................................................................................................................2
2. Specifications .................................................................................................................................................4
III. Verification and Validation .................................................................................................................................8
1. Bacteria Challenge Test and Correlation with Non-Destructive Integrity Test ........................................8
2. Hydraulic Stress............................................................................................................................................12
3. Air Flow Rate ................................................................................................................................................21
4. Thermal Resistance .....................................................................................................................................29
5. Chemical Compatibility ...............................................................................................................................37
6. Extractables (NVR) .......................................................................................................................................39
7. Particle Shedding ........................................................................................................................................40
8. Non-fiber Releasing ....................................................................................................................................48
9. Bacterial Endotoxins Test ............................................................................................................................51
10. USP <88> Class VI Biological Reactivity Test, In Vivo ................................................................................54
11. FDA 21 CFR Indirect Food Additive .............................................................................................................55
i
I. Introduction
This Validation Guide provides information of Cobetter Safesure™1 AFM 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 Safesure AFM series filters to meet require-
ments of regulatory authorities within the pharmaceutical industry.
Cobetter Safesure AFM series filters contain sterilizing-grade hydrophobic polytetrafluoroethylene (PTFE)
membrane, which are designed for sterile filtration of gases 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. All the products are
manufactured 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 hierar-
chically. The 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.
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 Safesure is trademark of Cobetter PTFE membrane.
1
Validation Guide Cobetter Safesure™ AFM Hydrophobic Filters
II. Product Specifications

1. Catalogue Numbers Description
Cobetter Safesure™ AFM Cartridge Filter
A A F M B P
Cartridge Type Membrane Type Filter Length Cartridge Adapter Type O-ring Material
A - Standard AFMB - Cobetter Safesure™ 05 - 5-inch 0 - Double open end S - Silicone
cartridge AFM 0.2 m 10 - 10-inch with flat gasket E - EPDM
20 - 20-inch 2 - 226 / Flat V - Fluoroelastomer
30 - 30-inch 7 - 226 / Fin P - FEP/PFA encap-
40 - 40-inch 3 - 222 / Flat sulated O-rings
8 - 222 / Fin
Adapter Schematic
0 2 7 3 8
2
Bricap® C Capsule Filters with Cobetter Safesure™ AFM Membrane
C 0 A F M B A 1 P
Capsule Size Membrane Type Quantity per package

C01 - Bricap® C01 AFMB - Cobetter Safesure™ AFM 0.2 m 1 - 1 / pkg.
C02 - Bricap® C02
C03 - Bricap® C03
Inlet & Outlet Type Sterilization
K - 14 mm (9/16") Sanitary Flange A - Autoclavable
T - 19 mm (3/4") Sanitary Flange
F - 31 mm (1 1/4") Sanitary Flange
Y - 9.6 mm (3/8") Hose Barb
B - 6-13 mm (1/4"-1/2") Stepped Hose Barb
2 Bricap is trademark of Cobetter capsule filter.
2
Bricap® L Capsule Filters with Cobetter Safesure™ AFM Membrane
L A F M B A 1 P

L02 - Bricap® L02 AFMB - Cobetter Safesure™ AFM 0.2 m 1 - 1 / pkg.
L03 - Bricap® L03
L05 - Bricap® L05
L10 - Bricap® L10
Inlet & Outlet Type Sterilization
S - 38 mm (1 1/2") Sanitary Flange A - Autoclavable
T - 19 mm (3/4") Sanitary Flange
K - 14 mm (9/16") Sanitary Flange
D - 25 mm (1") Hose Barb
M - 19 mm (3/4") Hose Barb
X - 16 mm (5/8") Hose Barb
V - 14 mm (9/16") Hose Barb
H - 13 mm (1/2") Hose Barb
Y - 9.6 mm (3/8") Hose Barb
3
Brisip® SP3 Capsule Filters with Cobetter Safesure™ AFM Membrane
S P 3 S S A F M B 1 P

SP3 - Brisip® SP3 AFMB - Cobetter Safesure™ 1 - 1 / pkg.
AFM 0.2 m
Inlet & Outlet Type Vent and Drain Valves

S - 38 mm (1-1/2") Sanitary Flange P - Both vent and drain valves using 6 mm (1/4") hose barb
X - Vent valve using quick coupling (compatible with
Stäubli connector), and drain valve is 6 mm (1/4")
hose barb.
T - Both vent and drain valves using quick coupling
(compatible with Stäubli connector).
3 Brisip is trademark of Cobetter capsule filter.
3
2. Specifications
Cobetter Safesure™ AFM Cartridge Filter (Per 10-inch Cartridge)
Filter Cobetter Safesure AFM

Length 254.0 mm (10 in.)
Materials of Construction
Filter membrane Hydrophobic polytetrafluoroethylene (PTFE)
Supports Polypropylene
Core, cage, end caps Polypropylene
Adapter internal support Stainless steel 316L
O-rings Silicone, EPDM, Fluoroelastomer
Pore Size 0.2 μm
Effective Filtration Area (EFA) 0.68 m2 (7.3 ft2)
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
Bubble Point at 20 °C ≥ 1.1 bar (16 psi) in 60% isopropanol (IPA) 40% water, air
Air Diffusion at 20 °C ≤ 24 mL/min at 0.95 bar (14 psi) wetted with 60% isopropanol (IPA) 40% water
Water Intrusion at 20 °C ≤ 0.75 mL/min at 2.5 bar (36 psi)
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 145 °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 200 cycles for 30 minutes at 130 °C.
Particle Shedding Autoclaved filter effluent meets the requirements in USP <788> for large volume parenterals.
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 <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.
4
Bricap® C Capsule Filters with Cobetter Safesure™ AFM Membrane
Filter Bricap C01 Bricap C02 Bricap C03

Capsule housing Polypropylene
Vent O-rings Silicone
Vent / Drain 6 mm (1/4 in.) hose barb with O-ring seal
Pore Size 0.2 μm
Effective Filtration Area (EFA) 0.020 m2 (0.2 ft2) 0.048 m2 (0.5 ft2) 0.075 m2 (0.8 ft2)

1.0 bar (15 psi) at 80 °C
1.0 bar (15 psi) at 80 °C
Sterilization
Autoclave Can be autoclaved 50 cycles for 30 minutes at 130 °C. (Cannot be steam sterilized in-line)
Particle Shedding 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 contains < 0.25 EU/mL as determined by Limulus Amebocyte Lysate
(LAL), USP <85>.
177–182.
5
Bricap® L Capsule Filters with Cobetter Safesure™ AFM Membrane
Filter Bricap L02 Bricap L03 Bricap L05 Bricap L10

Capsule housing Polypropylene
Vent / Drain 6 mm (1/4 in.) hose barb with O-ring seal
Pore Size 0.2 μm
Effective Filtration Area (EFA) 0.14 m2 (1.5 ft2) 0.20 m2 (2.2 ft2) 0.34 m2 (3.7 ft2) 0.68 m2 (7.3 ft2)

1.0 bar (15 psi) at 80 °C
1.0 bar (15 psi) at 80 °C
Air Diffusion at 20 °C 60% isopropanol (IPA) 40% water wetted, at a test pressure of 2.75 bar (40 psi):
N/A N/A ≤ 12 mL/min ≤ 24 mL/min
Water Intrusion at 20 °C at 2.5 bar (36 psi)
≤ 0.15 mL/min ≤ 0.22 mL/min ≤ 0.38 mL/min ≤ 0.75 mL/min
Bacterial Retention Retention of 10 cfu/cm Brevundimonas diminuta (ATCC® 19146) according to ASTM F838.
7 2
Sterilization
Autoclave Can be autoclaved 50 cycles for 30 minutes at 130 °C. (Cannot be steam sterilized in-line)
Particle Shedding 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).
(LAL), USP <85>.
177–182.
6
Brisip® SP3 Capsule Filters with Cobetter Safesure™ AFM Membrane
Filter Brisip SP3

Overall Length 159 mm (6.26 in.)
Body Diameter 81 mm (3.19 in.)
Capsule housing Polyetherimide
Adapter internal support Stainless steel 316L
O-rings Silicone
Pore Size 0.2 m
Effective Filtration Area (EFA) 0.2 m2 (2.2 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 Intrusion at 20 °C ≤ 0.25 mL/min at 2.5 bar (36 psi)
Sterilization
Steam in place Can be steam sterilized 10 cycles of 30 minutes at 142 °C (< 0.3 bar, 5 psi).
Autoclave Can be autoclaved for 50 cycles of 30 minutes at 131 °C.
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).
(LAL), USP <85>.
177–182.
7
III. Verification and Validation

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 Safesure AFM 0.2 m
cartridge filter 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 also should be
conducted after the filter is used in order to detect any filter leaks or perforations that may have occurred
during the filtration.”
8
Summary of Method
Cobetter Safesure AFM 0.2 m cartridge filters were tested with water intrusion at a pressure of 2.5 bar and
then steamed at 145 °C for 30 minutes prior to testing. The cartridge filters were wetted with 60% isopro-
panol (IPA) 40% water and subjected to integrity test. The filters were flushed with prefiltered water to
remove IPA and then challenged with Brevundimonas diminuta (ATCC® 19146) of the challenge level over
1×107 cfu/cm2 (EFA) 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
9
Cobetter Safesure AFM 0.2 μm Cartridge Filter (AAFMB107SP)
Water Intrusion Challenge Level

Lot Number @ 2.5 bar (mL/min) (cfu/unit) Filtrate Sterility LRV/cm2
YEG8288B17 0.19 1.82 × 1011 Sterile 7.43
11
YEG8148B17 0.20 1.22 × 10 Sterile 7.25
YEG8278B17 0.22 1.38 × 1011 Sterile 7.31

11
YCJ9158A08 0.24 1.22 × 10 Sterile 7.25
YCJ9158A09 0.29 7.88 × 1010 Sterile 7.06

11
YCJ9078A09 0.29 1.03 × 10 Sterile 7.18
YCJ9268A09 0.34 8.47 × 1010 Sterile 7.10

11
YCJ9258A10 0.34 1.82 × 10 Sterile 7.43
YCJ9118A11 0.35 1.38 × 1011 Sterile 7.31

11
YEG8138B17 0.38 1.44 × 10 Sterile 7.33
YEG8068B01 0.42 9.11 × 1010 Sterile 7.13

11
YEG8368B01 0.42 1.01 × 10 Sterile 7.17
YEG8018B03 0.43 9.52 × 1010 Sterile 7.15

10
YEG8298B03 0.45 9.52 × 10 Sterile 7.15
YEG8228B12 0.46 1.82 × 1011 Sterile 7.43

11
YEG8158B12 0.50 1.44 × 10 Sterile 7.33
YEG8198B12 0.54 1.03 × 1011 Sterile 7.18

11
YEG8288B13 0.57 1.44 × 10 Sterile 7.33
YEG8118B13 0.60 1.01 × 1011 Sterile 7.17

10
YCG8228B13 0.60 7.88 × 10 Sterile 7.06
YEG8168B13 0.61 7.94 × 1010 Sterile 7.07

11
YEG8148B17 0.63 1.38 × 10 Sterile 7.31
YEG8278B17 0.68 1.22 × 1011 Sterile 7.25

11
YCJ9158A09 0.72 1.16 × 10 Sterile 7.23
YCJ9078A09 0.74 1.01 × 1011 Sterile 7.17

11
YCJ9268A09 0.76 1.16 × 10 Sterile 7.23
YCJ9258A10 0.79 1.03 × 1011 Sterile 7.18

10
YEG8138B17 0.84 9.52 × 10 Sterile 7.15
YEG8368B01 0.85 9.11 × 1010 Sterile 7.13

10
YEG8018B03 0.89 8.47 × 10 Sterile 7.10
YEG8298B03 0.91 7.94 × 1010 Sterile 7.07

10
YEG8228B12 0.94 9.11 × 10 Sterile 7.13
YEG8158B12 0.96 8.47 × 1010 Non Sterile <7

10
YEG8198B12 0.98 7.88 × 10 Non Sterile <7
YEG8118B13 1.01 7.94 × 1010 Non Sterile <7

11
YCG8228B13 1.04 1.16 × 10 Non Sterile <7
10
Conclusion
Correlation of the ASTM Bacteria Challenge Tests

with Non-Destructive Integrity Test
1.4
Water Intrusion @ 2.5 bar (mL/min)
1.2 Sterile Sterile Threshold

Non sterile Water intrusion Spec
1.0
0.8
0.6
0.4
0.2
0.0
Lot No.
According to the results of the bacterial challenge test, Cobetter Safesure AFM 0.2 m cartridge filters can
completely retain a minimum concentration of 107 cfu/cm2 Brevundimonas diminuta (ATCC® 19146) with
a sterile filtrate when the water intrusion of tested filters is less than 0.94 mL/min. Taking into account the
safety factor, the integrity specifications for Cobetter Safesure AFM 0.2 m cartridge filter are set to:
Water Intrusion ≤ 0.75 mL/min at 2.5 bar (36 psi), 20 °C.
Diffusion ≤ 24 mL/min at 0.95 bar (14 psi), wetted with 60% isopropanol (IPA) 40% water at 20 °C.
Bubble Point ≥ 1.1 bar (16 psi) wetted with 60% isopropanol (IPA) 40% water at 20 °C.
11
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 the 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)
12
2.1. Hydraulic Stress Test at 25 °C
Summary of Method
Cobetter Safesure AFM cartridge filters were steamed at 145 °C for 30 minutes. Brisip SP3 capsule filters
with Cobetter Safesure AFM membrane were steamed at 142 °C for 30 minutes. Bricap series capsule
filters with Cobetter Safesure AFM membrane were autoclaved at 130 °C for 30 minutes prior to testing.
The filters were wetted with 60% isopropanol (IPA) 40% water and then integrity tested.
Cobetter Safesure AFM cartridge 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.
Capsule filters were plugged with test dust to increase the differential pressure across the upstream
and downstream of the filter. A hydraulic stress of 5.5 bar was applied to the capsules at 25 °C for
30 minutes in the forward direction with 6 cycles. Then a differential pressure of 2.1 bar was applied to
the capsules at 25 °C for 10 minutes in the reverse direction with 3 cycles.
The filter integrity test was carried out to find any changes in the process of the hydraulic stress tests.
Cobetter Safesure AFM Cartridge Filter (AAFMB107SP)
Prior to Hydraulic Stress Post Hydraulic Stress

Bubble Point Diffusion @ 0.95 bar Bubble Point Diffusion @ 0.95 bar
Lot Number (bar) (mL/min) (bar) (mL/min)
YEG8288B17 1.816 8.4 1.839 8.3
YCJ9158A08 1.737 8.8 1.796 8.5
YEG8068B01 1.922 8.6 1.884 8.6
13
Bricap C Capsule Filters with Cobetter Safesure AFM Membrane
Bubble Point (bar)
Lot Number Prior to Hydraulic Stress Post Hydraulic Stress
Bricap C01 capsule filter (C01FFAFMBA1P)
YKG8049619 1.821 1.766
YMF5139921 1.857 1.819
YKH6089403 1.830 1.851
YKG8049619 1.815 1.788
YMF5139921 1.791 1.780
YKH6089403 1.841 1.904
YKG8049619 1.765 1.783
YMF5139921 1.820 1.871
YKH6089403 1.892 1.867
14
Bricap L Capsule Filters with Cobetter Safesure AFM Membrane
Bubble Point (bar)
Bricap L02 capsule filter (L02SSAFMBA1P)
YKG8049619 1.662 1.607
YP68147C20 1.834 1.831
YNB4119A16 1.689 1.647
YKG8049624 1.732 1.763
YP68147C20 1.796 1.779
YNB4119A16 1.841 1.810

YGB3319123 1.602 3.2 1.604 3.2
YFB9139C24 1.704 4.6 1.637 4.7
YKG8049624 1.756 2.4 1.801 2.4
YHK6089402 1.723 5.9 1.767 5.7
YJW3079517 1.814 7.0 1.746 6.9
YKG8019716 1.898 5.9 1.885 6.1
Brisip SP3 Capsule Filter with Cobetter Safesure AFM Membrane (SP3SSAFMBX1P)
Bubble Point (bar)
YYY2200B21 1.419 1.644
YYY3090B21 1.665 1.830
Y14B200B21 1.473 1.648
Conclusion
Cobetter Safesure AFM series filters maintain integrity after a series of hydraulic stress tests at 25 °C
described above.
15

Summary of Method
Cobetter Safesure AFM cartridge filters were steamed at 145 °C for 30 minutes prior to testing. The filters
were wetted with 60% isopropanol (IPA) 40% 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 4.0 bar was applied to the filters at 60 °C for 30 minutes in
the forward direction with 6 cycles.
The filter integrity test was carried out to find any changes during the hydraulic stress tests.

YEG8288B17 1.466 8.6 1.419 8.4
YCJ9158A08 1.737 9.3 1.762 9.2
YEG8068B01 1.717 10.1 1.711 10.3
Conclusion
Cobetter Safesure AFM cartridge filter maintains integrity after a series of hydraulic stress tests at 60 °C
described above.
16
Summary of Method
Cobetter Safesure AFM cartridge filters were steamed at 145 °C for 30 minutes. Brisip SP3 capsule filters
with Cobetter Safesure AFM membrane were steamed at 142 °C for 30 minutes. Bricap series capsule
The filters were wetted with 60% isopropanol (IPA) 40% water and then integrity tested.
across the upstream and 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.
Capsule filters were plugged with test dust to increase the differential pressure across the upstream
and downstream of the filter. A hydraulic stress of 1.0 bar was applied to the capsules at 80 °C for
10 minutes in the forward direction with 6 cycles.
The filter integrity test was carried out to find any changes in the process of the hydraulic stress tests.

YEG8288B17 1.522 7.9 1.574 8.1
YCJ9158A08 1.858 8.2 1.873 8.4
YEG8068B01 1.813 9.3 1.835 9.1
17
Bricap C Capsule Filters with Cobetter Safesure AFM Membrane
Bubble Point (bar)
YKG8049619 1.645 1.592
YMF5139921 1.824 1.805
YKH6089403 1.861 1.910
YKG8049619 1.841 1.774
YMF5139921 1.844 1.796
YKH6089403 1.749 1.802
YKG8049619 1.807 1.813
YMF5139921 1.852 1.793
YKH6089403 1.789 1.838
18
Bricap L Capsule Filters with Cobetter Safesure AFM Membrane
Bubble Point (bar)
YKG8049619 1.701 1.749
YP68147C20 1.786 1.723
YNB4119A16 1.741 1.719
YKG8049624 1.759 1.710
YP68147C20 1.737 1.703
YNB4119A16 1.627 1.652

YGB3319123 1.791 3.9 1.738 3.9
YFB9139C24 1.678 3.0 1.682 3.1
YKG8049624 1.770 2.4 1.761 2.3
YHK6089402 1.783 4.8 1.794 4.7
YJW3079517 1.777 7.6 1.807 7.9
YKG8019716 1.675 8.9 1.624 9.0
Bubble Point (bar)
YYY2200B21 1.644 1.734
YYY3090B21 1.830 1.861
Y14B200B21 1.648 1.807
Conclusion
Cobetter Safesure AFM series filters maintain integrity after a series of hydraulic stress tests at 80 °C
described above.
19

Summary of Method
across the upstream and downstream of the filter, and integrity tested. Then the filters were steamed at
145 °C for 30 minutes with a differential pressure of 0.35 bar. The filter integrity test was carried out to find
any changes during the hydraulic stress tests.

YEG8288B17 1.583 8.7 1.618 8.7
YCJ9158A08 1.636 9.0 1.581 8.7
YEG8068B01 1.888 9.7 1.951 9.9
Conclusion
Cobetter Safesure AFM cartridge filter maintains integrity after a hydraulic stress test at 145 °C described
above.
20
3. Air Flow Rate
Cobetter AFM cartridge filters were steamed at 145 °C for 30 minutes. Bricap capsule filters with Cobetter
Safesure AFM membrane were autoclaved at 130 °C for 30 minutes. Brisip SP3 capsule filters with
Cobetter Safesure AFM membrane were wetted with water and steamed at 142 °C for 30 minutes. Then
the filters were dried prior to testing. The filters were installed into the air flow test device. After achieving
a constant differential pressure, the flow rate is recorded from the flow meter. The graph was plotted after
the pressure drop were measured from the filters at various air flow rates.
Air Flow Rate Test Schematic
Pressure
Gauge
Thermometer
Compressed Air
Pressure
Valve Flow Meter Valve
Gauge
Buffer Tank Test Filter To
Atmosphere
Cobetter Safesure AFM Cartridge Filter
Air Flow Rate — Cobetter Safesure AFM Cartridge Filter

(AAFMB107SP)
SCFM
0 20 40 60 80
0.15
Differential Pressure (bar)
psi
2.0
0 Psi Outlet
0.12
15 Psi Inlet
30 Psi Inlet 1.5
50 Psi Inlet
0.09
70 Psi Inlet
1.0
0.06
0.5
0.03
0.00 0.0
0 20 40 60 80 100 120 140 160
Air Flow Rate (Nm3/h)
21
Bricap C01 Capsule Filters
Air Flow Rate — Bricap C01 Capsule Filter with Cobetter Safesure AFM Membrane
(C01FFAFMBA1P)
SCFM
0 3 6 9 12
0.8
psi
0 Psi Outlet
10
15 Psi Inlet
0.6 30 Psi Inlet
50 Psi Inlet 8
70 Psi Inlet
0.4 6
0.2
2
0.0 0
0 4 8 12 16 20 24
3
Air Flow Rate (Nm /h)
(C01TTAFMBA1P)
SCFM
0 3 6 9 12
0.8
psi
0 Psi Outlet
10
15 Psi Inlet
0.6 30 Psi Inlet
50 Psi Inlet 8
70 Psi Inlet
0.4 6
0.2
2
0.0 0
0 4 8 12 16 20 24
22
(C02FFAFMBA1P)
SCFM
0 5 10 15 20 25
0.8
psi
0 Psi Outlet
10
15 Psi Inlet
0.6 30 Psi Inlet
50 Psi Inlet 8
70 Psi Inlet
0.4 6
0.2
2
0.0 0
0 8 16 24 32 40 48
3
(C02TTAFMBA1P)
SCFM
0 5 10 15 20 25
0.8
psi
10
0 Psi Inlet
0.6
30 Psi Inlet
8
0.4 6
0.2
2
0.0 0
0 8 16 24 32 40 48
23
(C03FFAFMBA1P)
SCFM
0 5 10 15 20 25
0.8
psi
0 Psi Outlet
10
15 Psi Inlet
0.6 30 Psi Inlet
50 Psi Inlet 8
70 Psi Inlet
0.4 6
0.2
2
0.0 0
0 8 16 24 32 40 48
3
(C03TTAFMBA1P)
SCFM
0 5 10 15 20 25
0.8
psi
10
0 Psi Inlet
0.6
30 Psi Inlet
8
0.4 6
0.2
2
0.0 0
0 8 16 24 32 40 48
24
Bricap L02 Capsule Filters
Air Flow Rate — Bricap L02 Capsule Filter with Cobetter Safesure AFM Membrane
(L02SSAFMBA1P)
SCFM
0 15 30 45 60
0.8
psi
0 Psi Outlet
10
15 Psi Inlet
0.6 30 Psi Inlet
50 Psi Inlet 8
70 Psi Inlet
0.4 6
0.2
2
0.0 0
0 20 40 60 80 100 120
3
(L02TTAFMBA1P)
SCFM
0 8 16 24 32
0.5
0 Psi Outlet 6 psi

0.4
15 Psi Inlet
30 Psi Inlet
50 Psi Inlet
0.3
70 Psi Inlet 4
0.2
2
0.1
0.0 0
0 10 20 30 40 50 60
25
Bricap L03 Capsule Filters
(L03SSAFMBA1P)
SCFM
0 15 30 45 60
0.4
psi
0 Psi Outlet
5
15 Psi Inlet
0.3 30 Psi Inlet
50 Psi Inlet 4
70 Psi Inlet
0.2 3
0.1
1
0.0 0
0 20 40 60 80 100 120
3
(L03TTAFMBA1P)
SCFM
0 15 30 45 60
1.0
0 Psi Outlet 12 psi

0.8
15 Psi Inlet
30 Psi Inlet
50 Psi Inlet 9
0.6
70 Psi Inlet
0.4 6
0.2 3
0.0 0
0 20 40 60 80 100 120
26
Bricap L05 Capsule Filter
(L05SSAFMBA1P)
SCFM
0 15 30 45 60
0.25
psi
0 Psi Outlet 3
0.20
15 Psi Inlet
30 Psi Inlet
50 Psi Inlet
0.15
70 Psi Inlet 2
0.10
1
0.05
0.00 0
0 20 40 60 80 100 120
3
Bricap L10 Capsule Filter
(L10SSAFMBA1P)
SCFM
0 15 30 45 60
0.10
psi
0 Psi Outlet
1.2
0.08
15 Psi Inlet
30 Psi Inlet
50 Psi Inlet 0.9
0.06
70 Psi Inlet
0.04 0.6
0.02 0.3
0.00 0.0
0 20 40 60 80 100 120
27
Brisip SP3 Capsule Filter with Cobetter Safesure AFM Membrane
Air Flow Rate — Brisip SP3 Capsule Filter with Cobetter Safesure AFM Membrane
(SP3SSAFMBX1P)
SCFM
0 20 40 60 80
0.8
psi
0 Psi Outlet
10
15 Psi Inlet
0.6 30 Psi Inlet
50 Psi Inlet 8
70 Psi Inlet
0.4 6
0.2
2
0.0 0
0 30 60 90 120 150
28
4. Thermal Resistance
Cobetter Safesure AFM cartridge filter and Brisip SP3 capsule filter can be either steamed in place (SIP)
or autoclaved. Bricap capsule filters with Cobetter Safesure AFM membrane can be autoclaved. Since
multiple autoclave sterilization may be required in actual use, the influences of the sterilization on the
performances of Cobetter Safesure AFM filters were examined. As a result, recommendations and limits
for multiple sterilization are given below.
Cobetter Safesure AFM series filters were subjected to integrity test prior to testing.
Cobetter Safesure AFM cartridge filters and Brisip SP3 capsule filters were installed in the steam steril-
ization device in the forward direction. The steam valve and downstream valve were slowly adjusted
to increase the temperature to 145 °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 145 °C for 30 minutes. After a 30-minute steam sterilization, 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. Continually 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 cycles had been achieved for
each cartridge filter. Brisip capsule SP3 filters were steam sterilized at 142 °C for 30 minutes with 10 cycles
under the differential pressure less than 0.1 bar. Cobetter Safesure AFM cartridge filters were installed in
the steam sterilization device in the reverse direction. The cartridge filters were steam sterilized at 145 °C
for 30 minutes with 50 cycles in the reverse direction under the differential pressure less than 0.1 bar.
Cobetter Safesure AFM cartridge filters were wraped with tinfoil or cleansteam bag. The cartridge filters
were autoclaved 200 cycles at 130 °C for 30 minutes.
Bricap capsule filters were wraped the inlet and outlet of the capsules with tinfoil or cleansteam bag,
loosening the vent valve. The Bricap capsule filters were autoclaved 50 cycle 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
29
4.1. Cobetter Safesure AFM Cartridge Filter (AAFMB107SP)
Lot Number Prior to Sterilization After Multiple Steam Cycles
After 150 SIP cycles
YEG8288B17 0.23 0.25
YCJ9158A08 0.22 0.24
YEG8068B01 0.18 0.20
After 200 autoclave cycles
YEG8288B17 0.22 0.24
YCJ9158A08 0.20 0.23
YEG8068B01 0.22 0.24
Effect on Water Intrusion

—— Cobetter Safesure AFM Cartridge Filter
0.32
0.24
0.16
0.08
Prior to Sterilization
0.00 After 150 SIP Cycles

YEG8288B17 YCJ9158A08 YEG8068B01
Effect on Water Intrusion

—— Cobetter Safesure AFM Cartridge Filter
0.32
0.24
0.16
0.08
0.00 After 200 Autoclave Cycles

YEG8288B17 YCJ9158A08 YEG8068B01
30
4.2. Cobetter Bricap C01 Capsule Filter (C01FFAFMBA1P)
Bubble Point (bar)
Lot Number Prior to Sterilization After 50 Autoclave Cycles
YKG8049619 1.688 1.766
YMF5139921 1.636 1.751
YKH6089403 1.788 1.900
Effects on Bubble Point —— Bricap C01 Capsule Filter

with Cobetter Safesure AFM Membrane
2.4
Bubble Point (bar)
psi
32
1.8
24
1.2 16
0.6 8
0.0 0 After 50 Autoclave Cycles

YKG8049619 YMF5139921 YKH6089403
Bubble Point (bar)
YKG8049619 1.753 1.894
YMF5139921 1.631 1.743
YKH6089403 1.731 1.841

2.4
Bubble Point (bar)
psi
32
1.8
24
1.2 16
0.6 8

YKG8049619 YMF5139921 YKH6089403
31
Bubble Point (bar)
YKG8049619 1.655 1.783
YMF5139921 1.723 1.828
YKH6089403 1.760 1.881

2.4
Bubble Point (bar)
psi
32
1.8
24
1.2 16
0.6 8

YKG8049619 YMF5139921 YKH6089403
4.5. Cobetter Bricap L02 Capsule Filter (L02SSAFMBA1P)
Bubble Point (bar)
YKG8049619 1.736 1.855
YP68147C20 1.776 1.892
YNB4119A16 1.647 1.749
Effects on Bubble Point —— Bricap L02 Capsule Filter

2.4
Bubble Point (bar)
psi
32
1.8
24
1.2 16
0.6 8

YKG8049619 YP68147C20 YNB4119A16
32
Bubble Point (bar)
YKG8049624 1.623 1.660
YP68147C20 1.794 1.910
YNB4119A16 1.701 1.789

2.4
Bubble Point (bar)
psi
32
1.8
24
1.2 16
0.6 8

YKG8049624 YP68147C20 YNB4119A16
33
Prior to Sterilization After 50 Autoclave Cycles

Bubble Point Water Intrusion Bubble Point Water Intrusion
Lot Number (bar) @ 2.5 bar (mL/min) (bar) @ 2.5 bar (mL/min)
YGB3319123 1.678 0.09 1.782 0.10
YFB9139C24 1.717 0.10 1.838 0.09
YKG8049624 1.625 0.09 1.683 0.09

2.4
Bubble Point (bar)
psi
32
1.8
24
1.2 16
0.6 8

YGB3319123 YFB9139C24 YKG8049624
Effect on Water Intrusion —— Bricap L05 Capsule Filter

0.16
0.12
0.08
0.04

YGB3319123 YFB9139C24 YKG8049624
34
Prior to Sterilization After 50 Autoclave Cycles

YHK6089402 1.726 0.20 1.836 0.20
YJW3079517 1.612 0.19 1.709 0.20
YKG8019716 1.722 0.19 1.804 0.20

2.4
Bubble Point (bar)
psi
32
1.8
24
1.2 16
0.6 8

YHK6089402 YJW3079517 YKG8019716
Effect on Water Intrusion —— Bricap L10 Capsule Filter

0.32
0.24
0.16
0.08

YHK6089402 YJW3079517 YKG8019716
35
4.9. Brisip SP3 Capsule Filter (SP3SSAFMBX1P)

Steam in Place
Prior to Sterilization After 10 SIP Cycles

YXU6270924 1.694 0.04 1.525 0.06
YXU6190924 1.734 0.06 1.533 0.07
YXU6230924 1.659 0.05 1.460 0.06
Effect on Bubble Point —— Brisip SP3 Capsule Filter

2.0
Bubble Point (bar)
psi
25
1.5
20
1.0 15
10
0.5
5 Prior to Sterilization
0.0 0 After 10 SIP Cycles

YXU6270924 YXU6190924 YXU6230924
Effect on Water Intrusion —— Brisip SP3 Capsule Filter

0.08
0.06
0.04
0.02
0.00 After 10 SIP Cycles

YXU6270924 YXU6190924 YXU6230924
Conclusion
The results indicate that the integrity of the Cobetter Safesure AFM series filters is not affected by the
recommended sterilization methods.
36
5. Chemical Compatibility
Summary of Method
The evaluation of chemical compatibility for Cobetter Safesure AFM series filters was determined using a
48-hour static soak in the test solvent at 25 °C.
Results
O-rings
Cartridge
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% R N N N
Hydrochloric Acid, 20% R N N L
Hydrochloric Acid, 3.3% R R N R
Nitric Acid, conc. 67% L N N R
Nitric Acid, 27% R N L R
Sulfuric Acid, conc. 96% R N — R
Sulfuric Acid, 16% R N — R
Ammonium Hydroxide, 3N, 5.7% R R — R
Ammonium Hydroxide, 6N, 11.4% R R — R
Potassium Hydroxide, 15% R N R R
Sodium Hydroxide, 3N, 11% R L R R
Sodium Hydroxide, 22% R 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 L N — N
Tetrahydrofuran L N N N
Tetrahydrofuran, 50% (v-v) L — — N
Acetone R N R N
Cyclohexanone L N L N
Methyl Ethyl Ketone (MEK) R N R N
Methyl Isobutyl Ketone (MIBK) N N R N
37
O-rings
Cartridge
Solvent Element Silicone EPDM Fluoroelastomer
Amyl Acetate L 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 R N R N
Carbon Tetrachloride L N N R
Chloroform L N N R
Ethylene Dichloride L — — —
Methylene Chloride L N N N
Tetrachloroethylene L — — —
Trichloroethane N N N R
Benzene L N N R
Toluene N 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 R N R N
Dimethyl Formamide (DMF) R N N N
Dimethyl Sulfoxide (DMSO) R — — —
Kerosene R N N R
Pyridine R N N N
Petroleum Spirits N N N R
Hydrogen Peroxide L R R R
Ozone N N L N
Phenol R 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.
38
6. Extractables (NVR)
The purpose of this test was to determine the quantity of material that can be extracted from Cobetter
Safesure AFM filters using purified water and typical organic solvent.
Summary of Method
Cobetter Safesure AFM cartridge filters were autoclaved at 130 °C for 30 minutes prior to testing. Brisip
SP3 capsule filters with Cobetter Safesure AFM membrane were autoclaved at 131 °C for 30 minutes. The
quantity of gravimetric extractables for filters were determined using a 24-hour static soak in purified
water at ambient room temperature. Partial extraction solution was evaporated to dryness using a rotary
evaporator and then dried to constant weight to evaluate non-volatile residues (NVR). At the same time,
using purified water as a blank control for NVR tests.
NVR (mg/10-inch)
Lot Number Purified Water Absolute Ethanol Isopropanol
YTK8230418 1.2 19.8 13.0
YTK8560504 1.6 20.4 13.8
YTK8170505 1.4 22.4 14.4
Lot Number Extractables (mg/unit)
YYY2200B21 0.8
YYY3090B21 1.0
Y14B200B21 0.8
Conclusion
The extractable level of the Cobetter Safesure AFM filters under laboratory conditions is for reference only.
It is recommended to test under actual process conditions.
39
7. Particle Shedding
Summary of Method
Cobetter Safesure AFM cartridge filters were autoclaved at 130 °C for 30 minutes. Brisip SP3 capsule filters
with Cobetter Safesure AFM membrane were autoclaved at 131 °C for 30 minutes. Bricap series capsule
The test devices and connected tubing were pre-flushed until the system condition meets the testing
requirements.
Cobetter Safesure AFM series filters were wetted with prefiltered IPA solution, and flushed with purified
water at a flow rate of 0.2-1.0 L/min for a total of 4-20 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
Cobetter Safesure AFM Cartridge Filter
Particle Count — Cobetter Safesure AFM Cartridge Filter

(AAFMB107SP)
25.5 3.1
Particles (≥ 10 μm) Count (Particles /mL)

25.0 3.0
1.5 ≥ 10 m Lot# YEG8288B17 ≥ 25 m Lot# YEG8288B17 0.3

≥ 10 m Lot# YCJ9158A08 ≥ 25 m Lot# YCJ9158A08
≥ 10 m Lot# YEG8068B01 ≥ 25 m Lot# YEG8068B01
1.0 USP <788> Specification for Large Volume Parenterals 0.2
0.5 0.1
0.0 0.0
0 2 4 6 8 10 12 14 16 18 20
Flush Volume (L)
Cobetter Bricap C01 Capsule Filter
Particle Count — Bricap C01 Capsule Filter with Cobetter Safesure AFM Membrane
(C01FFAFMBA1P)
25.5 3.1
25.0 3.0 Particles (≥ 25 μm) Count (Particles /mL)
1.5 ≥ 10 m Lot# YKG8049619 ≥ 25 m Lot# YKG8049619 0.3

≥ 10 m Lot# YMF5139921 ≥ 25 m Lot# YMF5139921
≥ 10 m Lot# YKH6089403 ≥ 25 m Lot# YKH6089403
0.5 0.1
0.0 0.0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
Flush Volume (L)
41
Cobetter Bricap C02 Capsule Filters
(C02FFAFMBA1P)
25.8 3.2

25.0 3.0
2.4 ≥ 10 m Lot# YKG8049619 ≥ 25 m Lot# YKG8049619 0.6

≥ 10 m Lot# YMF5139921 ≥ 25 m Lot# YMF5139921
≥ 10 m Lot# YKH6089403 ≥ 25 m Lot# YKH6089403
0.8 0.2
0.0 0.0
0 1 2 3 4 5 6
Flush Volume (L)
(C02TTAFMBA1P)
25.8 3.2

25.0 3.0
2.4 ≥ 10 m Lot# YKG8049619 ≥ 25 m Lot# YKG8049619 0.6

≥ 10 m Lot# YNB4039A11 ≥ 25 m Lot# YNB4039A11
≥ 10 m Lot# YMF5139921 ≥ 25 m Lot# YMF5139921
0.8 0.2
0.0 0.0
0 1 2 3 4 5 6
Flush Volume (L)
42
Cobetter Bricap C03 Capsule Filters
(C03FFAFMBA1P)
25.8 3.2

25.0 3.0
2.4 ≥ 10 m Lot# YKG8049619 ≥ 25 m Lot# YKG8049619 0.6

≥ 10 m Lot# YMF5139921 ≥ 25 m Lot# YMF5139921
≥ 10 m Lot# YKH6089403 ≥ 25 m Lot# YKH6089403
0.8 0.2
0.0 0.0
0 1 2 3 4 5 6
Flush Volume (L)
(C03TTAFMBA1P)
25.8 3.2

25.0 3.0
2.4 ≥ 10 m Lot# YKG8049619 ≥ 25 m Lot# YKG8049619 0.6

≥ 10 m Lot# YLE7129807 ≥ 25 m Lot# YLE7129807
≥ 10 m Lot# YKH6089403 ≥ 25 m Lot# YKH6089403
0.8 0.2
0.0 0.0
0 1 2 3 4 5 6
Flush Volume (L)
43
Cobetter Bricap L02 Capsule Filters
Particle Count — Bricap L02 Capsule Filter with Cobetter Safesure AFM Membrane
(L02SSAFMBA1P)
25.8 3.2

25.0 3.0
2.4 ≥ 10 m Lot# YKG8049619 ≥ 25 m Lot# YKG8049619 0.6

≥ 10 m Lot# YP68147C20 ≥ 25 m Lot# YP68147C20
0.8 0.2
0.0 0.0
0 1 2 3 4 5 6 7 8
Flush Volume (L)
(L02TTAFMBA1P)
25.8 3.2

25.0 3.0
2.4 ≥ 10 m Lot# YKG8049619 ≥ 25 m Lot# YKG8049619 0.6

≥ 10 m Lot# YP68147C20 ≥ 25 m Lot# YP68147C20
0.8 0.2
0.0 0.0
0 1 2 3 4 5 6 7 8
Flush Volume (L)
44
Cobetter Bricap L03 Capsule Filters
(L03SSAFMBA1P)
26.0 3.2

25.0 3.0
3.0 ≥ 10 m Lot# YKG8049624 ≥ 25 m Lot# YKG8049624 0.6

≥ 10 m Lot# YP68147C20 ≥ 25 m Lot# YP68147C20
1.0 0.2
0.0 0.0
0 1 2 3 4 5 6 7 8
Flush Volume (L)
(L03TTAFMBA1P)
25.8 3.2

25.0 3.0
2.4 ≥ 10 m Lot# YKG8049624 ≥ 25 m Lot# YKG8049624 0.6

≥ 10 m Lot# YP68147C20 ≥ 25 m Lot# YP68147C20
0.8 0.2
0.0 0.0
0 1 2 3 4 5 6 7 8
Flush Volume (L)
45
Cobetter Bricap L05 Capsule Filter
(L05SSAFMBA1P)
25.6 3.2

25.0 3.0
1.8 ≥ 10 m Lot# YGB3319123 ≥ 25 m Lot# YGB3319123 0.6

≥ 10 m Lot# YFB9139C24 ≥ 25 m Lot# YFB9139C24
≥ 10 m Lot# YKG8049624 ≥ 25 m Lot# YKG8049624
0.6 0.2
0.0 0.0
0 1 2 3 4 5 6 7 8 9 10
Flush Volume (L)
Cobetter Bricap L10 Capsule Filter
(L10SSAFMBA1P)
25.8 3.2
25.0 3.0 Particles (≥ 25 μm) Count (Particles /mL)
2.4 ≥ 10 m Lot# YHK6089402 ≥ 25 m Lot# YHK6089402 0.6

≥ 10 m Lot# YJW3079517 ≥ 25 m Lot# YJW3079517
≥ 10 m Lot# YKG8019716 ≥ 25 m Lot# YKG8019716
0.8 0.2
0.0 0.0
0 2 4 6 8 10 12 14 16 18 20
Flush Volume (L)
46
Brisip SP3 Capsule Filter
Particle Count — Brisip SP3 Capsule Filter with Cobetter Safesure AFM Membrane
(SP3SSAFMBX1P)
26.0 3.1

25.0 3.0
3.0 ≥ 10 m Lot# YYY2200B21 ≥ 25 m Lot# YYY2200B21 0.3

≥ 10 m Lot# YYY3090B21 ≥ 25 m Lot# YYY3090B21
≥ 10 m Lot# Y14B200B21 ≥ 25 m Lot# Y14B200B21
1.0 0.1
0.0 0.0
0 1 2 3 4 5 6 7 8
Flush Volume (L)
Conclusion
The particle count in effluent of autoclaved Cobetter Safesure AFM series filters meets the requirements in
USP <788> for large volume parenterals.
47
8. 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 Safesure AFM cartridge filters were autoclaved at 130 °C for 30 minutes. Brisip SP3 capsule filters
with Cobetter Safesure AFM membrane were autoclaved at 131 °C for 30 minutes. Bricap series capsule
Cobetter Safesure AFM series filters were wetted with prefiltered IPA solution and flushed with purified
water at a flow rate of 0.2-1.0 L/min. 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
Lot Number Number of Fibers in Effluent
YEG8288B17 0
YCJ9158A08 0
YEG8068B01 0
48
Bricap Capsule Filters with Cobetter Safesure AFM Membrane
YKG8049619 0
YMF5139921 0
YKH6089403 0
YKG8049619 0
YMF5139921 0
YKH6089403 0
YKG8049619 0
YMF5139921 0
YKH6089403 0
YKG8049619 0
YP68147C20 0
YNB4119A16 0
YKG8049624 0
YP68147C20 0
YNB4119A16 0
YGB3319123 0
YFB9139C24 0
YKG8049624 0
YHK6089402 0
YJW3079517 0
YKG8019716 0
49
YYY2200B21 0
YYY3090B21 0
Y14B200B21 0
Conclusion
Cobetter Safesure AFM series filters meet the criteria for a “Non-fiber-releasing filter” as defined in 21 CFR
210.3 (b) (6).
50
9. Bacterial Endotoxins Test
Bacterial endotoxins test for Cobetter Safesure AFM series 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 Safesure AFM cartridge filters were installed in non-pyrogenic stainless steel housing. Bricap
and Brisip SP3 Capsule filters with Cobetter Safesure AFM membrane were tested directly. The filters were
filled with endotoxin free water (Water for BET ) and static soak for one hour at ambient room tempera-
ture. Samples were then taken and evaluated with the 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.
51
Lysate Sensitivity Solution Result

(EU/mL) Lot Number A B C D (EU/mL)
0.25 YEG8288B17 —— ++ ++ —— < 0.25
0.25 YCJ9158A08 —— ++ < 0.25
0.25 YEG8068B01 —— ++ < 0.25

Legend: ' + ' —— A firm gel has formed that remains in place upon inversion, Positive.
'—' —— An intact gel is not formed, Negative.

0.25 YYY2200B21 —— ++ ++ —— < 0.25
0.25 YYY3090B21 —— ++ < 0.25
0.25 Y14B200B21 —— ++ < 0.25

Legend: '+' —— A firm gel has formed that remains in place upon inversion, Positive.
52
Bricap Capsule Filters with Cobetter Safesure AFM Membrane

0.25 YKG8049619 —— ++ ++ —— < 0.25
0.25 YMF5139921 —— ++ < 0.25
0.25 YKH6089403 —— ++ < 0.25
0.25 YKG8049619 —— ++ ++ —— < 0.25
0.25 YMF5139921 —— ++ < 0.25
0.25 YKH6089403 —— ++ < 0.25
0.25 YKG8049619 —— ++ ++ —— < 0.25
0.25 YMF5139921 —— ++ < 0.25
0.25 YKH6089403 —— ++ < 0.25
0.25 YKG8049619 —— ++ ++ —— < 0.25
0.25 YP68147C20 —— ++ < 0.25
0.25 YNB4119A16 —— ++ < 0.25
0.25 YKG8049624 —— ++ ++ —— < 0.25
0.25 YP68147C20 —— ++ < 0.25
0.25 YNB4119A16 —— ++ < 0.25
0.25 YGB3319123 —— ++ ++ —— < 0.25
0.25 YFB9139C24 —— ++ < 0.25
0.25 YKG8049624 —— ++ < 0.25
0.25 YHK6089402 —— ++ ++ —— < 0.25
0.25 YJW3079517 —— ++ < 0.25
0.25 YKG8019716 —— ++ < 0.25

Legend: ' + ' —— A firm gel has formed that remains in place upon inversion, Positive.
Conclusion
The aqueous extraction of Cobetter Safesure AFM series filters contains < 0.25 EU/mL as determined
by Limulus Amebocyte Lysate (LAL), meeting the requirements of USP monographs for Sterile Water for
Injection .
53
10. 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 test.
USP <88> Class VI-121 °C Biological Reactivity Tests were performed on all components of Cobetter
Safesure AFM series filters to estimate the biosafety. The tests were conducted in an accredited, indepen-
dent laboratory.
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 Safesure AFM series filters meet the criteria of the USP <88> Biolog-
ical Reactivity Test for Class VI-121 °C plastics.
54
11. FDA 21 CFR Indirect Food Additive
The raw materials used to manufacture Cobetter Safesure AFM 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 Polytetrafluoroethylene 177.1550
Supports Polypropylene 177.1520
Core, cage, end caps Polypropylene 177.1520
Capsule housing Polypropylene 177.1520
Vent O-rings Silicone 177.2600
O-rings Silicone 177.2600
O-rings EPDM 177.2600

O-rings FEP/PFA encapsulated 177.1550
Fluoroelastomer
55
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 2.5 2021 | Specifications subject to change without notice.

Validation Guide For Cobetter Safesure AFM Series Hydrophobic Filters - en V2.5 202101

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Validation Guide For Cobetter Safesure AFM Series Hydrophobic Filters - en V2.5 202101

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Validation Guide

Cobetter Safesure™ AFM Filters

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

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

III. Veriﬁcation and Validation .................................................................................................................................8

3. Air Flow Rate ................................................................................................................................................21

4. Thermal Resistance .....................................................................................................................................29

5. Chemical Compatibility ...............................................................................................................................37

6. Extractables (NVR) .......................................................................................................................................39

7. Particle Shedding ........................................................................................................................................40

8. Non-ﬁber Releasing ....................................................................................................................................48

9. Bacterial Endotoxins Test ............................................................................................................................51

10. USP <88> Class VI Biological Reactivity Test, In Vivo ................................................................................54

11. FDA 21 CFR Indirect Food Additive .............................................................................................................55

Raw Material Control

Lot Release and Traceability

1 Safesure is trademark of Cobetter PTFE membrane.

II. Product Specifications

Capsule Size Membrane Type Quantity per package

2 Bricap is trademark of Cobetter capsule filter.

Capsule Size Membrane Type Quantity per package

Capsule Size Membrane Type Quantity per package

Inlet & Outlet Type Vent and Drain Valves

3 Brisip is trademark of Cobetter capsule filter.

Filter Cobetter Safesure AFM

Effective Filtration Area (EFA) 0.68 m2 (7.3 ft2)

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

Water Intrusion at 20 °C ≤ 0.75 mL/min at 2.5 bar (36 psi)

Filter Bricap C01 Bricap C02 Bricap C03

Pore Size 0.2 μm

Maximum Operating Pressure 5.5 bar (80 psi) at 25 °C

Bricap® L Capsule Filters with Cobetter Safesure™ AFM Membrane

Filter Bricap L02 Bricap L03 Bricap L05 Bricap L10

Pore Size 0.2 μm

Maximum Operating Pressure 5.5 bar (80 psi) at 25 °C

Filter Brisip SP3

Body Diameter 81 mm (3.19 in.)

Effective Filtration Area (EFA) 0.2 m2 (2.2 ft2)

Maximum Operating Pressure 6.9 bar (100 psi) at 40 °C

Water Intrusion at 20 °C ≤ 0.25 mL/min at 2.5 bar (36 psi)

III. Verification and Validation

Bacterial Challenge Test Schematic

Puriﬁed Water Pressure

Cobetter Safesure AFM 0.2 μm Cartridge Filter (AAFMB107SP)

Water Intrusion Challenge Level

YEG8278B17 0.22 1.38 × 1011 Sterile 7.31

YCJ9158A09 0.29 7.88 × 1010 Sterile 7.06

YCJ9268A09 0.34 8.47 × 1010 Sterile 7.10

YCJ9118A11 0.35 1.38 × 1011 Sterile 7.31

YEG8068B01 0.42 9.11 × 1010 Sterile 7.13

YEG8018B03 0.43 9.52 × 1010 Sterile 7.15

YEG8228B12 0.46 1.82 × 1011 Sterile 7.43

YEG8198B12 0.54 1.03 × 1011 Sterile 7.18

YEG8118B13 0.60 1.01 × 1011 Sterile 7.17

YEG8168B13 0.61 7.94 × 1010 Sterile 7.07

YEG8278B17 0.68 1.22 × 1011 Sterile 7.25

YCJ9078A09 0.74 1.01 × 1011 Sterile 7.17

YCJ9258A10 0.79 1.03 × 1011 Sterile 7.18

YEG8368B01 0.85 9.11 × 1010 Sterile 7.13

YEG8298B03 0.91 7.94 × 1010 Sterile 7.07

YEG8158B12 0.96 8.47 × 1010 Non Sterile <7

YEG8118B13 1.01 7.94 × 1010 Non Sterile <7

Correlation of the ASTM Bacteria Challenge Tests