Filter Validation

Validation Guide
Sartolon
Cartridges, Maxicaps® & Midicaps®
Table of Contents
1. Introduction 3 5. Integrity Test Limits 21

1.1 cGMP Quality Assurance 5.1 Basis for the Determination
from Sartorius 4 of Integrity Test Values 21
1.2 Quality Assurance 4 5.2 Bacteria Retention Test 22
1.3 Prevention of Contamination 4 5.3 Diffusion Test Limits 23
1.4 Complete Traceability 4 5.3.1 Cartridges|Maxicaps® 23
1.5 Sartorius Drug Master File 4 5.3.2 Midicaps® 25
1.6 Quality Management System 4 5.4 Manual Determination of
1.7 Test Methods for the Quality Assurance Maximum Allowable Pressure Drop 26
of Sartorius 5.4.1 Examples of the Maximum
Sartolon Filter Elements 5 Allowable Pressure Drop for
Sartolon Midicaps® 26
2. Technical Specifications 6
2.1 Type and Part Number Overview 6 6. Thermal Stability 27
2.1.1 Standard Cartridges 6 6.1 Steam Sterilization of Cartridges 27
2.1.2 Mini Cartridges 7 6.1.1 Effects on Water Flow Rates 28
2.1.3 Maxicaps® 8 6.1.2 Effects on Diffusion Test Values 29
2.1.4 Midicaps® 9 6.1.3 Effects on Bubble Point Values 30
2.2 Filter Material 10 6.1.4 Effects on Bacteria Challenge Test 31
2.3 Mechanism of Filtration 10 6.2 Autoclaving of
2.4 Pore Size Combination 10 Maxicaps® & Midicaps® 32
2.5 Materials of Construction 10 6.2.1 Effects on Water Flow Rates 33
2.6 Fiber Release 10 6.2.2 Effects on Diffusion Values 35
2.7 Dimensions 11 6.2.3 Effects on Bubble Point Values 37
2.7.1 Standard Cartridges 11 6.2.4 Bacteria Challenge Test Values 39
2.7.2 Mini Cartridges 11
2.7.3 Maxicaps® 12 7. Testing According to USP 41
2.7.4 Midicaps® 13 7.1 Particle Content of the Filtrate 42
2.8 Maximum Allowable 7.1.1 Standard Cartridges 43
Differential Pressure 14 7.1.2 Maxicaps® 43
2.8.1 Cartridges 14 7.1.3 Midicaps® 43
2.8.2 Maxicaps® 14 7.2 Determination of Oxidizable
2.8.3 Midicaps® 14 Substances of the Filtrate 44
2.9 Maximum Back Pressure 7.2.1 Standard Cartridges 44
for Cartridges, Maxicaps® 7.2.2 Maxicaps® 44
and Midicaps® 14 7.2.3 Midicaps® 44
2.10 Wetting the Filters for 7.3 Determination of pH Values and
Integrity Testing 14 Conductivity of the Filtrate 45
2.11 Rinse-Up Required for 7.3.1 Standard Cartridges 46
Particle Removal 15 7.3.2 Maxicaps® 47
2.12 Sterilization 15 7.3.3 Midicaps® 47
2.13 Integrity Test Limits 15 7.4 Determination of Chloride 48
2.13.1 Cartridges and Maxicaps® 15 7.4.1 Standard Cartridges 48
2.13.2 Cartridges and Midicaps® 15 7.4.2 Maxicaps® 48
7.4.3 Midicaps® 48
3. Flow Rates 16 7.5 Determination of Sulfate 49
3.1 Water Flow Rates for 10", 20" 7.5.1 Standard Cartridges 49
and 30" Cartridges and Maxicaps® 17 7.5.2 Maxicaps® 49
3.2 Water Flow Rates for Mini 7.5.3 Midicaps® 49
Cartridges with 2.000 cm2|2.2 ft2 7.6 Determination of Ammonia 50
Filtration Area 17 7.6.1 Standard Cartridges 50
3.3 Water Flow Rates for Midicaps® 7.6.2 Maxicaps® 50
with 2.000 cm2|2.2 ft2 7.6.3 Midicaps® 50
Filtration Area 18 7.7 Biocompatibility 51
4. Chemical Stability – Sartolon 19 8. Endotoxin Testing 55

1. Introduction
Pharmaceutical products, such as Therefore, a prior membrane Guidelines for validation are given
injectable and infusion solutions or filtration run is required by cGMP in the US Code of Federal Regula-
those which come in contact with regulations (Current Good Manufac- tions Title 21 and the current
open wounds, must conform to turing Practice of the US Food and USP. In addition, guidelines have
exactly defined quality standards. Drug Administration) to ensure that been established jointly by the
The desired quality of the final particles and microbes are removed. Committee for Laboratories and
product can only be obtained when Solutions containing heat-labile Official Drug Product Inspection
the entire production process is products, such as antibiotics, can Services and the Department of
adequately safeguarded against be cold sterilized by membrane Industrial Pharmacists of the
contamination. Final product filtration immediately before aseptic Federation Internationale
quality meeting the standards of filling. Microbe retentive filtration Pharmaceutique (F.I.P.), which is
the respective pharmacopeias can (bacteria retentive according to the the European counterpart of the
be achieved by using membrane European Pharmacopeia 6) or sterile FDA. The term validation is defined
filter technology at critical points filtration (sterilization by filtration by the F.I.P. guidelines as follows:
where particles or microbes could in conformance with the current ”Validation, as used in these guide-
contaminate a product or must be USP), respectively, is an important lines, comprises the systematic
separated from it. Heat-stable final process step in the manufacture testing of essential production
products can be sterilized practically of sterile pharmaceutical products. steps and equipment in the R & D
and effectively by autoclaving. This When sterilizing filters are used and production departments,
process, however, does not remove in the manufacture of pharma- including testing and inspection of
particles or dead microorganisms ceuticals, the aseptic process must pharmaceutical products with the
which may release pyrogens. be validated, taking all aspects of goal of ensuring that the finished
the product and the production products can be manufactured
process into consideration. Sartolon, reliably and reproducibly and in
a pleated filter cartridge with a the desired quality in keeping with
reinforced double layer membrane, the established production and
reliably fulfills the product-specific quality control procedures“. We
requirements which have to be have compiled this validation guide
imposed on a sterilizing grade so users of Sartolon filter cartridges
filter. Validation is indispensable can plan, implement and document
for guaranteeing the safety of their own validation procedures.
pharmaceuticals, and is a logical
supplement and significant part of
the cGMP regulations which have
been in force for quite some time.
|3
1.1 cGMP Quality Assurance from 1.3 Prevention of Contamination 1.6 Quality Management System
Sartorius Sartorius capsules and filter Sartorium Stedim Biotech imple-
Consistent high quality of Sartorius cartridges are sealed in mented Quality Management
Membrane Filters, Capsules gas-permeable protective plastic Systems to assure consistent high
(ready-to-connect filtration units) bags in a controlled production quality of Membrane Filters and
and Filter Cartridges is assured area. Following this step, they are Filter Cartidges.
by careful selection of the raw heat treated with steam to reliably
materials, well-planned and prevent microbial growth, and thus Exemplary Quality Systems
validated production technologies rule out the possibility of pyrogen Certificates:
and an exceptionally efficient synthesis during shipping and
Quality Assurance Department, all storage. Quality Management System
of which results in high batch- ISO 9001
to-batch reproducibility. The test 1.4 Complete Traceability Quality Management System
procedures used are based both on The pore size (or retention rating), ISO 13485
external standard methods, such type and lot number are printed on
as the USP, EP and ASTM, and on the label of the protective plastic The complete Quality Systems
in-house methods which are the or paper bag and on the label of Certificates are continuously
result of Sartorius’ experience over the box in which the cartridge or updated and can be downloaded
the past 60 years. capsule is packed. In addition, these on our website:
specifications are imprinted on the
1.2 Quality Assurance outer cage of each filter cartridge www.sartorius-stedim.com/
For quality assurance, all materials or on the housing of each capsule. qm-certificates
are selected carefully in accordance The traceable lot number allows
with current regulations, such as convenient retrieval of all data
the FDA CFR’s, cGMP’s in-house complied on the materials used,
guidelines and the specifications production steps and QC tests.
of our Research and Development
Department including the terms 1.5 Sartorius Drug Master File
of delivery and acceptance of our This product is registered with the
Purchasing Department. Documen- Food and Drug Adminstration (FDA).
tation begins with the inspection The DMF number is available upon
of the incoming raw materials request.
including in-process materials,
molded parts and sealing materials,
etc. for manufacture. Adherence to
cGMP requirements (clean-room
conditions, gowning and employee
hygiene, etc.) which are monitored
by documented in-process controls,
ensures optimal quality control
in standard operating procedures
for production. Finished Sartorius
Capsules and Filter Cartridges
undergo final product quality
control. This involves 100 %
non-destructive testing of each
individual product and other
individual tests carried out on a
representative number of samples.
A lot is not released until all
in-process and final quality control
data are available.
4|
1.7 Test Methods for the Quality
Assurance of Sartorius
Sartolon Filter Elements
Routine Testing of Testing Conducted

Lot Related Tests
Randomly Sampled Filter for the Validation of the
100 % Individual Testing
Elements Filter Elements
Bubble Point of the Cartridge Bacteria Challenge Testing Correlation of Diffusion and
Bubble Point Values with the ASTM
Diffusion Value of the Cartridge Endotoxin Testing Bacteria Challenge Tests
Flow Rate and Throughput of the Flow Rate Testing Current USP Class VI Plastics Tests
Membrane Intracutaneous Test
Steam Sterilizability Systemic Injection Test
Bacteria Challenge Testing of Every Implantation Test
Lot of Filter Membrane Extractable Substances
Particle Release
pH Change of the Filtrate
Conductivity Changes of the Filtrate
Water Flow Rates
Temperature and Pressure

Resistance
Sterilizability
In-line Steam Sterilization
(cartridges only) Autoclavability
Evaluation of Integrity Test Values

After Long Term Storage
|5
2. Technical Specifications
2.1 Type and Part Number Overview
2.1.1 Standard Cartridges Explanation
510 25 07H 1 510

Sartolon, heterogeneous
Polyamide double layer
membrane filters
Adapter
Adapter
21 Double Open end
Pore Size cartridge with flat
gasket
25 S-adapter top, locking
bayonet adapter with
Height 226 double O-ring
bottom
27 Flat top, double 222
O-ring bottom
Pore Size
07H 0.2 µm final membrane
Height Filtration Area

1 10" 0.6 m2| 6.5 ft2
2 20" 1.2 m2|12.9 ft2
3 30" 1.8 m2|19.4 ft2
6|
2.1.2 Mini Cartridges Explanation
510 15 07H 9 B 510

membrane filters
Adapter
Type of Adapter
15 Bayonet adapter with
Pore Size O-ring
Filtration Area Pore Size

Units per Package

Effective Filtration Area
9 0.2 m2|2.2 ft2
Units per Package

B Five pieces
|7
2.1.3 Maxicaps® Explanation
510 73 07H 1 00 510

membrane filters
Pore Size
Pore Size
Filtration Area

Connector 1 0.6 m2| 6.5 ft2
2 1.2 m2|12.9 ft2
3 1.8 m2|19.4 ft2
Connectors
0 Hose barb
S 11⁄2" Tri-Clamp
(Sanitary)
F 3⁄4" Tri-Clamp
(Sanitary)
Note
The first code letter of the
connector code represents the inlet,
the second code letter represents
the outlet connector.
8|
2.1.4 Midicaps® Explanation
510 53 07H 9 00 A 510

membrane filters
Pore Size
Pore Size
Filtration
Area

Connector 9 0.2 m2|2.2 ft2
Units per Connectors

Package 0 Hose barb
S 11⁄2" Tri-Clamp
(Sanitary)
F 3⁄4" Tri-Clamp
(Sanitary)
Units per Package

A Four pieces
Note
The first code letter of the
connector code represents the inlet,
the second code letter represents
the outlet connector.
|9
2.2 Filter Material 2.3 Mechanism of Filtration 2.5 Materials of Construction
Heterogeneous double layer The retention of particles and All materials meet the FDA require-
Polyamide membrane filters, with microorganisms is achieved by a ments as defined in Title 21 Code
the upstream filter membrane sieving mechanism through the of Federal Regulations. Biosafety
having a larger pore size than the Polyamide filter membrane. The testing, such as the Class VI Plastics
final membrane. throughput is enhanced through Testing as described in the current
the use of fractionated filtration USP, are also met and exceeded.
due to the heterogenous double
layer membrane. Upstream Support Layer:
Polypropylene
2.4 Pore Size Combination
0.45 µm + 0.2 µm Prefilter Membrane:
Reinforced Polyamide
Final Filter Membrane:

Polyamide
Downstream Support:
Polypropylene
Outer Cage:
Polypropylene
Inner Core:
Polypropylene
Endcaps:
Polypropylene
Capsule Housing:
Polypropylene
O-Rings|Gaskets:
Silicone; Optional:
EPDM or Fluoroelastomer
Filling Bell:
Polycarbonate
2.6 Fiber Release

Sartolon Filter elements comply
with Title 21 Code of Federal Regu-
lations, Section 211.72 and 210.3
(b) (6) for non-fiber releasing filters.
10 |
Diameter
2.7 Dimensions
2.7.1 Standard Cartridges
Height
Adapter 10" [mm] 20" [mm] 30" [mm] Diameter [mm]
25 321 568 817 70
± 3 mm per 10"
Height measurement include adapter and S-top where indicated in the diagram.
Height
Diameter
2.7.2 Mini Cartridges
Filtration Area Height Diameter

[m2|ft2] ± 1 [mm] ± 1 [mm]
0.2|2.2 133 mm 56 mm
Height
| 11
Diameter without Valves
2.7.3 Maxicaps®
Total Height
Size Connector Combinations [mm]

SS SO OO FF
10" 365 371 377 365
20" 615 621 627 615
30" 865 871 877 865
Height
Total Diameter
(including valves)
Size All Connector

Combinations
[mm]
10" 137
20" 137
30" 137
Diameter with Valves

Total Diameter
(without valves)
Size All Connector

Combinations
[mm]
10" 110
20" 110
30" 110
12 |
2.7.4 Midicaps® Diameter Midicaps® Housing without Valves
Total Height
Filtration Area Connector Combinations [mm]

[m2|ft2] SS SO OO FF FO
0.2|2.2 197 204 210 197 204
Total Diameter Midicaps® Housing

(including valves)
Filtration All Connector

Area Combinations
[m2|ft2] [mm]
0.2|2.2 108.5
Total Diameter Midicaps® Housing

(without valves)
Filtration All Connector

Diameter Midicaps® Housing with Valves
Area Combinations
[m2|ft2] [mm]
0.2|2.2 77
| 13
2.8 Maximum Allowable
Differential Pressure
The maximum allowable differential
pressure depends on the temper-
ature at which the pressure is
exerted. Maximum allowable differ-
ential pressures in the direction of
filtration.
2.8.1 Cartridges
Temperature [°C] 20 100 121 134 140

Pressure [bar] 5 3 1.5 0.5 0.5
Pressure [psi] 72.5 43.5 22 7.2 7.2
2.8.2 Maxicaps®
Temperature [°C] 20 50
Pressure [bar] 4 3
Pressure [psi] 58 43.5
2.8.3 Midicaps®
Temperature [°C] 20 30
Pressure [bar] 5 3
Pressure [psi] 72.5 43.5
2.9 Maximum Back Pressure

for Cartridges, Maxicaps®
and Midicaps®
The maximum allowable pressure in
reverse of the direction of filtration:
Temperature [°C] 20 100 121 134

Pressure [bar] 2 1 0.5 0.3
Pressure [psi] 29 14.5 7.2 4.4
2.10 Wetting the Filters for Integrity

Testing
For each 10"|250 mm filter
cartridge, rinse the filters in the
direction of flow for 5 minutes
with a differential pressure of
0.3 bar|4 psi backpressure
0.5 bar|7 psi in order to assure
that the filters have been wetted
completely. Generally, filters are
wetted with water. In cases where a
different wetting medium is used,
if the surface tension of the fluid is
different from water (> 70 dynes/cm),
different integrity test values than
indicated on the next page may be
required.
14 |
2.11 Rinse-Up Required for Particle
Removal
The requirements for filtrate quality
according to the current USP
”Sterile Water for Injection“ are met
without the need for initial flushing
of the filter cartridge and Midicap®.
2.12 Sterilization
Autoclaving of wet filter cartridges ,
Maxicaps® & Midicaps® up to a
maximum temperature of 134 °C,
for 30 minutes
or
In-line steam sterilization of wetted
cartridges with a maximum of
2.3 bar|34 psi inlet pressure and
2 bar|29 psi outlet pressure
(max. Dp = 0.3 bar|5 psi).
Number of sterilizing cycles:

at least 25.
Note
Maxicaps® and Midicaps® cannot be
in-line steam sterilized.
2.13 Integrity Test Limits
2.13.1 Cartridges and Maxicaps®
Pore Size of the Height Test Pressure Maximum Diffusion Minimum Bubble Point
Final Membrane [bar|psi] [mL/min] [bar|psi]
0.2 µm 10" 2.5|36 13 3.0|43.5
20" 2.5|36 26 3.0|43.5
30" 2.5|36 39 3.0|43.5
2.13.2 Cartridges and Midicaps®
Pore Size of the Filtration Area Test Pressure Maximum Diffusion Minimum Bubble Point
Final Membrane [m2|ft2] [bar|psi] [mL/min] [bar|psi]
0.2 µm 0.2|2.2 2.5|36 4 3.0|43.5
| 15
3. Flow Rates
Background Results
Test filter cartridges are placed into The flow rate curves for water
individual Sartorius filter housings through Sartolon standard
(Sartorius housings, Type cartridges, mini cartridges,
340011P25TT112A or Maxicaps® & Midicaps® of the given
331019P15TT112A). Capsules are pore sizes and lengths versus differ-
directly installed into the piping ential pressure are on the following
system, using sanitary flanges. pages.
The piping system to and from the
filters has an inner diameter of Note
25 mm|1 inch resp. 15 mm|0.6 inch. The flow rate is strongly influenced
The water inlet is opened and the by the viscosity of the medium
filter housings are completely being filtered. For this reason, all
vented. flow rate measurements are taken
at 20 °C so that the influence of
The filters are rinsed for approxi- temperature on viscosity is not a
mately 5 minutes at 0.3 bar|4 psi factor.
differential pressure to assure
complete wetting. The filter For flow rate measurements of
cartridges are then integrity tested 20" and 30" filter cartridges, the
to assure that only integral filters flow rates reach a point where the
are tested. The inlet pressure (Pi) is geometry of the piping and the
held constant at 2.5 bar|36 psi. filter housing begin to contribute
to the overall differential pressure
By adjusting the valves on the (resistance to flow). At a flow rate
downstream side of the filter of approximately 7000 L/h
housing, the required differential (120 L/min), the filter membrane
pressure for the test measurements surface area is no longer the flow
is established. After achieving a limiting factor, but the housing
constant differential pressure, the and piping system begin to have
flow rate is recorded from the increasing effects on differential
flow meter and the temperature is pressure. For this reason the flow
noted. The flow meter used in this rates are only recorded at limited
testing was a Fisher & Porter COPA differential pressures.
XM Magnetic Inductive Flow Meter
Model D10D1465.
Test Set-up
Diffusion and Bubble Point

measurements with the
automated integrity test system,
Sartocheck® 4 Plus
Regulating Valve,
Inlet
Test Filter
Element
Water Water
Stream Pressure Gauge Regulating Valve, Thermometer Flow Meter Stream
Outlet
16 |
3.1 Water Flow Rates for 10", 20" and 30" Cartridges and Maxicaps®
Sartolon 0.45|0.2 µm
Differential Pressure [bar] [psi]
2.0 30
10" 20" 30"

1.5
1.0 15
0.5
0 0
0 2500 5000 7500 10000 12500 15000
Flow Rate [L/h]
Standardized at 20 °C
3.2 Water Flow Rates for Mini Cartridges with 2.000 cm2|2.2 ft2 Filtration Area
1 15
0.75
0.50 7.5
0.25
0 0
0 250 500 750 1000
Flow Rate [L/h]
| 17
3.3 Water Flow Rates for Midicaps® with 2.000 cm2|2.2 ft2 Filtration Area
1 14.5
OO FO|SO FF SS
0.75
0.5 7.25
0.25
0 0
0 300 600 900
Flow Rate [L/h]
18 |
4. Chemical Stability – Sartolon
Compatibility measurement with complete filter element, but different O-ring materials:
Silicone EPDM Fluoroelastomer
Acids:
Acetic acid, 10 % ––
Acetic acid, conc. –– –– ––
Citric acid
Formic acid, 10 %
Formic acid, conc. –– –– ––
Hydrochloric acid, 25 % –– –– ––
Hydrochloric acid, 30 % –– –– ––
Lactic acid
Nitric acid, 10 % –– –– ––
Nitric acid, 65 % –– –– ––
Phosphoric acid, 25 % –– –– ––
Sulfuric acid, 25 % –– –– ––
Sulfuric acid, conc. –– –– ––
Tartaric acid
Trichloracetic acid, 10 % –– –– ––
Trichloracetic acid, 25 % –– –– ––
Bases:
Ammonium hydroxide, 10 % ––
Ammonium hydroxide, 30 % –– ––
Potassium hydroxide, 1 M
Sodium hydroxide, 1 M
Sodium hydroxide, 2.5 M –– ––
Solvents:
Acetone –– ––
Amyl acetate ––
n-Amyl alcohol
Aniline –– ––
Benzene –– ––
Benzyl alcohol
n-Butanol
Legend Carbon tetrachloride –– ––
= Compatible
= Limited compatibility Chlorbenzene –– ––
depending on concentration, Chloroform –– ––
temperature etc.
– – = Not compatible Cyclohexanone
Decalin ––
Test Specifications
Diethyl ether –– ––
7 days contact at 20 °C
Dimethyl formamide –– ––
Important Dimethyl sulfoxide
Compatibility is influenced by
various factors, such as temper- Dioxane ––
ature, concentration, etc. Ethanol, 10 %
If necessary, test the compatibility
with the solution you wish to Ethanol, 98 %
filter before performing the actual Ethyl acetate
filtration run.
| 19
Ethylene glycol
Glycerol
n-Hexane
Isopropyl alcohol
Methanol, 98 %
Methyl acetate
Methylene chloride –– ––
Methylene glycol
Methyl ethyl ketone
Methyl isobutyl ketone
Perchloroethylene –– ––
Propyl acetate ––
n-Propyl alcohol
Sodium hypochloride
Tetrahydrofuran –– ––
Tetralin –– ––
Toluene –– ––
Legend
= Compatible Trichloroethylene –– ––
= Limited compatibility Triethanolamine
depending on concentration,
temperature etc. Turpentine ––
– – = Not compatible Xylene –– ––
Test Specifications Aqueous Solutions:

7 days contact at 20 °C Ammonium persulfate, 25 %
Important Formaldehyde, 30 %
Compatibility is influenced by Hydrogen peroxide, 30 %
various factors, such as temper-
ature, concentration, etc. Phenol, 10 % –– –– ––
If necessary, test the compatibility Sodium hypochloride, 5 %
with the solution you wish to
filter before performing the actual Starch solution
filtration run. Water
20 |
5. Integrity Test Limits
5.1 Basis for the Determination of Test-Method Integrity Test

Integrity Test Values Several hundred Sartolon filter The Sartolon filter elements were
Establishing a correlation between elements with 0.2 μm pore size integrity tested by Diffusion and
bacterial retention of a sterilizing membranes, from different Bubble Point Test methods in order
grade filter and a non-destructive production lots were tested to correlate the results of the
integrity test is critical in order to according to a Bacteria Challenge destructive Bacteria Challenge Test
ensure filter reliability prior to the Test in accordance with the with these non-destructive integrity
filter being used to produce a sterile current ASTM F838 Guideline, and tests.
effluent. DIN 58356, Part 1.
The Diffusion Test and the Bubble
According to the current ASTM Test Organism Point Test are performed utilizing
F838 Guideline, and the FDA Brevundimonas diminuta a Sartocheck® 4 Plus automated
”Guideline on Sterile Drug Products (ATCC 19146) integrity test unit.
Produced by Aseptic Processing“,
June 1987, a sterilizing grade filter Note The diffusion values are determined
cartridge should produce a sterile For validation studies of the at a test pressure of 2.5 bar|36 psi.
effluent when challenged with a Sartolon filter cartridges, a For the determination of the bubble
minimum concentration of 107 minimum concentration of point, air pressure is slowly
Brevundimonas diminuta 1 × 107 Brevundimonas diminuta increased on the upstream side of
organisms/cm2 of filter area. per cm2 filtration area for each the filter housing by Sartocheck® 4
element tested was used. Plus integrity tester.
The FDA ”Guidelines on Sterile
Drug Products Produced by Aseptic
Processing“, June 1987 states:
”After a filtration process is

properly validated for a given
product, process and filter, it is
important to assure that identical
filter replacements (membrane or
cartridge) used in production runs
will perform in the same manner.
One way of achieving this is to
correlate filter performance 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 or perfora-
tions that may have occurred
during filtration.”
| 21
5.2 Bacteria Retention Test
Test Set-up
Diffusion and Bubble

Point Measurements
Bacteria with the automated
Suspension integrity test system,
Sartocheck® 4 Plus
Dosing
Pump
Regulating Valve Capsule or
Housing with Analytical
Sterile Prefil- Test Filter Filters
Pressure
tration
Gauge
Mixing Flow Meter
Water Tube Water
Stream Stream
Water flow is initiated and the The bacterial challenge bioburden Test Procedure
water stream first passes through a that will be introduced to the test The Sartolon filter cartridges or
sterilizing grade filter cartridge. The filter cartridge is controlled by capsules are installed and wetted
purpose of this filter is to remove dosing of the bacterial suspension as described in the operating
particles and bacteria to assure the into the water stream with a instructions. The filter system is
Test Filter is only challenged with peristaltic pump. After the bacterial then sterilized.
the bacterial load as described in suspension is added to the water
the ASTM Document. stream, the flow is directed through The system is then rinsed with
a mixing tube to ensure that proper water and the test filter is integrity
Sterilizing Filter Cartridge: mixing of the bacterial suspension tested with the Sartocheck® 4 Plus.
Sartobran® P 0.45|0.2 µm has occurred. For the control and The water flow is controlled with
Membrane Filter 5232507H1-P monitoring of the differential the valving of the system and set
pressure during the Bacteria so that the bacterial suspension can
Challenge Test, pressure gauges and be dosed into the water stream.
valves have been installed on the After the Bacteria Challenge Test,
upstream and downstream side of the analytical filters are incubated
the filter cartridges. The filtrate that on agar plates to determine if there
passes through the test filter flows was passage of bacteria through
through two parallel analytical the test filter. The analysis of the
filters. After the completion of analytical filters is conducted
the Bacteria Challenge Test, these according to the ASTM Method.
analytical filters can be examined
according to the analytical methods
described in the ASTM document.
22 |
5.3 Diffusion Test Limits Results
5.3.1 Cartridges|Maxicaps® Lot Number Diffusion [mL/min] Bioburden [CFU] Filtrate Quality
019141 8.4 2.4 × 1011 sterile
Note
Since most of the 10"|250 mm 019141 8.6 4.7 × 1011 sterile
filter cartridges tested during 019141 8.6 4.7 × 1011 sterile
the validation studies had low
diffusion values and produced 020041 8.8 2.4 × 1011
sterile
sterile filtrates, the following data 019141 8.8 1.8 × 1011 sterile
represents a sampling from all
filters tested during the validation 020341 9.0 2.4 × 1011
sterile
testing, indicating results near the 019141 9.0 2.4 × 1011 sterile
diffusion|sterile filtrate limits. 020041 9.0 6.3 × 1011
sterile
019141 9.2 2.4 × 1011
sterile
020041 9.2 2.9 × 1011 sterile
019141 9.2 5.0 × 1011
sterile
020341 9.4 2.4 × 1011 sterile
020041 9.4 5.0 × 1011
sterile
020041 9.8 9.0 × 1010 sterile
019141 9.8 3.4 × 1011
sterile
020341 9.8 5.0 × 1011
sterile
020341 10.3 1.3 × 1011 sterile
020041 10.6 3.4 × 1011
sterile
019141 11.4 2.1 × 1010 sterile
019141 11.5 2.1 × 1010
sterile
020041 11.7 2.1 × 1010 sterile
020041 12.0 2.1 × 1010
sterile
020341 12.0 3.4 × 1011 sterile
019141 12.0 2.4 × 1011
sterile
019141 12.6 2.1 × 1010
sterile
020041 12.6 5.0 × 1011 sterile
020341 12.8 3.4 × 1011
sterile
020341 13.2 4.7 × 1011 sterile
020041 13.4 3.4 × 1011
sterile
020041 13.8 9.0 × 1010 sterile
020341 14.4 3.4 × 1011
sterile
019141 14.4 5.8 × 1011
sterile
019141 15.0 3.4 × 1011 sterile
019141 18.4 3.4 × 1011
sterile
020041 23.7 1.7 × 1011 non sterile
020041 27.9 1.3 × 1011
non sterile
020341 50.0 1.3 × 1011 non sterile
020341 63.6 9.0 × 1010
non sterile
* CFU = Colony Forming Units
| 23
Cartridges (10"|250 mm)
Diffusion [mL/min]
70
60
50
40
Non Sterile
30
20
Safety margin
Steril
10
0
02 41
02 41
02 41
02 41
02 41
02 41
02 41
02 41
01 41
01 41
02 41
02 41
02 41
01 41
02 41
02 41
01 41
41
01 41
02 41
01 41
02 41
01 41
02 41
02 41
01 41
02 41
02 41
01 41
01 41
02 41
02 41
01 41
01 41
02 41
01 41
02 41
01 41
91
91
03
00
00
00
03
91
03
91
00
03
03
91
00
03
00
03
91
00
91
00
91
03
03
00
91
91
03
91
91
00
91
00
91
00
91
00
01
Test Cartridge Lot Number
Conclusion Based on conclusive results Sartolon Note

The data shows that filter cartridges filter elements of various lengths The diffusion and Bubble Point
that have diffusion values have the following maximum Test results are influenced by the
< 18.4 mL/min always produced allowable diffusion values at a test nature of the wetting medium. The
a sterile filtrate with 100 % pressure of 2.5 bar|36 psi at 20 °C: diffusion and bubble point values
retention of the test organism, listed in this validation guide are
Brevundimonas diminuta. In order for a 10" filter cartridge: for Sartolon filter cartridges wetted
to have a high degree of safety 13 mL/min with water at 20 °C. It should be
when evaluating the test results, noted that a modification of the
and considering that other filter for a 20" filter cartridge: test conditions such as temperature,
integrity test units or other test 26 mL/min wetting liquid or type of gas may
methods may be used, a safety require a different integrity test
margin of 5.4 mL/min has been for a 30" filter cartridge: limit related to those mentioned
defined. For a thoroughly water 39 mL/min above.
wetted 10" Sartolon
0.45|0.2 µm filter cartridge, Bubble Point: > 3.0 bar|43.5 psi
(keeping in mind this safety factor),
the maximum allowable diffusion
value at a test pressure of
2.5 bar|36 psi at 20 °C is:
13 mL/min.
24 |
5.3.2 Midicaps®
Sartolon 0.2 µm, Size 9 with

2.000 cm2|2.2 ft2 Filtration Area
Lot Number Bioburden Bacteria Challenge Test

[CFU/cm2] after Autoclaving
423743 > 1 × 107 passed
423843 > 1 × 10 7
passed
423943 > 1 × 107 passed
According to the explained
procedure the integrity test param-
eters for Sartolon Midicaps® with
0.2 µm pore size for all filter sizes
are set as follows:
Filter Filtration Area Max. Diffusion Min. Bubble Point

Size [m2|ft2] at 2.5 bar|36 psi [bar|psi]
9 0.2|2.2 4 3.0|43.5
| 25
5.4 Manual Determination of 5.4.1 Examples of the Maximum
Maximum Allowable Pressure Drop Allowable Pressure Drop for
Slowly pressurize the filter housing Sartolon Midicaps®
containing the wetted filter
cartridge. The required test pressure
is dependent upon the pore size of Midicaps® Max. Diffusion Upstream Volume Max. Allowable
the membrane to be tested. (See at 20 °C and [mL/min] Pressure Drop at 20 °C
integrity test data table). Once the 4 bar|58 psi and 2.5 bar|36 psi
correct pressure is attained, allow Sartolon 4 320 mL 62 mbar/5 min
for a 5 minute stabilization period 5105307H9––SS (0.9 psi/5 min)
and then close the pressure supply.
During the 5 minute test period, the
pressure drop should not exceed the
permissible value. This maximum
pressure drop is dependent upon
a variety of criteria, including the
upstream volume of the special
filter housing at a constant
temperature and must be calcu-
lated according to the general gas
equation:
VD·t·PO
PA– PE=
V
PA–PE: Pressure drop in mbar
after test period (t)
VD: Gas diffusion in mL/min

(see table)
t: Test time (min)
PO: Atmospheric pressure

(= 1000 mbar|14.5 psi)
V: Volume of housing on
the inlet side in mL
(net volume of housing
with installed cartridge
+ volume of the inlet
line to the stop valve
+ volume of the gas
tubing)
Note
With the use of the Sartorius
automated integrity test system,
Sartocheck® 4 Plus, the upstream
volume is calculated during every
integrity test.
In order to have a reliable deter-

mination of the integrity of the
filtration system without the
influence of the upstream volume,
it is suggested that either the
Diffusion or Bubble Point Test are
used. These tests are not dependent
on the upstream volume of the
filter system.
26 |
6. Thermal Stability
6.1 Steam Sterilization of Cartridges Important Note for In-line Steam In order to demonstrate that the
The materials and construction of Sterilization Sartolon filter cartridges have
Sartolon filter cartridges allow for After the installation and wetting of good thermal stability, three filter
exposures to multiple steam steril- the filter cartridges, the upstream cartridges from three different
ization cycles. Since multiple steam vent valve on the filter housing, manufacturing lots were tested
sterilization cycles may be required all drainage and inlet and outlet under the following procedure:
in actual practice, the influences valves on the filter housing should
of the thermo-mechanical stresses be slightly opened and the steam 1. The new filter cartridges are
on the integrity of Sartolon filter inlet valve should be opened slowly wetted with water.
cartridges were examined. As a to allow for a slow steam stream
result, recommendations and limits coming into the filter system. 2. The filters are then integrity
for multiple in-line steam steril- During the initial phase of pressure tested by Bubble Point and
ization are given. increase, the maximum differ- Diffusion Tests. The flow rates
ential pressure should not exceed were also recorded for these new
Test Method: 0.5 bar|7 psi. As soon as steam is filters.
Sartolon 10" filter cartridges, with passing through the outlet valves of
a pore size of 0.45|0.2 µm from the housings, the inlet and outlet 3. The filters are in-line steam
a number of different production valves should be manipulated so sterilized.
lots, were installed into stainless that the outlet pressure is not more
steel filter housing (Sartorius Part than 2 bar|30 psi. Additionally, the 4. After the first in-line steam
Number 340011P25TT112A) wetted, inlet pressure should not be more sterilization cycle, the filters are
and were in-line sterilized with than 0.2 to 0.3 bar (3 to 4 psi) integrity tested by Bubble Point
saturated steam at 2 bar|30 psi above the sterilization pressure. and Diffusion Tests.
for 30 minutes after reaching a After steam sterilization pressures
steaming temperature of 134 °C have been achieved, the filters are 5. The filters are then steam
(measured at the outlet of the steamed for 30 minutes under these sterilized 25 times.
housing). Additionally, the differ- conditions. After steaming and
ential pressure was held constant closing of the steam inlet valve, the 6. After the 25 cycles, the filters are
and did not exceed 0.3 bar|4 psi upstream and downstream pressures integrity tested by Bubble Point
during steam sterilization. After are allowed to drop to atmospheric and Diffusion Tests. The flow
the steam sterilization cycle, the pressure, the drain valves are closed rates were also recorded.
steam pressure is allowed to drop and the venting valve is opened.
to atmosphere (in about 3 to 5 If fasten cooling is required, the 7. The cartridges are then Bacterial
minutes) and the system is cooled system can be rinsed with water Challenge tested to determine
by filtration with water at a differ- at a differential pressure of 0.2 if the steam sterilization cycles
ential pressure of 0.2 to 0.3 bar to 0.3 bar (3 to 4 psi). In order had any effect on the bacteria
(3 to 4 psi) for 5 minutes. The to assure that the filters are retention properties of the
in-line steam cycle is then repeated. not chemically attacked during Sartolon filter cartridges.
Before beginning these tests and steaming, only steam generated
after 20 in-line steam cycles, the with pure water should be used.
integrity of the filter cartridges
is verified through diffusion and
Bubble Point Testing, as well as the
water flow rates. After 25 steam
cycles, the filters are tested by the
ASTM Bacteria Challenge Test to
verify that the filters could still
produce a sterile effluent.
| 27
6.1.1 Effects on Water Flow Rates
Test Procedure
Nine Sartolon 10" filter cartridges
from three different lot numbers
were installed and wetted in
standard filter housings. The flow
rate was measured at a differential
pressure of 0.5 bar|7 psi. The values
are the average of the filters from
the production lot.
Values have been normalized for

temperature and viscosity.
Sartolon 10" Filter Cartridges
Lot Number Flow Rate Prior to Flow Rate

Steaming after 25 Steam Cycles
[L/min] [L/min]
6005443 22.0 20.0
6005543 20.8 18.4
6005643 25.9 23.0
Flow Rate [L/min]
30
25
20
15
10
5 Flow Rate
Prior to Steaming
0 After 25 Steam Cycles
6005443 6005543 6005643
Lot Number
28 |
6.1.2 Effects on Diffusion Test Values Test Pressure: 2.5 bar|36 psi
Test Procedure Stabilization Time: 5 minutes

Sartolon 10" filter cartridges were
wetted in standard filter housings. A Test Time: 5 minutes
Diffusion Test utilizing the following
parameters was conducted utilizing The following results are the
an automated integrity test system, averages for the filters from the
the Sartocheck® 4 Plus: three different production lots
tested.
Lot Number Diffusion Prior Diffusion

to Steaming after 25 Steam Cycles
[mL/min] [mL/min]
6005443 9.5 8.0
6005543 9.6 8.8
6005643 9.3 8.8
Flow Rate [L/min]
10
2
Flow Rate
Prior to Steaming
6005443 6005543 6005643
Lot Number
| 29
6.1.3 Effects on Bubble Point Values
Test Procedure
After Diffusion Testing, the same
Sartolon 10" filter cartridges are
then tested by the Bubble Point
Test, utilizing the Sartocheck®
4 Plus automated integrity test
system. The following results are
the averages for the filters from
the three different production lots
tested.
Lot Number Bubble Point Bubble Point

Prior to Steaming after 25 Steam Cycles
[bar|psi] [bar|psi]
6005443 3.7|53.5 3.8|55
6005543 3.7|53.5 3.8|55
6005643 3.6|52 3.7|53.5
Bubble Point [bar]
4.0
3.5
3.0
2.5
2.0
1.5
1.0
Flow Rate
0.5
Prior to Steaming
6005443 6005543 6005643
Lot Number
30 |
6.1.4 Effects on Bacteria Challenge Test
Test Procedure
With the Sartolon 10" filter
cartridges previously mentioned,
a Bacterial Challenge Test was
performed. This test was conducted
according to the current ASTM F838
Guideline. The following bacteria
concentrations are averages for the
elements tested.

[CFU] after 25 Steam Sterilization Cycles
6005443 1.7 × 1011 Sterile Filtrate
6005643 4.7 × 10 11
Sterile Filtrate
Conclusion
The results indicate that the
integrity and bacterial retentive
properties of the Sartolon filter
cartridges are not effected by 25
In-line Steam Sterilization Cycles at
134 °C for 30 minutes.
| 31
6.2 Autoclaving of In order to demonstrate that the
Maxicaps® & Midicaps® Sartolon Maxicaps® & Midicaps®
The materials and construction have good thermal stability,
of the Sartolon Maxicaps® & multiple capsules from three
Midicaps® allow for exposures to different manufacturing lots
multiple autoclaving cycles. Since were tested under the following
multiple autoclaving cycles may procedure:
be required in actual practice,
the influences of the thermo- 1. The new Maxicaps® & Midicaps®
mechanical stresses on the integrity are wetted with water.
of Sartolon Maxicaps® & Midicaps®
were examined. As a result, recom- 2. The filters are then integrity
mendations and limits for multiple tested by bubble point and
autoclaving are given. diffusion tests. The flow rates
were also recorded for these new
Test Method filters.
Sartolon Maxicaps® & Midicaps®,
with a pore size of 0.2 μm from a 3. The filters are autoclaved.
number of different production lots,
were installed and were autoclaved 4. After the first autoclaving cycle,
at 2 bar|30 psi and a temperature the filters are integrity tested by
of 134 °C for 30 minutes. Before bubble point and diffusion tests.
beginning these tests and after The flow rates were also recorded.
25 autoclaving cycles, the integrity
of the Maxicaps® & Midicaps® 5. The filters are then autoclaved
is verified through diffusion and 25 times.
bubble point testing, as well as the
water flow rates. After 25 cycles, 6. After the 25 cycles, the filters are
the filters are tested by the ASTM integrity tested by bubble point
Bacteria Challenge Test to verify and diffusion tests. The flow rates
that the filters could still produce a were also recorded.
sterile effluent.
7. The capsules are then Bacteria
Challenge tested to determine if
the autoclaving cycles had any
effect on the bacteria retention
properties of the Sartolon
Maxicaps® & Midicaps®.
32 |
6.2.1 Effects on Water Flow Rates
Test Procedure
Sartolon filters from three different
lot numbers were installed and
wetted. The flow rate was measured
at a differential pressure of
0.5 bar|7 psi. The following table
contains the average values for the
capsules tested. Flow rate values
have been standardized at 20 °C.
6.2.1.1 Maxicaps®
Lot Number Flow Rate Flow Rate after

Prior to Autoclaving 25 Autoclaving Cycles
[L/min] [L/min]
019141 24.3 22.5
020041 21.8 21.3
020341 18.7 18.2
Flow Rate [L/min]
25
20
15
10
5
Diffusion
Prior to Autoclaving
0 After 25 Autoclaving Cycles
019141 020041 020341
Lot Number
| 33
6.2.1.2 Midicaps®
Lot Number Flow Rate Prior to Flow Rate

Autoclaving after 25 Autoclaving Cycles
[L/min] [L/min]
423943 6.1 6.6
500743 7.2 6.8
500643 6.7 6.5
Flow Rate [L/min]
2
Flow Rate
1
423943 500743 500643
Lot Number
34 |
6.2.2 Effects on Diffusion Values
Test Procedure
Sartolon filters from three different
production lots were wetted. A
Diffusion Test utilizing the following
parameters was conducted utilizing
an automated integrity test system,
the Sartocheck® 4 Plus:
Test Pressure:
2.5 bar|36 psi
Stabilization Time:
5 minutes
Test Time:
5 minutes
The following results are the

averages for the capsules tested.
6.2.2.1 Maxicaps®

to Autoclaving after 25 Autoclaving Cycles
[mL/min] [mL/min]
019141 22.6 22.1
020041 22.9 22.3
020341 23.0 22.7
Flow Rate [L/min]
25
20
15
10
5
Flow Rate
019141 020041 020341
Lot Number
| 35
6.2.2.2 Midicaps®

to Autoclaving after 25 Autoclaving Cycles
[mL/min] [mL/min]
423943 8.1 7.5
423743 6.8 7.4
423843 6.7 6.8
Flow Rate [L/min]
10
2
Flow Rate
423943 423743 423843
Lot Number
36 |
6.2.3 Effects on Bubble Point Values
Test Procedure
After diffusion testing, the same
Sartolon filters are then tested
by the Bubble Point Test, utilizing
the Sartocheck® 4 Plus automated
integrity test system. The following
results are the averages for the
elements tested.
6.2.3.1 Maxicaps®

prior to Autoclaving after 25 Autoclaving Cycles
[bar|psi] [bar|psi]
019141 4.0|58 4.1|59.4
020041 3.5|50.7 3.6|52.2
020341 3.5|50.7 3.5|50.7
Flow Rate [L/min]
1
Flow Rate
019141 020041 020341
Lot Number
| 37
6.2.3.2 Midicaps®

Prior to Autoclaving after 25 Autoclaving Cycles
[bar|psi] [bar|psi]
423943 3.8|55.1 3.9|56.5
423743 3.7|53.7 3.6|52.2
423843 3.7|53.7 3.6|52.2
Bubble Point [bar]
1
Flow Rate
423943 423743 423843
Lot Number
38 |
6.2.4 Bacteria Challenge Test Values
Test Procedure
With the Sartolon filters previously
mentioned, a Bacterial Challenge
Test was performed. TThis test was
conducted according to the current
ASTM F838 Guideline. The following
bacteria concentrations are
averages for the elements tested.
6.2.4.1 Maxicaps®

[CFU] after 25 Steam Autoclaving Cycles
020041 9.6 × 10 10
Sterile Filtrate
Conclusion Note
The results indicate that the The service life of the filter
integrity and bacterial retentive elements is determined by process
properties of the Sartolon conditions, for instance the particle
Maxicaps® are not effected by load of the solution being filtered.
25 autoclaving cycles at 134 °C for The service life can also be influ-
30 minutes. enced by the steaming conditions.
Different qualities of steam and
steam process conditions may
lead to variations in the service
life of the filters when filters are
in-line steam sterilized repeatedly.
Additional service life can affected
by product residues which are
not removed completely from the
membrane by flushing.
| 39
6.2.4.2 Midicaps®

[CFU] after 25 Steam Autoclaving Cycles
423943 3.5 × 10 10
Sterile Filtrate
Conclusion
The results indicate that the
integrity and bacterial retentive
properties of the Sartolon
Midicaps® are not effected by
25 autoclaving cycles at 134 °C for
30 minutes.
40 |
7. Testing According to USP
Test Purpose The following filter types were

The tests for extractable substances used for extractables and particle
and particle release of Sartolon elements testing of Sartolon
filter elements are performed in filter elements, representing the
dynamic extraction mode. This individual filter types available:
methodology provides the best
representative of actual filtration Standard filter cartridges
applications determining levels of 5102507H1
extractable substances and particles
present in varving filtrate volumes. Maxicaps®
The samples for all tests are taken 5101307H1––SS
after 1, 2.5, 5 and 10 liters flush
volume for each element. Midicaps®
5105307H9--SS
According to the specifications
given in section ”Sterile Water
for Injection” of the current USP,
filtrate samples of Sartolon filter
elements are analyzed for Partic-
ulate Matter, Oxidizable Substances,
pH and conductivity, Ammonia,
Sulfate and Chloride. The tests are
performed according to the
descriptions given in the current
USP. The test results obtained are
compared to the relevant USP
specifications.
| 41
7.1 Particle Content of the Filtrate Test Set-up Particle analysis of the samples
Two filter cartridges, two Maxicaps® is conducted utilizing a particle
Purpose & two Midicaps® each from three sensor system. This system consists
In general, the particle release from production lots were wetted of a Pacific Scientific Hiac Royco
filters should be minimized. For and autoclaved prior to being sampler (Model 3000 SOS, serial
parenteral solutions, the require- tested. The wetting of the filters No. 93023007), in which a particle
ments are defined in the USP is achieved through a static soak, sensor (Model HRLD 150, serial
Monographs, which set maximum not through fluid flow, in order to No. 9208-012) is installed to
limits for particle content based avoid removing potential particles analyse the filtrate in accordance
on defined particle sizes. The that may be present. As a wetting with the current USP requirements.
particle release of Sartolon filter and flushing medium, Reverse The system also incorporates a
cartridges, Maxicaps® & Midicaps® Osmosis (RO) generated water is particle counter (Model 8000, serial
should lie well below the limits set used during the testing. An integrity No. 91078805). The particle sensor
forth in the current USP for ”Large test is performed to assure that system is calibrated twice a year in
Volume Parenterals for Single Dose only integral filters are used for line with USP Standards.
Infusion“. this testing. In order to generate
particle-free water, the water is A sampling vessel is placed into
Limits first filtered through two 0.2 µm the sampler. The sample medium is
From the current USP, the following membrane filter cartridges. This drawn in through a glass bulb and a
limits have been set as a maximum water is used to flush the filter sample volume of 25 mL/min. is set
number of particles per mL of housing and all contact surface to exactly on the sampler. The particle
product (in this case, large volume remove surface particles prior to count begins automatically when
injections for single dose infusion): testing. The filter elements that the sampler is started. The average
have been autoclaved and integrity particle value is calculated from a
25 particles/mL > 10 µm tested are then installed in the total of six measurements, 25 mL
3 particles/mL > 25 µm pre-rinsed system. each.
After attachment of the collection Summary of Results

vessel that was also prerinsed with In order to have an overview of
the filtered water, the inlet valve the effluent’s particle content
is opened and the water is filtered of Sartolon filter cartridges and
through the test filters. The samples filtrates of Maxicaps® & Midicaps®,
are taken after 1, 2.5, 5 and 10 the following table contains
liters for analysis. The balance is the average values for the test
used to determine gravimetrically performed. These averages are for
when a sample should be taken. the three different production lots.
Test Set-up
Particle Sensor
System
Particle Test Filter
Filtration Element
Regulating
Valve Pressure
Gauge
Water flow
Overflow
Sampling
Vessel
Collection
Vessel
Balance
42 |
Particle Size Particle Count Particle Count Particle Count Particle Count Limits
[µm] per mL per mL per mL per mL According
after 1 L Flush after 2.5 L Flush after 5 L Flush after 10 L Flush to USP
> 10 1 0 0 0 25
> 25 1 0 0 0 3
7.1.2 Maxicaps®
> 10 5 4 2 0 25
> 25 1 1 0 0 3
7.1.3 Midicaps®
> 10 0 0 0 0 25
> 25 0 0 0 0 3
Conclusion
The tables above show that for
Sartolon 10" filter cartridges,
Maxicaps® and Midicaps®, the
requirements of the current USP
and BP for particle content are met
in the first liter of rinse volume.
This shows that the initial filtrate
conforms to these standards, as it is
not technically feasible to test the
first mL of solution filtered. Accord-
ingly, the Sartolon filter cartridges,
Maxicaps® and Midicaps® do not
have to be rinsed prior to being
able to produce a filtrate that
conforms with the current USP and
BP for particle content.
| 43
7.2 Determination of Oxidizable 7.2.1 Standard Cartridges
Substances of the Filtrate
Results
Test Procedure
Three Sartolon standard cartridges, Blank passed
three Maxicaps® & three Midicaps®
each from three different Lot Test Results Test Results Test Results Test Results
production lots were wetted (by Number after after after after
soaking) and autoclaved. After 1 L Flush 2.5 L Flush 5 L Flush 10 L Flush
installation the filter elements were 6005443 passed passed passed passed
flushed with Water for Injection
and 100 mL samples were taken 6005543 passed passed passed passed
after 1, 2.5, 5 and 10 L flush 6005643 passed passed passed passed
volumes for each element.
As described in the current USP to 7.2.2 Maxicaps®

the 100 mL samples 10 mL of 2 N
sulfuric acid were added and heated Results
to boiling.
Blank passed
Than 0.2 mL of 0.1 N potassium
permanganate were added and the Lot Test Results Test Results Test Results Test Results
solution was boiled for 5 minutes. Number after after after after
If a precipitate forms, it is cooled to 1 L Flush 2.5 L Flush 5 L Flush 10 L Flush
room temperature. If the precipitate 019141 passed passed passed passed
remains its color after cooling to
room temperature, the test sample 020041 passed passed passed passed
and respectively the tested filter 020341 passed passed passed passed
element meets the USP specifica-
tions for oxidizable substances.
7.2.3 Midicaps®
Results
Blank passed
Lot Test Results Test Results Test Results Test Results

Number after after after after
1 L Flush 2.5 L Flush 5 L Flush 10 L Flush
423743 passed passed passed passed
Conclusion
The Sartolon filter cartridges,
Maxicaps® & Midicaps® produced
filtrates that, when measured
by this method, were below the
requirements set by the current USP
Limits for Oxidizable Substances for
”Sterile Water for Injection”.
44 |
7.3 Determination of pH Values and
Conductivity of the Filtrate
Test Procedure
Three Sartolon standard cartridges,
three Maxicaps® & three Midicaps®
each from three different
production lots were wetted (by
soaking) and autoclaved. After
installation the filter elements were
flushed with Water for Injection
and samples were taken after 1, 2.5,
5 and 10 L flush volumes for each
element.
Conductivity and pH value of the

samples were measured using
appropriate calibrated pH meters
and conductivity meters according
to the USP regulations.
Test Limits
The following table lists the limits
for pH and conductivity given by
the current USP in conjunction with
“Sterile Purified Water” and the
filters were tested in the specified
pH range of 5 to 7.
The relationship between the pH

value and the maximum allowable
conductivity for “Sterile Water for
Injection“ according to the current
USP is:
pH Value Maximum Allowable Conductivity [µm/cm]

5 4.7
5.1 4.1
5.2 3.6
5.3 3.3
5.4 3.0
5.5 2.8
5.6 2.6
5.7 2.5
5.8–6.1 2.4
6.2 2.5
6.3 2.4
6.4 2.3
6.5 2.2
6.6 2.1
6.7 2.6
6.8 3.1
6.9 3.8
7.0 4.6
| 45
Results for the pH Values
Blank pH 5.7
Lot pH pH pH pH Note
Number after after after after Due to the interrelationship
1 L Flush 2.5 L Flush 5 L Flush 10 L Flush between the pH value determi-
6005443 5.2 5.3 5.4 5.5 nation and the measurement of the
conductivity, results for both tests
6005543 5.2 5.2 5.3 5.4 must be viewed together.
6005643 5.2 5.3 5.3 5.5
Results for the Conductivity
Blank 0.7 µS/cm
Lot Conductivity Conductivity Conductivity Conductivity Conclusion

Number after after after after Both parameters, pH and pH
1 L Flush 2.5 L Flush 5 L Flush 10 L Flush dependent conductivity of the
[µS/cm] [µS/cm] [µS/cm] [µS/cm] filtrate, when filtering with the
6005443 2.8 2.7 2.5 2.3 Sartolon 10" filter cartridges are
well below the limit requirements
6005543 2.9 2.7 2.4 2.3 of the current USP.
6005643 2.3 2.2 2.0 1.9
46 |
7.3.2 Maxicaps®
Blank pH 5.9
Lot pH after pH after pH after pH after Note

Number 1 L Flush 2.5 L Flush 5 L Flush 10 L Flush Due to the interrelationship
019141 5.4 5.4 5.4 5.5 between the pH value determi-
nation and the measurement of the
020041 5.3 5.3 5.3 5.4 conductivity, results for both tests
Blank 0.7 µS/cm
Lot Conductivity Conductivity Conductivity Conductivity Conclusion

Number after after after after Both parameters, pH and pH
1 L Flush 2.5 L Flush 5 LFlush 10 L Flush dependent conductivity of the
[µS/cm] [µS/cm] [µS/cm] [µS/cm] filtrate, when filtering with the
019141 2.7 2.6 2.5 2.0 Sartolon Maxicaps® are well below
the limit requirements of the
020041 3.2 3.0 2.7 2.1 current USP.
020341 2.6 2.3 2.1 1.8
7.3.3 Midicaps®
Blank pH 5.8
Note
Lot pH after pH after pH after pH after Due to the interrelationship
Number 1 L Flush 2.5 L Flush 5 L Flush 10 L Flush between the pH value determi-
423743 5.4 5.5 5.65 5.7 nation and the measurement of the
conductivity, results for both tests
423943 5.45 5.55 5.65 5.75
Blank 0.8 µS/cm

Conclusion
Lot Conductivity Conductivity Conductivity Conductivity Both parameters, pH and pH
Number after after after after dependent conductivity of the
1 L Flush 2.5 L Flush 5 L Flush 10 L Flush filtrate, when filtering with the
[µS/cm] [µS/cm] [µS/cm] [µS/cm] Sartolon Midicaps® are well below
423743 1.9 1.3 1.0 0.8 the limit requirements of the
current USP.
423843 1.9 1.4 1.1 0.9
423943 1.5 1.2 0.9 0.9
| 47
7.4 Determination of Chloride 7.4.1 Standard Cartridges
Test Procedure Blank passed

three Maxicaps® and three Lot Test Results Test Results Test Results Test Results
Midicaps® each from three different Number after after after after
production lots were wetted (by 1 L Flush 2.5 L Flush 5 L Flush 10 L Flus
soaking) and autoclaved. After 6005443 passed passed passed passed
flushed with Water for Injection 6005543 passed passed passed passed
and 20 mL samples were taken after 6005643 passed passed passed passed
1, 2.5, 5 and 10 L flush volumes for
each element.
7.4.2 Maxicaps®
To the 20 mL samples 5 drops of
nitric acid and 1 mL of silver nitrate Blank passed
are added and gently mixed. If the
turbidity formed within 10 minutes Lot Test Results Test Results Test Results Test Results
is below the control reagent Number after after after after
consisting of 20 mL of high purity 1 L Flush 2.5 L Flush 5 L Flush 10 L Flus
water containing 10 µg of Chloride 019141 passed passed passed passed
the test is passed.
7.4.3 Midicaps®
Blank passed

Conclusion
Sartolon standard filter cartridges,
Maxicaps® and Midicaps® produced
requirements set by the current
USP Limits for Chloride for “Sterile
Water for Injection”.
48 |
7.5 Determination of Sulfate 7.5.1 Standard Cartridges

three Maxicaps® & three Midicaps® Lot Test Results Test Results Test Results Test Results
each from three different Number after after after after
production lots were wetted (by 1 L Flush 2.5 L Flush 5 L Flush 10 L Flush
after 1, 2.5, 5 and 10 L flush
volumes for standard cartridges,
Maxicaps® & Midicaps®. 7.5.2 Maxicaps®
To the 100 mL samples 1 mL of Blank passed

barium chloride is added. If no
turbidity forms the test is passed. Lot Test Results Test Results Test Results Test Results
7.5.3 Midicaps®
Blank passed
Lot pH pH pH pH
Conclusion
Maxicaps® & Maxicaps® produced
requirements set by the current USP
Limits for Sulfate for “Sterile Water
for Injection”.
| 49
7.6 Determination of Ammonia 7.6.1 Standard Cartridges

three Maxicaps® & three Midicaps® Lot Test Results Test Results Test Results Test Results
each from three different Number after after after after
production lots were wetted (by 1 L Flush 2.5 L Flush 5 L Flush 10 L Flush
after 1, 2.5, 5 and 10 L flush
volumes.
7.6.2 Maxicaps®
To 100 mL of each recirculation
samples and sample blank, added Blank passed
2 mL of ammonium oxalate (2 %).
A sample passed the rest, if no Lot Test Results Test Results Test Results Test Results
turbidity was produced. Number after after after after
7.6.3 Midicaps®
Blank passed

Conclusion
Maxicaps® & Midicaps® produced
requirements set by the current
USP Limits for Ammonia for “Sterile
Water for Injection”.
50 |
7.7 Biocompatibility
Purpose
These tests are to determine
that all components used in the
manufacture of Sartolon filter
elements are biosafe and meet or
exceed the requirements for the
current USP Class VI Plastics Tests.
Test Method and Results

Sartolon filter elements were
supplied to an independent testing
facility for evaluation under the
requirements of the current USP
Class VI Plastics Tests, including the
following tests:
Intracutaneous test Systemic

injection test (Extraction at 121 °C)
Systemic Injection test
Implantation test (7 days)
The complete test report is available

upon request.
Result
The following certificate was
released as a result of the testing of
Sartolon filter elements. All material
used in the construction of the
Sartolon filter elements meet or
exceed the requirements of the USP
Class VI. Plastics Tests.
| 51
Certificate Standard Cartridges
52 |
Certificate Inline Maxicaps® Housing
| 53
Certificate Midicaps®
54 |
8. Endotoxin Testing
Purpose Results
The goal of these tests is to
determine whether the amount of Standard Cartridges
endotoxins released in the effluent
of a Sartolon filter element meets Lot Number LAL Test Results
the requirements of EP and USP 6005443 passed
monographs for “Sterile Water for
Injection” (0.25 EU/mL). 6005543 passed
6005643 passed
Test Method
The filter cartridges are shaken in
a defined, smallest possible volume Maxicaps®
of endotoxin free water. Sartolon
filter, Maxicaps® & Midicaps® Lot Number LAL Test Results
from a variety of production lots 019141 passed
are placed into glass vessels and
filled with the required amount of 020041 passed
endotoxin free water. In contrast to 020341 passed
filter cartridges Capsule filters are
filled from both sides of the plastic
housing with the required amount Midicaps®
of endotoxin free water.
Lot Number LAL Test Results
Then the vessels or Capsule filters 423743 passed
are placed on a shaker in order
to free any endotoxins that may 423843 passed
be present. They are shaken for 423943 passed
60 minutes with 100 rpm. Samples
are then taken and evaluated with
the LAL gel clot test with a sensi- Conclusion
tivity of 0.06 EU/mL. All Sartolon 10" filter elements,
under the conditions of the
Along with these samples a positive extraction test described above,
control containing 0.06 EU of gave results below 0.18 EU/mL
endotoxin per mL is incubated bacterial endotoxin.
as well as the endotoxin free
water itself as a negative control.
A clot indicates the presence of
endotoxins. No clot indicates
absence of endotoxins
(i.e. < 0.06 EU/mL).
| 55
Sales and Service Contacts
For further contacts, visit www.sartorius-stedim.com
Europe Americas Asia|Pacific

Germany Italy USA Australia
Sartorius Stedim Biotech GmbH Sartorius Stedim Italy S.r.l. Sartorius Stedim North America Inc. Sartorius Stedim Australia Pty. Ltd.
August-Spindler-Strasse 11 Via dell’Antella, 76/A 5 Orville Drive, Suite 200 Unit 5, 7–11 Rodeo Drive
37079 Goettingen 50012 Antella-Bagno a Ripoli (FI) Bohemia, NY 11716 Dandenong South Vic 3175
Phone +49.551.308.0 Phone +39.055.63.40.41 Toll-Free +1.800.368.7178 Phone +61.3.8762.1800
Fax +49.551.308.3289 Fax +39.055.63.40.526 Fax +1.631.254.4253 Fax +61.3.8762.1828
Sartorius Stedim Systems GmbH Netherlands Argentina China

Robert-Bosch-Strasse 5–7 Sartorius Stedim Netherlands B.V. Sartorius Argentina S.A. Sartorius Stedim Biotech (Beijing) Co. Ltd.
34302 Guxhagen Int. A. Ávalos 4251 No. 33 Yu’an Road
Phone +31.30.60.25.080
B1605ECS Munro Airport Industrial Park Zone B
Phone +49.5665.407.0 Fax +31.30.60.25.099
Buenos Aires Shunyi District, Beijing 101300
Fax +49.5665.407.2200
filtratie.nederland@sartorius-stedim.com
Phone +54.11.4721.0505 Phone +86.10.80426516
France Fax +54.11.4762.2333 Fax +86.10.80426580
Poland
Sartorius Stedim FMT S.A.S.
Sartorius Stedim Poland Sp. z o.o.
ZI des Paluds Brazil Sartorius Stedim (Shanghai)
ul. Wrzesinska 70
Avenue de Jouques – CS 91051 Sartorius do Brasil Ltda Trading Co. Ltd
62-025 Kostrzyn
13781 Aubagne Cedex Avenida Senador Vergueiro 2962 3rd Floor, North Wing, Tower 1
Phone +48.61.647.38.40 São Bernardo do Campo No. 4560 Jinke Road
Phone +33.442.845600
Fax +48.61.879.25.04 CEP 09600-000 - SP - Brasil Zhangjiang Hi-Tech Park
Fax +33.442.845619
Pudong District
Phone +55.11.4362.8900
Russian Federation Shanghai 201210, P.R. China
Sartorius Stedim France SAS Fax +55.11.4362.8901
LLC “Sartorius Stedim RUS”
ZI des Paluds Phone +86.21.6878.2300
Uralskaya str. 4, Lit. B
Avenue de Jouques – CS 71058 Mexico Fax +86.21.6878.2882
199155, St. Petersburg
13781 Aubagne Cedex Sartorius de México, S.A. de C.V.
Phone +7.812.327.53.27 Libramiento Norte de Tepotzotlan s/n, Sartorius Stedim Biotech (Beijing) Co. Ltd.
Phone +33.442.845600
Fax +7.812.327.53.23 Colonia Barrio Tlacateco, Guangzhou Representative Office Unit K,
Fax +33.442.846545
Municipio de Tepotzotlan, Building 23
Spain Estado de México, Huihua Commerce & Trade Building
Austria
Sartorius Stedim Spain, S.A.U. C.P. 54605 No. 80 Xianlie Middle Road
Sartorius Stedim Austria GmbH
Avda. de la Industria, 32 Guangzhou 510070
Modecenterstrasse 22 Phone +52.55.5562.1102
Edificio PAYMA
1030 Vienna Fax +52.55.5562.2942 Phone +86.20.37618687|37618651
28108 Alcobendas (Madrid)
Fax +86.20.37619051
Phone +43.1.7965763.18 leadsmex@sartorius.com
Phone +34.913.586.098
Fax +43.1.796576344
Fax +34.913.589.623 India
Peru
Sartorius Stedim India Pvt. Ltd.
Specifications subject to change without notice. Printed in Germany on paper that has been bleached without any use of chlorine.
Belgium Sartorius Peru S.A.C.
Switzerland #69/2–69/3, NH 48, Jakkasandra
Sartorius Stedim Belgium N.V. Av. Emilio Cavenecia 264 San Isidro
Sartorius Stedim Switzerland AG Nelamangala Tq
Rue Colonel Bourg 105 15073 Lima, Perú
Ringstrasse 24 a 562 123 Bangalore, India
1030 Bruxelles
8317 Tagelswangen Phone +51.1.441 0158
Phone +91.80.4350.5250
Phone +32.2.756.06.80 Fax +51.1.422 6100
Phone +41.52.354.36.36 Fax +91.80.4350.5253
Fax +32.2.756.06.81
Fax +41.52.354.36.46
Japan
Hungary
U.K. Sartorius Stedim Japan K.K.
Sartorius Stedim Hungária Kft.
Sartorius Stedim UK Ltd. 4th Fl., Daiwa Shinagawa North Bldg.
Kagyló u. 5
Longmead Business Centre 8-11, Kita-Shinagawa 1-chome
2092 Budakeszi
Blenheim Road, Epsom Shinagawa-ku, Tokyo, 140-0001 Japan
Phone +36.23.457.227 Surrey KT19 9 QQ
Phone +81.3.4331.4300
Fax +36.23.457.147
Phone +44.1372.737159 Fax +81.3.4331.4301
Fax +44.1372.726171
Malaysia
Ukraine Sartorius Stedim Malaysia Sdn. Bhd.
LLC “Sartorius Stedim RUS” Lot L3-E-3B, Enterprise 4
Post Box 440 “B” Technology Park Malaysia
01001 Kiev, Ukraine Bukit Jalil
57000 Kuala Lumpur, Malaysia
Phone +380.44.411.4918
Fax +380.50.623.3162 Phone +60.3.8996.0622
Fax +60.3.8996.0755
Singapore
Publication No.: SPK5716-e | Status 12|2020
Sartorius Stedim Singapore Pte. Ltd.

1 Science Park Road,
The Capricorn, #05-08A,
Singapore Science Park II
Singapore 117528
StatSSSSS
Phone +65.6872.3966
Fax +65.6778.2494
South Korea
Sartorius Korea Biotech Co., Ltd.
8th Floor, Solid Space B/D,
PanGyoYeok-Ro 220, BunDang-Gu
SeongNam-Si, GyeongGi-Do, 463-400
Phone +82.31.622.5700
 www.sartorius-stedim.com Fax +82.31.622.5799

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Validation Guide

1. Introduction 3 5. Integrity Test Limits 21

4. Chemical Stability – Sartolon 19 8. Endotoxin Testing 55

Routine Testing of Testing Conducted

pH Change of the Filtrate

Conductivity Changes of the Filtrate

Water Flow Rates

Temperature and Pressure

Evaluation of Integrity Test Values

2.1 Type and Part Number Overview

2.1.1 Standard Cartridges Explanation

510 25 07H 1 510

Height Filtration Area

510 15 07H 9 B 510

Filtration Area Pore Size

Units per Package

Units per Package

510 73 07H 1 00 510

Effective Filtration Area

510 53 07H 9 00 A 510

Effective Filtration Area

Units per Connectors

Units per Package

Final Filter Membrane:

2.6 Fiber Release

2.7.1 Standard Cartridges

Filtration Area Height Diameter

Size Connector Combinations [mm]

Size All Connector

Diameter with Valves

Size All Connector

Filtration Area Connector Combinations [mm]

Total Diameter Midicaps® Housing

Filtration All Connector

Total Diameter Midicaps® Housing

Filtration All Connector

Temperature [°C] 20 100 121 134 140

2.9 Maximum Back Pressure

Temperature [°C] 20 100 121 134

2.10 Wetting the Filters for Integrity

Number of sterilizing cycles:

2.13 Integrity Test Limits

2.13.1 Cartridges and Maxicaps®

2.13.2 Cartridges and Midicaps®

Diffusion and Bubble Point

Differential Pressure [bar] [psi]

10" 20" 30"

Differential Pressure [bar] [psi]

Differential Pressure [bar] [psi]

Test Specifications Aqueous Solutions:

5.1 Basis for the Determination of Test-Method Integrity Test

”After a filtration process is

Diffusion and Bubble

* CFU = Colony Forming Units

Test Cartridge Lot Number

Conclusion Based on conclusive results Sartolon Note

Sartolon 0.2 µm, Size 9 with

Lot Number Bioburden Bacteria Challenge Test