Filter Integrity Testing in The Pharmaceutical Process Environment - Automat

Filter Integrity Testing in the Pharmaceutical Process Environment - Automat... to ensure that GMP sterility requirements are met.
- BioPharm International
Filter Integrity Testing in the Pharmaceutical Process

Environment
Automating filter integrity testing helps to ensure that GMP sterility requirements are
met.
Jun 1, 2006
By: Reinhard Baumfalk, Jerry Finazzo
BioPharm International
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Integrating filtration steps into an aseptic pharmaceutical

process has some unusual complications. Various factors, such
as particle load, fluctuations in pressure and temperature, and
cleaning steps (which may have high temperatures or severe
changes in pH), can cause wear to the filter elements.
Continued performance of the filter elements becomes one of

the critical process parameters that must be controlled.1,2,3
Using a filter in a process can lead to various damage
phenomena such as irreparable blockage of the filter
Reinhard Baumfalk,
membrane and cracks or changes to the membrane or pore
Ph.D
structure. While blockage can be easily detected during the
process run, cracks or changes in pore structure cannot be detected that easily.4
There is a method for checking these filter element

properties throughout the course of the process—
the filter integrity test. A typical four-step integrity
test procedure (algorithm) is Figure 1.5 We will
delve first into the test methods and then we will
describe how to ease the burden by automating the
entire cycle. Many industry-specific terms are
defined in the glossary at the end of this article.
INTEGRITY TEST METHOD
The four integrity test steps are implemented upstream and downstream of the
filtration unit in order to be able to detect any possible changes in filter element
properties and thereby supply positive results to confirm the success of the filtration
step. The diffusion test and the bubble point test are established, non-destructive test
methods. To determine validity, compare the test results to the filter manufacturer's
tolerance data. The bases of the tolerance data are validation processes conducted by
the manufacturer. These are used to determine tolerances by correlating absolute,
destructive test methods (bacteria challenge test) with filter integrity tests. Both test
methods rely on a procedure of wetting the filter membrane with a pre-defined
medium (typically ultrapure water, but also customer-specific liquids).4
To start the automatic filter test, the filtration housing is disconnected from the actual
process, or the filter is installed in a separate test housing. In this procedure, the filter
element is pressurized at a specific value on the upstream (non-sterile) side. At this
test pressure, the diffusion through the filter membrane is determined for values
starting at 0.1 mL/min. By contrast, when the bubble point test is carried out, the
applied test pressure is raised successively and the diffusion measured in parallel is
monitored to determine any disproportionate increase. This increase in diffusion is
caused by the wetting medium being pressed out of the pores of the filter membrane,
which initially occurs in the largest pores, thereby providing information about the
upper limit of the pore size distribution. Typical bubble point values for microfilters
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Filter Integrity Testing in the Pharmaceutical Process Environment - Automat... to ensure that GMP sterility requirements are met. - BioPharm International
range between 3,000 mbar and 4,000 mbar and, in ultrafiltration, can go up as high as
8,000 mbar. These methods also allow reliable detection of cracks or blockage.
Air filtration also needs a filter integrity test method to guarantee the sterility of
critical parameters. Applications for these filter elements include pharmaceutical and
biotechnological production systems. Unlike liquid filtration, air filtration elements
are based on hydrophobic membranes, which prohibit the test methods previously
mentioned (membrane wetting with ultrapure water).
In this context, an alternate, non-destructive method—the water intrusion test (WIT)6

—is an established test. During the WIT test, or the very similar water flow test
(WFT), the penetration of water into the hydrophobic membrane is measured under
pressure and evaluated by comparing the results to a limit value. Additionally, this
filter type can be tested by a diffusion test after wetting the membrane by liquids with
low surface tension such as isopropanol or mixtures of WFI and isopropanol.
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2007
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Reinhard Baumfalk, PhD is head of systems development of the Biotechnology
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2007
Author Info
Search Jerry Finazzo

Product Manager
Jerry Finazzo is a product manager of process filtration integrity testing at Sartorius
North America, Inc.
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All of these test methods give results as either a
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flow test) or a pressure value (bubble point test,
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pressure drop test) which has to be compared to
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the given limit value of the tested filter element in
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Classifieds Search customer-specific parameters and correlate to a Table 1. Typical limit values for different filter
7 types
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Career Opportunities a typical set. Short test descriptions appear in the glossary.
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Advertiser Profile several steps to be performed by an automated
Form integrity tester (Figure 2). An automated integrity
Figure 2. Standard integrity test algorithm 11
Application tester therefore needs to be able to handle
Notebook pressurized air or WFI, in order to pressurize the filter cartridge with the appropriate media.
Instructions Based on this requirement, hardware such as valves, pressure transducers, and
Contact Sales flowmeters are standard components of a today's integrity tester. Typically these parts are
controlled by micro-controller-based hardware and run by proprietary firmware (GAMP
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Marketplace/ class 2 or 3).8 Since integrity testers are not only used in a well-defined laboratory
Technology environment, but also installed in a rough production process, the integrity tester
Showcase Guidelines manufacturer has taken these conditions into consideration. Hardware components should
Marketing Services be made of appropriate materials (stainless steels are favored) and have the needed
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separate software control loops within the test procedure.
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Talk to BioPharm To meet the needs of process integration, most of the available integrity testers have
Contact Marketing interfaces in order to use additional external hardware. External valves mounted on the
Services filter housing can be handled directly, or controlled by sending commands via a PLC
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at the filter housing, because long tubing lengths could interfere with the accuracy of the
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Because the WIT and WFT test use WFI as penetration media for the
filter membranes, additional dedicated equipment has been
developed by most of the integrity test manufacturers. A trolley
equipped with a stainless steel vessel stores the needed water
volume under sterile conditions. A PLC allows automated CIP or even
SIP procedures for the vessel, with valves permanently connected.
Filter Integrity
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Reinhard Baumfalk
PhD
About Reinhard Baumfalk
email: reinhard.baumfalk@sartorius.com
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based on the Ethernet/TCP/IP protocol. These interfaces allow a data transfer, or even a
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Resources All topics
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generally be accomplished in one of two ways: electronic data storage in a 21 CFR Part
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under 21 CFR Part 11.9,10
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21 CFR Part 11
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Products and tester needs to be qualified before it can be used in the production
Services environment. Qualification is typically divided into three steps, namely
Classifieds Search Installation Qualification (IQ), Operational Qualification (OQ) and a
Contact Sales Performance Qualification (PQ). We cover this later.
When working with electronic data storage, many factors must be
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considered to properly integrate the integrity tester into the IT process.
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Not only must the integrity tester fit into the 21 CFR Part 11
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environment, but also all other equipment (PLCs, computers, SCADA
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Form Ethernet and OPC servers for communication to computers and RS-232 and Profibus DP
Application for communication to PLCs.
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Pay attention to when and how often data are to be transferred from the integrity tester.
Integrity testers usually have the ability to transfer data automatically (as it is being created

Marketplace/ or time based) and manually. It is important that the data be transferred in a timely fashion
Technology to a designated computer where the data can be properly archived and backed up. While
Showcase Guidelines integrity testers may have the memory to store large amounts of data, they are not
Marketing Services intended as the sole data storage location for integrity test data (transient data).
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Your Subscription devices to process and store data. The device is only connected from time to time to the
Talk to BioPharm process network containing the archive servers or MES systems. This device needs to
Contact Marketing have the capability to store data (integrity test parameters as well as test results) since
Services GMP-relevant data are being stored. An audit trail, or user access management, is
Contact Editorial required since all 21CFR Part 11 requirements have to be met in the device.
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Board In the second setup, the devices are permanently connected to the process network. Due
to this permanent connection, in most cases all relevant GMP data are not stored on the
device, but directly received from or sent to the MES or PLC system ("unique source
principle"). The supervising network can handle the start of integrity tests and running the
complete test procedure. Since GMP data are not stored on the integrity test device, it is
only a part of a 21 CFR Part 11 system.
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requirements have to be fulfilled as mentioned above. But because the software
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Resources have to be found. For instance, electronic data should be stored in separate files. By All topics
Buyers Guide adding a checksum to each file and naming it with a unique non-reproducible name, it will
Corporate have the required 21 CFR Part 11 features. Then, the computer or data historian (audit
Capabilities trail) can link the data file to the proper filter and product batch records. This is commonly
Reader Service described as traceability and the file content can be checked for integrity based on the
FDA Links specific checksum. The data file includes all test parameters as well as the actual integrity
test value with a definitive pass or fail result. Typically, additional information is also
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included in the integrity test result file such as product, product lot, filter part number, and
Information for filter lot or serial number.
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21 CFR Part 11 A large majority of existing processes do not have electronic data transfer capability and
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are organized by a paper-based documentation system. Most integrity testers on the
market will have an onboard printer, or a serial port for an external printer. A printout is the
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is stored in a safe location while another is incorporated into the batch records for each
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process run.
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QUALIFICATION
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2007 Media Planner Qualification of an integrity tester is an important part of the process integration. Suppliers
of integrity testers support customers with the device, and with qualification protocols that
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Form are optimized for an efficient and secure qualification process based on the supplier's
know-how. Qualification support is typically available from the supplier and ensures that
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the qualification can be performed in a professional manner. The documentation used,
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Instructions whether the integrity test results are electronic records or hardcopy printouts, is very
similar. Additional protocols are used when data transfer is involved.
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Installation qualification. A qualification generally starts with the IQ. The purpose of the
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design intentions and the manufacturer's recommendations or requirements. Verification
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that the proper documentation has been supplied with the unit, a physical inspection of the
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equipment, and a facility requirements check are common items included in the IQ.
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that the equipment performs as intended. There are many items verified during an OQ,
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with some of the more difficult tests confirming that the actual integrity test result is within
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specification. Typically, for bubble point, diffusion (forward flow), and water intrusion, the
integrity test result will be compared with a measured reference. For example, when
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testing for diffusion, it is common for the integrity result to be verified using a mass-flow
Contact Circulation meter. IQ and OQ can be performed by the manufacturer of the integrity tester, or by the
Editorial Advisory end user. Similarly, the IQ and OQ protocols will typically originate from the manufacturer,
Board with the end user using them as is, or modifying them to their validation standards.
Performance qualification. The last part of a validation is the PQ. The purpose of a PQ is
to provide documented verification that the equipment can perform effectively and
reproducibly based on approved standard operating procedures (SOPs). Typically, actual
process filters in the production environment are used during this testing. The end user's
SOPs, as well as personnel, are used to perform the PQ. The integrity tester manufacturer
may be consulted during the PQ, but typically will not perform the protocols.
CONCLUSION
The integration of filter integrity testers impacts the

filtration process, as well as the IT environment.
Available integrity testers offer a wide variety of
integration options to perform in a laboratory and also in
the process environment. Because the integration
concept is based on a standard device, which only has to
be configured in an appropriate way, qualifying the
device within the customer's validation process can be
done by using the integrity tester manufacturer's
documentation. This possibility leads to dramatically
reduced efforts in the qualification procedure and should
therefore result in a preferred choice of standard integrity
testers to carry out a filter integrity test step in a filtration
process.
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Filter Integrity Testing in the Pharmaceutical Process Environment - Automat... to ensure that GMP sterility requirements are met.

Filter Integrity Testing in the Pharmaceutical Process

Integrating filtration steps into an aseptic pharmaceutical

Continued performance of the filter elements becomes one of

There is a method for checking these filter element

INTEGRITY TEST METHOD

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In this context, an alternate, non-destructive method—the water intrusion test (WIT)6

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Filter Integrity Testing in the Pharmaceutical Process

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The integration of filter integrity testers impacts the

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