Overview
Filter integrity testing has undergone significant changes over the last 40 years as industry needs and the evolution of regulatory expectations have driven solutions to reduce risk and increase patient safety. The first generations of sterilizing-grade filters were supported by manual bubble point, and forward flow (diffusive flow) testing. These were simple tests requiring little more than calibrated pressure gauges and gas-volume measuring apparatus supported by simple operating procedures and paper records. These tests paved the way for the first purpose-built integrity test instruments, developed in the 1980s specifically for the pharmaceutical market. The introduction of FDA guidance and European Good Manufacturing Practice (GMP) in 1987 mandated the integrity testing of critical filters, and this accelerated the development of high-performance automated test equipment suitable for use in a regulated environment (1,etc).
By the mid-to-late 90s, regulatory bodies had expanded guidance for filter integrity testing. The FDA recommended integrity testing of critical vent filters in place, and new EU guidelines for GMP were published: Medicinal Products for Human and Veterinary Use (Annex 1) (3). The latter required that the integrity of a sterilizing-grade filter be tested pre-use and post-sterilization (PUPSIT), in addition to after use. This topic still generates discussion more than 20 years later and is the subject of recent reinforcement of the guidance.
The acceptance of manual testing and paper batch records has been largely replaced by automated and digital alternatives. The subsequent need for data integrity throughout digital manufacturing systems has been driven through Good Automated Manufacturing Practice (GAMP) guidelines and guidance from the FDA in the form of 21 CFR part 11 (4). Today, some models of filter integrity test instruments can offer secure data management and transfer and deliver confidence that a static filter integrity test result is valid and cannot be altered. But not all instruments are equal, nor do they all offer the same features to suit your process as it evolves.
This guide gives you a helping hand to select the filter integrity test instrument that works best for your process and that is fully compliant with current regulations.
2. Design
2.1 How easy is it to use?
Ease of use is often cited by operators as the primary factor that affects their selection of an instrument. This is a significant aspect to consider when deciding on the right choice for any application. Automated instruments that have intuitive navigation across a well-designed human machine interface (HMI), tend to be quick to learn and easy to adopt to reduce deviations by minimizing operator errors. Easy to use instruments also simplify the training and routine re-training burdens demanded in any GMP process. Simplicity saves operator time, and reduces training costs.
TIP 1: If possible, obtain a demonstration instrument for evaluation and allow a cross-section of users to experience the instrument and perform each of the tests that the instrument is expected to run. If a knowledgeable operator requires more than basic direction to perform the tests, this may be an indication that the instrument takes some time to master and may continually present usability challenges throughout its lifetime.
TIP 2: Ask about options to reduce transcription errors by using technology such as barcode readers for the entry of test data. Build this functionality into your SOP for a direct impact on the number of investigations and deviations that share a root cause of a simple data entry mistake.
2.2 Where will the instrument be used?
Integrity test instruments might be used in a wide variety of settings ranging from uncontrolled plant areas to highly controlled and monitored cleanrooms. The physical design of the instrument should be suitable for each of the environments that it may be used within. Best-in-class equipment will have design features to support the use in clean environments. These features may include an absence of internal ventilation that could generate particles, or the instrument being dust and splash proof; perhaps with appropriate IP ratings that support the external cleaning requirements, common in the most challenging environments.
2.3 Will it be reliable?
Most integrity test instruments are exposed to wetting liquids that might contaminate their internal components. If not managed properly, this may lead to increased service costs, or cause a loss of function or accuracy of the instrument over time.
Best-in-class equipment will have methods to avoid process liquids draining back into the instrument and may also utilize an internal diagnosis program to check the critical hardware performance at regular intervals. This is executed to highlight any potential issues before using the instrument in critical tests.
TIP 3: Ask the manufacturer for their recommendations on how to apply additional process controls through good instrument design and test installation practices.
3. Function
3.1 What tests can it perform?
In certain environments, some instruments could be better suited to particular types of integrity test than others. In general, there are three types of filter integrity test: Forward Flow (diffusive flow), bubble point and water intrusion.
TIP 4: Ensure that the instrument you are planning to purchase is capable of each of the tests that you wish to perform. Consider how the use of your instrument may evolve so you can cover the tests you want to perform in the future.
Best-in-class instruments may be able to do more than test filters. The application of the same measuring technology within the instrument may be able to be applied to other pneumatic tests such as leak testing of various fixed volume vessels or systems, or the installation testing of some single-use systems. This additional functionality may provide future opportunities to control process risks with no further investment.
TIP 5: Obtain a demonstration instrument for evaluation and run each of the tests that you expect to perform.
3.2 Is it accurate?
The claimed accuracy of different integrity test instruments might vary from 3% to as much as 10%, for different measurement ranges.
The higher the accuracy of the test instrument the lower the process risk that arises from the potential for a filter integrity test to provide a false result. Both false filter passes and false filter failures impact either the process safety or efficiency. Both are undesirable but any instrument feature that helps to prevent a false pass should be considered critical.
The calibration method use underpins the accuracy claim of any instrument. Should you wish to confirm those claims, comparisons can be performed using gas flow measurement references that are typically available from 1 mL/min to 1000 mL/min. These can be used to confirm the performance for diffusive flow testing. No equivalent references exist for the measurement of the bubble point, therefore a claim for accuracy based on reproducible measurements cannot be given.
TIP 6: Find out what safeguards are provided to prevent false pass results and false failures for any instrument you are considering. For example, methods are available to assure that the differential pressure across the tested filter is not impaired by an elevated pressure on the downstream side of the filter. There are also instruments that can prevent a pass result being reported if the integrity test is run against a closed valve.
TIP 7: Ask if there are any peripheral devices that might assist in reducing any residual risks by identifying issues before they lead to batch deviations. For critical applications, or for instruments that may be relocated regularly, consider using an external device that can check the flow accuracy between calibrations.
3.3 Will I get my results quickly?
Some flow measurement technologies are faster than others. Some, such as the Forward Flow test, when coupled with validated algorithms, may be able to shorten the filter test times without any compromise of the measurement accuracy. Some of the latest instrumentation models offer faster network integration and up to 20% reduction in test time when compared with older models. These shorter test times can release valuable resources for other process tasks and speed the progress of process operations.
TIP 8: Compare how quickly each instrument performs each test, especially those you expect to do routinely. While comparing test speeds, also check that instruments that offer the highest speed of testing still maintain the test accuracy.
For users that need to test large numbers of filters, even more time can be saved by using instruments and extensions that can support the testing of multiple filters without the operator returning to the instrument during the testing.
TIP 9: Check to see if the instrument can be used to support the testing of multiple filters without increasing the number of units that require calibration.
4. Compliance
4.1 What is the instrument validation package?
According to GAMP5 guidelines filter integrity test instruments should be manufactured in accordance with the latest industry standards and designed with FDA approved components. They should also possess technological controls required for use in a 21 CFR Part 11 compliant environment.
Integrity test instrumentation is defined as 'off-the-shelf'. For such instruments a comprehensive validation/qualification package prepared by the vendor can significantly reduce the qualification efforts for the user.
TIP 10: Look for tools and resources that the manufacturer can provide to assure that the instrument will be successfully validated - ask what documentation is available to support IQ/OQ/PQ.
4.2 What needs to be calibrated?
Regular calibration of instrumentation is an integral part of GMP compliance. However, it can be easily overlooked when focusing on the design and function of an integrity test instrument.
TIP 11: Find out how and where the instrument is calibrated. For integrity test instruments which report pressure and flow, this should be a calibration against pressure and flow references in order to assure accurate results. Some integrity test instruments actually measure pressure decay and report flowrate which can complicate validation.
4.3 Is data safe and secure?
Electronic records need to be controlled in a way that supports use in a 21 CFR Part 11 compliant environment. This typically means that there are features to ensure data integrity and that support electronic records and signatures. Assurance of data integrity and simple electronic audit trails that confirm 'static' test records with date/time of test and electronic signatures, are essential.
TIP 12: Look out for instruments that have been designed using ALCOA Plus principles to ensure data security and protection is observed, and the highest product quality and patient safety is maintained.
4.3.1 What is ALCOA Plus?
Attributable: Controlled access records the user, time, and date for each test, creation/modification of tests and configuration and date/time changes, all of which become part of the record audit trail.
Legible: All parameters defining a test and all metadata are included in the test results so the raw data can be understood. This allows a clear picture of the sequencing steps or events in the record.
Contemporaneously recorded: Test results are recorded as they are generated and completed.
Original: Test results are the first captured data and do not require recalculation, and only electronic signatures with comments can be added.
Accurate: Test results are based on flow measurements that are properly calibrated against traceable pressure and flow references and the system verifies that the screen display, print result and data contents all match.
Plus:
Complete and consistent: Test results are static records. All data are available to view with nothing deleted. The test result is complete and cannot be modified after the result is stored. Test results are stored chronologically with date and time.
Enduring: Test results are recorded with a time stamp, and each test is linked to the serial number of the instrument, which has the time synchronized with the time of the host PC or relevant server. A continuous test counter also maintains the sequence of tests independent of the time stamp.
Available: Configuration, test programs, user data and test results can be easily exported to a computer network or an external flash drive for long-term storage.
4.4 What is the after-sales service and support like?
Access to agile, efficient, and effective service support is critical for a best-in-class instrument. Services that keep it in top operational condition, optimize its accuracy and productivity throughout its service life help you get the best out of your test instrument.
TIP 13: Challenge the manufacturer to see if they have well-trained and certified service technicians as well as sufficiently equipped facilities to support installations, annual calibrations, re-qualifications, maintenance, software upgrades and other service procedure. In addition, find out if there are services, support, or software to help find and fix the root cause of any failed filter tests.
TIP 14: Ensure the recommended maintenance servicing schedule is followed to protect the instrument, increase its day-to-day efficiency, and to maximize its service lifetime. Be proactive and discover how your supplier can respond to any issues.
4.5 Can the supplier help with training?
Look into the practical and theoretical operator training that can be provided to support your in-house training programs. Sufficient training in instrument operation is essential to reduce risk and contribute to operator compliance. If you have an in-house training program, train-the-trainer courses may be available to help you pass on knowledge effectively throughout the facility.
TIP 15: Ask the manufacturer if they have an eLearning platform that will support real-time training and continuous learning with qualification records that are saved, certified, and traceable.
TIP 16: Ask your instrument supplier if they can provide training to support different learning preferences, such as virtual reality training.
5. Automation
5.1 Does the instrument speak your automation language?
In an age of multiple digital pathways and interfaces, ensure the test instrument meets current industry communication standards with regard to automation protocols. Typical requirements are likely to include …
- ProfiBus, ProfiNet, DeviceNet or OPC UA for control levels to other systems
- SCADA for transmitting results into central storage, ethernet for downloading results for backup or archiving
- PAS-X for integration into a manufacturing execution system (MES) platform for remote control and data collection.
TIP 17: Ask if the test instrument has multiple interfaces to help adapt to existing or future manufacturing environments. These can save both operational time and costs.
5.2 Is it just the filter test that you need to automate?
Filter integrity testing has often been seen as a stand-alone challenge that needs to be managed separately with off-line processes and preparative apparatus. Advances in automation in surrounding processes, often coupled with single-use solutions and an increased awareness of the value of automation for risk control, should cause us to challenge historic solutions for critical unit operations.
TIP 18: Consider combining multiple processes in a single automated solution for the ultimate approach to operations that depend upon filters. Solutions that support virus filtration and sterilizing-grade filtration during bulk and final filling are available, and these can help you introduce PUPSIT without additional process risks.
5.3 Are there any other advanced solutions that might help me?
Performing the filter integrity test, managing the test results, and integrating these into the batch records in a compliant manner drives you every day. Are there any features of services that may help you achieve this and are there other features or services that may help? These may simplify or reduce the frequency of deviation investigations and help you to identify and introduce preventive actions, and action change that reduces the frequency or impact of deviations.
TIP 19: Ask about options that may provide additional operational insights. Software solutions may be available that help you manage data or monitor performance across multiple instruments. They may also help you analyze results and provide guidance for troubleshooting and improvement to help to ensure trouble-free operation.
5.4 Can I customize the instrument?
Instrumentation should be designed with some degree of flexibility and adaptability to meet your unique application set-up.
TIP 20: Review the instrument capabilities and degree of flexibility before purchase, and if needed, discuss options for customizing your filter integrity test instrument to meet your present and future needs.
5.5 Can I get a third-party opinion?
A strong user-base is often an indicator that you're on the right track. Obtain references and published reports describing the instruments. Seek out other users in your company (perhaps in a different location), who have knowledge and experience they can share.
TIP 21: If you don't have users in your network, ask if the manufacturer can connect you with some existing instrument users.
By taking all of the above criteria into account, and obtaining feedback from other users, you will be on the right track to choosing the best filter integrity test instrument for your process.
But, if you need a stronger helping hand or a quicker route to a solution, check out our Palltronic Flowstar filter integrity test devices and suite of software, peripherals, and services. If you wish to investigate this further, we look forward to hearing from you and answering any questions you may have.
REFERENCES
- FDA
- EU
- Annex 1
- GAMP guidelines, FDA 21 CFR part 11