Overcoming challenges to carry out successful filter integrity testing within a regulated environment
The need to comply with regulatory authorities and provide assurance of patient safety when manufacturing drug substances has, over time, increasingly progressed filter integrity testing into a high place of significance.
Since we first developed automated filter integrity test instruments in 1983 and the subsequent mandatory requirements for testing critical use filters by the FDA guidance and European GMP (regulators) in 1987, filter integrity testing has been refined and updated to reduce testing times, increase efficiency, accuracy, and reliability and remain up-to-date with data integrity guidelines.
However, the challenges of data integrity, membrane wetting, and the potential risk from contamination during and after testing remain constant.
With a little knowledge from the experts and the use of modern automated filter integrity testers, such as the Palltronic® Flowstar V Integrity Test Instrument, wetting and contamination challenges can be addressed and filter integrity testing can become simple, reliable, and auditable.
Blog: Filter Integrity Testing – Protect Your Product!
Regulatory Authorities and Filter Integrity Guidelines
Filters used in pharmaceutical processes require validation in accordance with Good Manufacturing Practice (GMP), as such they must be routinely tested for integrity. Although both the FDA and EU GMP guidelines state this necessity, they differ in their requirements.
Both regulatory bodies are aligned in their need for post-use filter integrity tests. However, where FDA GMP only recommends a pre-use filter integrity test, pre-use post-sterilization testing (PUPSIT) is compulsory when adhering to EU GMP guidelines.
Data Integrity and Ensuring Regulatory Compliance
Data integrity underpinned by sufficient electronic records and signatures in accordance with cGMP and 21 CFR Part II, has been the focus of regulatory bodies such as the FDA and MHRA in recent years. The challenge to assure the integrity of records as they are generated and to maintain them is essential to the development and production of high quality, safe and effective drugs.
The expectation of regulatory bodies is that all records generated by automated filter integrity testers is both accurate and reliable, with risk-based strategies implemented to detect and prevent data integrity issues.
Effective and compliant data handling can be assured when automated filter integrity test instruments are designed following ALCOA Plus principles. ALCOA stands for:
- Contemporaneously recorded
- Original or true copy
ALCOA Plus extends the criteria to include complete, consistent, enduring, and available.
Successful Wetting of Filter Membranes
To ensure integrity test results are accurate, and to avoid false failures, complete wetting of the filter membrane is essential. This challenge, more often seen with pre-use filter integrity tests, can be sufficiently overcome if wetting procedures are carefully considered.
The most commonly-used liquids for wetting filter membranes are
- A mixture of alcohol and water
- The product to be filtered
Alcohol is often considered to be a back-up wetting fluid used for offline post-use tests. It is often difficult to thoroughly remove alcohol from a filter prior to processing, as such the use of alcohol for pre-use testing is typically avoided.
However, for certain applications such as virus filtration, alcohol-based solutions can be a suitable fluid as long as it is thoroughly removed from the filter prior to further processing.
Wetting a filter membrane to allow post-use filter integrity testing is a straightforward process with few challenges. Using product as the wetting fluid is the simplest option for filter membrane wetting prior to post-use filter integrity testing. The filter is almost always very well wetted because it has been in contact with the product during the whole filtration process.
If it is desirable to conduct a post-use filter integrity test with water or alcohol, any product that remains on the filter membrane must be removed by flushing with enough water to remove product residues, as product residues can compromise the test result.
Wetting of a filter membrane prior to pre-use filter integrity testing can be more of a challenge. For pre-use filter integrity testing, the primary decision is whether to use product or water as the wetting fluid. When wetting a filter with product, dilution effects and additional filter preparation like flushing can be avoided.
Whereas when wetting with water, the first portion of product running through the system will be diluted, which can result in a need to discard a certain amount of product at the start of the filtration process. Flushing is a recommended step however, to equilibrate the system and reduce the amount of extractables.
Contact our Scientific and Laboratory Services group for Recommended Product-Wet Integrity Testing Parameters
After steam sterilization of a filter it is common practice to flush the system with water. Not only does this cool the system down to ambient temperature, but it will reduce the amount of extractables and particles in the effluent. Flushing with water makes water-wet integrity testing a convenient and, in most cases, logical membrane wetting option for the pre-use test.
There are numerous factors,(e.g. wetting fluid, filter membrane material, filter size, and the filter integrity testing set-up unique to your process/environment) that will influence creation of an optimal wetting procedure. With over 40 years of technical expertise and documented procedures, we are here to help you with every conceivable membrane wetting challenge or demanding system setup.
Choosing the Right Filter Integrity Test Instrument
Choosing the right filter integrity test instrument to meet your needs is an important decision. Our expertise in automated instrumentation has led to the creation of this detailed application note: How to Select the Right Filter Integrity Test Instrument
Studies on the Theoretical Basis of the Water Intrusion Test (WIT)
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Reducing Risk from Hazardous Product During Filter Integrity Testing
Reducing risk from potentially hazardous product during filter integrity testing is a challenge that must be faced. The reality is that during filter integrity testing, test instruments and their environment can become contaminated, and operators exposed to liquids, aerosols, hazardous substances, particulates or biological components such as microorganisms or viruses.
Strategies can be implemented to reduce/avoid contamination. Depressurization whilst venting, at the end of a filter integrity test, is where contamination is most likely to occur. During the venting step, the flow direction changes with the venting gas (potentially containing residues of the wetting fluid or product) now traveling towards the test instrument. As such, some form of protection should be put in place to protect the instrument and the environment surrounding it. Even if the liquid is not considered hazardous, sensitive test instrumentation should be protected and risk of cross-contamination eliminated.
A simple cleaning method can be implemented for contamination considered to be low risk. However, the procedure should be qualified with evidence confirming that cleaning the inner parts of the test instrument has not affected equipment calibration.
A cleaning strategy alone is insufficient for higher risk contamination scenarios and avoidance strategies come to the fore. ‘Avoidance’ in these circumstances essentially means not using the filter integrity test instrument to depressurize the filter. Instead, the filter can be vented under controlled conditions (e.g. into a kill tank), and the test instrument, environment and operator are kept safe.