Blog Details

 

 

Maik Jornitz

 

 

Theodore H. Meltzer

 

Introduction

Sterilizing grade filtration has been used for decades with reliability and assurance. The reliability of this particular aseptic processing step increased with filter stability improvements, robust integrity test methodologies and especially process validation requirements, which evaluate the performance of a particular sterilizing grade filter under process conditions utilizing either the actual fluid or a placebo, if the fluid is bactericidal or bacteriostatic (1-3).

To routinely verify that the sterilizing grade membrane filter is flawless, non-destructive integrity tests, like Bubble Point, diffusive flow or pressure decay, are used successfully since the first regulatory requests in the mid-1970s. The integrity test can be performed pre-use/presterilization, pre-use/post-sterilization and post-use, use meaning the actual filtration process, whereby the ratio of the actual integrity test employment varies (Table 1). Post-use testing is requested obligatory.

The integrity test of a sterilizing grade filter has to be, and most commonly is, performed after the filtration process (post-use). Some filter users test the integrity before the filtration process and before the filter is sterilized. Exceptionally rare are integrity tests pre-use/ post-sterilization, as such test would require downstream, filtrate side manipulation and therefore can be considered precarious.

Regulators request the test of the integrity of a sterilizing grade filter after the filtration, post-use, but recommend an integrity test pre-use, without specifying whether pre- or post-sterilization (2-6). However EU Annex 1 (7), paragraph 113. states: “113. The integrity of the sterilised filter should be verified before use and should be confirmed immediately after use by an appropriate method such as bubble point, diffusive flow or pressure hold test….” The paragraph, in its first sentence, recommends the rare and, potentially, risk attached pre-use/post-sterilization integrity test. This in itself is not new, as this statement has been made in earlier versions of Annex 1 and the word should require to be considered as a strong recommendation, but recommendation as such. However in some instances it seems the recommendation has been interpreted by inspectors as compliance. This caused major problems within the industry, in new and existing applications. Proven, validated existing application, especially, are subjected to undesirable changes, as the enforcement would mean new downstream equipment installations and re-validating. The paper discusses the pre-use/post-sterilization concept and the risk assessment to determine whether or not there is a compelling argument for its use.

Pros for Pre-use/Post-sterilization

First of all, pre-use/post-sterilization integrity testing is not a common practice, but rather a rare event. This means that most sterilizing grade filtration application perform very successful, processing a sterile filtrate. Incidences of post-use filter failure were detected and the filtered product either discarded or reprocessed. These post-use failure detections or the risk of not being able to detect such is the only reason why one would enforce a pre-use/post-sterilization integrity test.

Sterilizing grade filtration systems require to be sterilized; either presterilized when assembled to a containment bag or sterilized at the site after assembly into the process or filter housing. The pre-sterilization, gamma irradiation process is highly qualified by the vendor of the single-use assembly and experience show that filter systems are not at risk to be damaged by this process. However, when the filter is installed into a housing and in-situ steam sterilized, filters experience thermal and mechanical stresses. Therefore, steam sterilization qualification is a necessity not only to determine the sterilization efficacy, but also whether the sterilization process stays within the operating parameters given by the filter manufacturer. Now, theoretically, if the qualification process has either been insufficient or an end-user mistake occurs and the filter is damaged during steam sterilization, the result would be a retentively underperforming filter. The fear in this case is twofold; a) the pore structure or parts of it become enlarged due to the steam sterilization or b) a minor flaw is created. This in itself causes the problem of a potential unsterile filtrate, but is detectable by the postuse test. The hypothesis though is that in either instances, the enlarged pore structure or minor flaw are plugged by contaminants separated from the fluid and are not detected by the post-use integrity test (8). Based on these two theories, the pre-use/post-sterilization integrity necessity is validated, as every other potential problem, like flawed installation etc., can be detected by the post-use test. The remainder of the paper therefore will focus on this theoretical risk basis.

Cons for Pre-use/Post-sterilization

Before the risk assessment, let’s appraise the integrity test method needs first. Any integrity test requires manipulation of the downstream side, as the filter needs to be wetted with fluid, except when performing the post-use test, a product wet integrity test could be performed. In addition, when the integrity test is performed, the downstream, filtrate side requires being under atmospheric pressure.

Both, wetting and venting manipulations are most commonly undesirable after the filter and filtrate side have been sterilized, either in-situ by steam or as single-use assembly by gamma irradiation. The severity of a sterile filtrate side manipulation can be as critically compared as any human intervention in a filling process. Both times, the sterile side of the process is potentially subjected to environmental influences.

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Figure 1 - Integrity test and downstream set-up example for pre-use/post-sterilization integrity testing

Certainly, engineering options are or can be made available to divert the wetting fluid into a fluid receiver, as well as utilize this receiver or other options for venting purposes (Figure 1).

Nevertheless, any supplementary construction creates as increase in connections, risk and potential of oversight. Vent filters or flush filter barriers require integrity testing and the associated tasks, as installation, steaming, flushing, drying, etc. Any added equipment and piping needs to be cleaned, set up and sterilized. All gaskets require check-up and potential testing. To summarize, there are engineering solutions possible and accomplishable, however it creates an additional burden and risk to an already complex downstream process (Figure 2).

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Figure 2 - Example of a filter set-up with associated pipe work

More importantly, sterilized filtrate systems are commonly kept under pressure after steam sterilization or in case of single-use systems are pre-assembled containment systems. The introduction of a vent filter and/or atmospheric pressures on the sterilized downstream side can cause an undetected breach of the sterile filtrate side. Pre-use/post-sterilization integrity test presumably increases the safety of a drug product, respectively risk reduction. This is not so.

Risk Assessment

Utilizing the PQRI (9) risk assessment process, the actual risk of a preuse/ post-sterilization activity is higher than the lack of this activity.

According to this document the level of risk is calculated as:

Risk = (S) x (F) x (D)

(S): Severity of the event (consequence)
(F): Frequency estimation (likelihood of event occurring)
(D): Level of detectability

The three categories are measured as:

The scenario of the use of the pre-use/post-sterilization integrity test and the lack thereof are now compared side-by-side:

The difficulty of detection of a potential breach or an ingress or mistake made elevates the risk level of performing the pre-use/poststerilization test. This risk assessment has been used from the PQRI. Other risk assessment formats are possible, but all example cases showed very similar results as described above. The benefit of the pre-use/post-sterilization test is questionable, this much, that it is advisable not to perform such test.

It might be that the end-user is performing only a post-use test or a post and pre-use test. The important fact is that any of these tests are intended to add a safety improvement to the drug, not to the process. If the drug is compromised due to a lack of process safety it is undeniably undesirable. However, the inability to detect a possible microbial ingress by using filtrate manipulations introduces an unacceptable, elevated risk level to the drug’s safety.

Other aspects to consider, before one chooses to perform a pre-use/ post-sterilization test:

• Every single sterilizing grade filter is integrity tested by the filter manufacturer before it leaves the facility.
• Packaging and transportation of filters is validated by drop, shake and vibration tests. Furthermore, the bioburden or contaminant level within a common pharmaceutical process stream is far lower.
• Fluid streams used within the industry are commonly not as contaminated as experienced during bacteria challenge tests with 107 cfu per cm2 (10). However, in these tests it has so far never been experienced that a pre-use integrity tested failed filter became integral and passed the post-use test.
• Minor flaws could be 0.45 μm, which still create retention of 105 per cm2, depending on the process conditions.
• Steam sterilization damaged filters are often dramatic failures (Figure 3).

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Figure 3 - Example of a steam damaged filter cartridge (courtesy of Sartorius Stedim Biotech GmbH)

• The risk of filter failure also depends on the sterilization method, whereby gamma sterilization is most commonly less stressful to a filter than steam sterilization. This fact might also be part of the risk assessment.
• Post-use integrity test failures due to wrongly installed or damaged filters are an economical risk, not a drug safety risk, as the drug is either discarded or reprocessed.
• Pre-use/post-sterilization test designs become extremely complex and contain a multitude of additional downstream connection and filter devices, therefore one should be cautious when filter suppliers seem to be motivated to recommend these designs or describes these as easy to implement.
• The wetted filter requires to be dried to avoid product dilution. In instance, especially with single-use systems it will cause difficulty to dry the filter.

Recommendations

As in paragraph 113, the word “should” within guidance documents is meant as a recommendation, a strong one though (13). This means a flat out enforcement of a pre-use/post-sterilization integrity test ought not to be the common practice, but only required when there is a compelling reason for such test action. Diligent risk assessment of the process, with or without a pre-use/post-sterilization test, will result in an appropriate evaluation of the value of such test. Having performed a proper risk assessment creates a risk review platform for the inspector to work with and from, in mutual discussions with the end-user. Regulators and drug manufacturers alike ultimately strive for drug safety. When risks increase, drug safety decreases, therefore any risk elevation requires to be avoided.

As many times stated “you cannot test quality into your product, you have to produce it”.