Product Release vs. Pyrogen Test on each Lot - Medical devices

We are testing every third batch of administration set. Of course, if anything will be changed we will have to consider the influence on the product. We also did risk assessment for all of the process that can produce some level of „pirogens“ and that depends on (mostly) microbiological cleanliness of process inputs.

The auditors were satisfied with this reproach.

Have a nice day!
Tomislav

Thanks for your input. We are currently examining the baseline 510k to see if there was any original agreement with FDA to continue to do the batch pyrogen testing. If not, I am going to suggest not eliminating the testing, but reduce how often.

Miregmgr:

I took interest in your comments regarding pyrogen testing folded into a 510k as we currrently have a external communicating device that has been on the market for a long time which we do lot to lot pyrogen testing. Due to expense, manufacturing would like to eliminate this testing to a quarterly test only as there have been no negative results in years. My question is if we want to change from batch testing to quarterly testing, do we need to file a 510k to basically ask FDA permission to make this change? I am not sure that is the purpose of a premarket notification or is there some other venue to FDA for this modification?

Miregmgr:

I took interest in your comments regarding pyrogen testing folded into a 510k as we currrently have a external communicating device that has been on the market for a long time which we do lot to lot pyrogen testing. This pyrogen lot to lot testing was in the baseline 510k for this device. Due to expense, manufacturing would like to eliminate this testing to a quarterly test only as there have been no negative results in years. My question is if we want to change from batch testing to quarterly testing, do we need to file a 510k to basically ask FDA permission to make this change? I am not sure that is the purpose of a premarket notification or is there some other venue to FDA for this modification?

MIREGMGR said:

For FDA Class II devices the general requirement is that all patient-contact product materials be ISO10993 biocompatible. Non-pyrogenicity is a baseline ISO10993 requirement, so that would apply to all released product. The normal assumption is that materials need be tested only once to qualify them for continued use. This of course assumes that the materials are consistently biocompatible and that the processing does not change their biocompatibility.

If those latter assumptions were not correct, I can understand a self-imposed requirement for batch testing, perhaps incorporated into a 510(k) as a means of finessing what might otherwise be a barrier to FDA approval.

Otherwise, I'm not familiar with a specific FDA requirement for batch pyrogenicity testing of devices for which general materials biocompability has already been established.

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"Bacterial endotoxins produced by gram-negative bacteria are the fever-causing chemicals most often found on medical devices. The most common source of such contaminants is the water used in the manufacturing process. Thus, it should be noted that the contamination of finished products with bacterial endotoxins is not a biocompatibility issue, but rather a manufacturing control issue." [http :// www. mddionline .com/article/practical-guide-iso-10993-11-systemic-effects - OBSOLETE BROKEN 404 LINK(s) UNLINKED - PLEASE HELP - REPORT POSTS WITH BROKEN LINKS]

Maybe the following has some answers:
ANSI/AAMI ST72:2004/(R)2010

Bacterial endotoxins - Test methodologies, routine monitoring, and alternatives to batch testing

Cheers,
Ronen.

Ronen E said:

"Bacterial endotoxins produced by gram-negative bacteria are the fever-causing chemicals most often found on medical devices. The most common source of such contaminants is the water used in the manufacturing process. Thus, it should be noted that the contamination of finished products with bacterial endotoxins is not a biocompatibility issue, but rather a manufacturing control issue."

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Certainly the recommendation would make sense for production of a machined metal component, such as an implantable, that is subject to a washing process using water of uncontrolled quality. That however is not representative of many other kinds of devices.

Many external-communicating medical devices do not have water contact during production, but nonetheless are subject to requirements for pyrogen evaluation. For those devices, pyrogenicity logically would be related to either a fundamental materials biocompatibility issue, or a problem with materials having become surface-contaminated at some point through contact or airborne transfer. Surface contamination of that kind in effect is another form of biocompatibility, in the sense that if you test the finished device for biocompatibility including pyrogenicity, you have inherently established that your processing conditions do not result in surface contamination of a type that leads to pyrogenicity.

Certainly the recommendation to review ST72 is a good one.

As to how to interact with the FDA regarding a change to a processing condition that was established in a 510(k), you need to consider the relevant guidances on changes to manufacturing processes for 510(k)ed devices. My guess is that the FDA will want you to submit your argument that your accumulated negative problem-history is sufficient evidence that a change to less testing is acceptable, in the form of a Special 510(k). However, you might want to call DSMICA and see if they are willing to call the situation one that you can judge on your own and document with a Memo to File.

The New 510(k) Paradigm - Alternate Approaches to Demonstrating Substantial Equivalence in Premarket Notifications - Final Guidance

https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080235.htm

Thanks both Ronen E and Miregmgr for your input. Why do you think a Special 510k would be appropriate if we decide to file? I am considering a letter to file under Category I with documentation to file in support of the less frequent testing. This type of modification does not seem to apply to the FDA decision tree. Am I missing something? Does one need to identify the medical device company if one contacts DSMICA on this subject? Appreciate your response.

mijenca said:

Why do you think a Special 510k would be appropriate if we decide to file?

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It appears to me from reading the relevant guidances that your question--a change to a production process that was defined in an approved earlier filing--is specifically defined as being an appropriate use for a Special. If the FDA saw the situation similarly, then they might determine that a Memo to File approach evidentiated intent to not comply with the prior approval, which would invalidate it.

This type of modification does not seem to apply to the FDA decision tree. Am I missing something?

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Well, this requires interpreting:

The regulatory criteria state that a premarket notification must be submitted when:
(3) The device is one that the person currently has in commercial distribution or is reintroducing into commercial distribution, but that is about to be significantly changed or modified in design, components, method of manufacture, or intended use. The following constitute significant changes or modifications that require a premarket notification:
(i) A change or modification in the device that could significantly affect the safety or effectiveness of the device, e.g., a significant change or modification in design, material, chemical composition, energy source, or manufacturing process.

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(Highlight added for quoting purpose.)

Does one need to identify the medical device company if one contacts DSMICA on this subject?

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No.

Hi there,

I work for a manufacturer of a class II medical device, a wound dressing with silver incorporated, and the FDA has asked that we perform endotoxin testing on each lot. We performed an endotoxin validation last year to allow for a "pyrogen-free" claim for our OTC version of the dressing and now that we are actually having to perform the test (LAL chromogenic) we are getting results that are all over the board. We have tested and confirmed that the process water, raw material substrate, and silver itself is endotoxin free but cannot get consistent, repeatable results when restesting dressings from the same lot. We are starting to think that our product is causing interference with the test method. Does anyone in the cove have experience with testing silver coated dressings for endotoxins?

If the contract manufacturer is doing an end-product pyrogen testing already, do we still need to test it?