Number of Destructively Tested Devices Needed for Ethylene Oxide Validation

We do not currently manufacture any sterile products, but have a few devices in development that we plan to sterilize with EO. While disposable, the devices are expensive and supplies are tight. As they are figuring out the quantities needed for V&V supplies I've been asked to tell them how many will be needed for sterilization validation (overkill method via half-cycles) and associated testing.

Assuming that we will be sterilizing only 1 pallet at a time with a volume of less than 1.3 m3, and that we will need to use devices as PCDs, I came up with 62 devices assuming (big assumption!) everything goes according to plan. Of course we will need other devices (or appropriate dunnage) to fill the rest of the pallet, but does 62 devices destructively testing sound like the correct minimum number required?

Here's how I got to 62 devices:


Thanks in advance!
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Super Moderator

without knowing the specifics of your product, several general comments, food for thought and questions:

1) PCDs: You seem to employ both internal and external PCDs. Both are really your very same device at the same time? Your "Purpose" column seems to indicate that the iPCDs are actually BI (spore strips?) co-packaged with your product? What are the ePCDs exactly and what is their purpose since you only seem to employ them in the fractional cycles, but neither in the half cycles nor full cycles?

2) Bioburden: typically, recovery factors are established employing more than 3 samples. Would you have a rationale to use only 3?

3) Bacteriostasis/fungistasis testing: this could be combined with product sterility testing. Would you have planned any product sterility testing, e.g. at least for the fractional cycles?

4) Number of half cycles and full cycles: you could actually combine 2 mapped half cycles with 1 mapped full cycle run in order to demonstrate both SAL and cycle reproducibility.

5) Endotoxins: do you have a rationale for the sample size of 3? Have a look into AAMI ST72 for the typically required sample size.

6) Have you considered sterilization residuals according to ISO 10993-7 and functional verification of the device after sterilization?

7) What is the specific reason that for most of the tests you cannot employ dummies/product representatives, but have to employ actual devices?

Thanks PlanB for your detailed response, I appreciate it. I'd like to add that I love that avatar photo.

1) PCDs: So this is my understanding from talking to a few test labs and contract sterilizers. The ones we've talked to have recommended taking our product and adding some sort of BI (not sure if it's test strip or not, I thought it was more like a liquid that could be placed on the device) to the most difficult to sterilize location of our device. On our device this would be at the end of a long blind lumen or on a barbed fitting inserted into a polyurethane hole. Then we'd reseal the pouch and place these internal PCDs throughout the load, inside cartons, etc. These would be the iPCDs. We'd use the same PCDs on the outside of the pallet for the external PCDs. Then the fractional cycle would (hopefully) demonstrate that the ePCDs are at least as difficult to sterilize as the iPCDs and in future routine sterilization runs, we wouldn't need to place a bunch of iPCDs throughout the load, we'd just place them on the outside of the pallet (ePCDs). We would continue to use these iPCDs made with the BIs placed on actual product for all half/full cycles and the ePCDs for future routine sterilization runs. This just seems excessive to me.
When I first started digging into this, and from reading ISO 11135 I had the impression that we would be doing more of what you described: placing pore strips inside some device packages (the iPCDs) and just using pore strips on the outside of the load (the ePCDs); or using some sort of mock device or a portion of a device; such as just creating a long blind lumen out of relatively cheap material or using just the barbed component inserted into polyurethane to simulate the final device. Obviously, this would be preferable to destroying so much 'good' product. Is this what is typically done?

2) Bioburden: no justification for just three. I thought that was the normal quantity. I don't have and haven't read the standard yet. What's the normal quantity?

3) Bacteriostasis/fungistasis testing: You're right! I am missing tests of sterility on the product. For a single pallet of 1.3 m3, would that be 5 devices for each fractional, half, and full cycle run?

4) Number of half cycles and full cycles: You suggest that a fractional cycle, two half-cycles, and one full cycle is sufficient. This is the one part of the whole validation process I thought was pretty clear cut. In Annex B of ISO 11135 [B.1.2.a)] it describes the Half-cycle overkill approach as "...a total of three consecutive experiments resulting in total inactivation of the BIs..." Are you suggesting one of the "cycle calculation" overkill approaches?

5) Endotoxins: no rationale, just thought that was the normal quantity. I don't currently have that standard and as we get further along I'll have to dig into it. What is the "normal" quantity?

6) EO residual and functional verification of device: Correct again, no EO residuals listed. Is this test run once or for every cycle? How many devices are needed for this and can it be performed on devices being used for other tests (say, test of sterility)? As for functional verification, this will be done as part of real-time shelf life testing performed on sterilized devices.

7) I don't have a specific reason to not use dummies/representative products. In fact, that's what I'd love to do. The vendors we've spoken to don't seem too interested in that. I'm not sure if that's because they're just so use to having thousands of relatively cheap disposable products in every load that that is what they normally do, or if it's because they've seen the device and think it presents some special difficulty. Looking at other long sterile devices like endoscope tools, this device doesn't seem any more complicated than most of those. What is typically done? Placing pore test strips internal to some mock product? just using portions/components of final device rather than fully functional finished devices? Just placing pore strips inside the sterile barrier system?

Thanks again for your time!


Super Moderator

seems to me that this is your very first aim at EO sterilization validation? If yes, a word of caution - and in no way meant to curb you enthusiasm or meant as criticism - when you talk to related test labs and sterilization contractors: while they are experts in their core stuff (ie. microbiological testing and processing loads, respectively) they might sometimes lack the "big (validation) picture" that only you as a manufacturer might and should have. Therefore, professional support in pulling together your validation protocol might be worthwhile to consider.

ad 1 PCD: there are all sorts of BIs (biological indicators). Typically you avoid applying the challenge organism directly on your product because the related procedure of application and recovery is much more of a hassle and requires dedicated validation. (refer also to the note in ISO 11135:2014, section D.7.1.6)

In case you want to use dummy product, this is what you want to demonstrate in terms of bioburden resistance R during a fractional cycle:

R (natural product bioburden) < R (iPCD actual product) < R (iPCD dummy product) < R (ePCD), by demonstrating actual-product sterility and the largest number of survivors on your ePCD.

Once you have demonstrated this during a fractional cycle, you only have to demonstrate inactivation of your ePCDs in the half cycle, no less resistant iPCDs or actual product required.

ad 2 Bioburden: have a look into ISO 11737-1:2018, section C.1.3.2.:
Common approaches are to utilize three to ten products for recovery validation testing. The sample size should be based primarily on the purpose for which the testing is being performed (e.g. in support of substantiation of a radiation sterilization dose, or an overkill sterilization cycle). When reviewing bioburden recovery efficiency results, a review of the consistency of results, or lack thereof, can indicate that a different extraction method should be applied. Alternatively, a larger sample size can provide a more accurate determination of bioburden recovery efficiency.
ad 4 Number of cycles: have a look into ISO 1135:2014, section
The PPQ shall include a minimum of three planned qualification cycles, consecutive in the same study, in which all the specified acceptance criteria are met. PPQ may be conducted during the MPQ. If PPQ is performed in parallel with at least three MPQ runs, then a minimum of one additional PPQ run shall be performed using the full routine process specification
ad 5: have a look into AAMI ST72:2019:
The Sample size can be lowered when justified by a risk assessment, described also in this standard.

ad 6 Residuals: have a look into ISO 10993-7:2008/A1:2019, section 5, Product Release.

I would caution you to verify functionality as part of real-time shelf life testing for two potential reasons: in case of a test failure you would not be in a position to unambiguously identify the cause, and you would have quite a delay (real-time...) for evidence of continued functionality after sterilization.

ad 7 Dummies: there is no "typical" approach, other than the more expensive the product the higher the motivation to employ a PCD in line with ISO 11135:2014, section D.7.1.6:
b) Inoculated simulated product: a simulated product is used [...]
c) Inoculated object: such as a package, piece or tubing, [...]
Placement of PCDs depend on your product and load configuration: quote from ISO 11135, section 8.6 "[...] shall present a challenge to the sterilization process that is equivalent or greater than the challenge presented by the natural bioburden at the most difficult to sterilize location within the product."

Thanks again PlanB for you detailed responses, they've been a big help. And I agree that a little bit of consulting help from the right person will go a long way to helping us see the big picture.

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