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sterilization wrap up

i promised a while ago to summarize the sterilization situation, hopefully someone will find our experiences useful. our disposable product was designed for eto sterilization, an important potential add on to the product made by another company has been approved using eto and changing their sterilization method at some point would be a huge hassle. so we built the validation samples, shipped them off to the sterilizer, they wrote the batch release protocol, based upon the add on's protocol and we ended up failing sterility testing for both the half cycle and full cycle.

a qa and i forced a meeting and flew immediately to the sterility test lab, i think the lab is still unhappy with us for this- they avoid talking to the qa at all now, but thats what we were told to do. anyway, we sat around a table with the lab personnel and they told us in not so many words, what we already knew because they said the same things on the phone, its just one of those things. the lab actually handled it very well and had some useful minor suggestions, but there is not much they could do. you don't want to do sterility testing if you can avoid it because these things happen, obviously you have to do it a few times to validate. we made a few very minor changes to the testing procedure, doubled the sterilization time and flew back to help finish build more samples, working through many a weekend. when we tried again with the new protocol it worked out well for us, and it was done quickly enough.

since at the time of the failure the company had more money than time, we decided to hedge our bets and also approached anderson to run a batch release in almost parallel. the anderson folks wanted to do some development work first, due to our previous failed sterilization attempt as generally their sterilization method is gentler than standard eto sterilization so there was some question about if it would work at all. we got the samples to them, they ran the development work and everything came out roses- it was on. they sterilized the samples and sent them to apptec for sterility testing and everything tested sterile. fwiw, the anderson half cycle process sterilized what the 2 hour standard eto cycle did not, but i don't put too much stock into that bit of info, as i know several devices which use a sterilization time less than ours and are triple the size and more complicated. overall, the anderson sterilization cost about half as much and was performed more quickly from start to report, if you take into into account that they did some development work first.

going forward we're going to file the 510(k) initially with the standard eto sterilization, but in the future add anderson, especially since we have plans for a series of low volume, high cost disposables that would be perfect for anderson. the fda considers the anderson sterilization a "non-traditional" method, but i don't think it would be much of a problem to get approval for as the method is becoming more common and is well documented.

theoretically you can use 3 successful batch releases to validate sterilization, if they are exactly the same composition, that is not going to happen. i've been pushing the company to go through a full sterilization validation, but i don't think that is in the cards for this year. i have theoretically officially turned all sterilization duties over to qa although i think that will be forgotten next time we need to sterilize something.

bench testing

i've spent the last few weeks dealing with bench tests as we wait for other results to come in. bench testing or performance testing gets stuck in section 18 of the 510(k), since it is in the back means they don't read it right? you will save yourself a lot of grief if you read the format guidance and make sure your protocols and reports line up nicely with their requirements, although you will need more than what is listed in the guidance, at least a scope.

for a small company there are several challenges to bench testing, all revolving around the number of people that have enough understanding to run the tests. my company has three plus one consultant that can run the majority of the tests, it is preferable to have employees sign off on everything so the consultant is out, and one of the three has the understanding to run the tests, but not the personality type to see it through. that leaves the two engineers, one of which is on vacation this week, so that leaves me for now. md&di sums up the who should do the bench testing very well.

the first problem is the protocol, which must be signed off before the test begins, the problem here is that no one besides the engineer authors are likely to really understand what is going on. this means no problems will be caught until the engineer testers try it for real. sure, we've tested it some previously, but when everything is recorded things change. i wrote a protocol and discovered i couldn't hold a negative pressure i thought i could so had to change it up a bit. this means rewriting and walking around getting signatures to get it approved before i can start again. this is not much of a problem, unless it is after 3:30pm and qa has gone home for the day. then i'm forced to wait around until they come in at 9 the next day. i have argued that by having my signature on it that the protocol has therefore been predefined and good to go, but i haven't gained much ground with that.

the next problem is that these tests take time, we are shooting for 24 hours of use. i rallied around testing for 26 hours but my boss vetoed that saying 1.5 times is standard, meaning 36 hour tests and every other day i have to come in at an awkward time (do not worry, i am getting my revenge- see below). i am amazed my wife hasn't accused me of cheating on her yet with the late night stops by work. the 1.5 times the maximum limit you're shooting for is a good rule of thumb, and appropriate here, but it doesn't work for everything, like negative pressures.

the last of my whining centers around the sample sizes that will not be high enough to make everyone happy. with limited product and limited resources, running a dozen 36 hour tests could take a month. unless you are going to manufacture, sterilize, and shipping simulate a batch of samples yourself in the next week, complaining about sample size doesn't accomplish much. do a reasonable job and if the fda picks on it the most likely thing that will happen is they'll ask for more testing.

i mentioned in my previous post that the deadline slipped (still not my fault), this has given me time to come up with some additional bench testing to put in motion. i say put in motion because i was so confident i'd meet my part of the original 510k deadline that i planned a two week hawaii trip starting one day before the deadline. now all the loose ends will have to be tied up by my boss and the other engineer, i sorta feel guilty now, but about 20 minutes after landing it will be forgotten. i give the extra testing a 40% chance of not being done when i get back. i have to say though that the last year has been a blast and if you're an engineer with a good work ethic that can tolerate the risk of working for a smaller company then go for it.

sterlization finally resolved

i posted previously on failing a natural product sterility (nps) test in a lot release using ethylene oxide (eto) sterilization, and we finally have everything somewhat resolved, well really a couple weeks ago we did, but i've been too busy to post. an iso 11135 lot release requires a half cycle, then biological indicator (bi) and nps testing which must come back sterile, then a full cycle and further bi testing which comes back sterile. residuals and pyrogen samples are taken from the full cycle. in the previous post i mentioned we failed the half cycle nps testing.

after that we made our full cycle the half cycle and tested the full cycle samples for nps and doubled the sterilization time for the rest of the samples (this still confuses some people at the company). unfortunately those nps samples failed as well, or more precisely one of forty samples failed on day 7 of 14. all bi samples were negative. after much debate and me being the ever eager middleman between management and the sterilizer we decided to double our sterilization time once again then proceed. however, we had to start all over with the samples because we had used so many in testing.

while we were building more samples we looked into the nps testing. the most notable thing was that we discovered we were using twice as many samples as required, 40 instead of 20. 20 samples assumes you use 10 samples with aerobic media and 10 samples with anaerobic media. you can even use 10 samples if you use the membrane method instead of using the two types of media on the device. for us, each sample was tested individually and had their own large media jar. we made a couple minor, mostly for show changes to how the test was conducted.

so we built more samples and re-sterilized at a fairly ridiculous length of time for the half cycle and twice this ridiculous length of time for the full cycle, the length of time is so high it borders on what the fda considers non standard sterilization. hopefully we can lower the time some in an actual sterilization validation in the future. oddly (imo), the sterilizer doesn't charge by time in the chamber, so sterilizing for 1 hour costs approximately the same as sterilizing for 5 hours.

it took much begging, but we actually managed to get these sterilized half and full cycle in less than three weeks. we passed all the required testing and we are finally on our way. there is another part to our product sterilization that i'll get back to when its done. talking to the 510(k) consultant afterwards he said sometimes companies don't file with sterility test results. i'm not exactly sure what they're filing with then.

since then we've been bench testing like crazy and i have been unsuccessfully trying to delegate tests, but it seems like we don't have any people that understand the product well enough to pass most tests on to. we did have a dec 31 filing deadline, but its been moved. i am happy to say that my disposables part isn't the thing that is holding everything up despite a completely failed sterilization.









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