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.

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.

Sterilization with a master carton or the product carton?

For some reason I can't remember now, my company has decided to ship product to sterilization in pallets of the final product carton instead of a master carton. Over the last three or so months I have come to the conclusion that this is a bad idea for a start up company and probably for all companies who don't have tight controls on the shipping and sterilization.

The master carton method consists of a few large, sectioned, pallet size boxes that the product is placed in, then onto a pallet, once the product is received back from the sterilizer the master carton has to be unpacked and product repackaged into the final product carton, the master carton can be reused. When you sterilize in the final product carton you just pile them all on a pallet, you can theoretically receive the product back from the sterilizer and quickly ship it out without the repacking.

The paperwork and inventory control are theoretically harder with the master carton method, as you have to document additional unpacking/packing as well as be sure to keep sterile and non-sterile loads separate. We are planning on selling only thousands of disposables a year for the foreseeable future, which also makes repacking not so horrible. Additionally, in practice the work required on the final product carton turns out to be just as bad as you have to repack (and document) some product if any boxes come back damaged from the sterilizer. Also, with the final carton method, you have to contend with short boxes due to sample pulling and the odd lot size. Another point to consider for the start up company is if you ever do change your final packaging carton, you will have to re-validate sterilization, or justify the change.

We still haven't done a final sterilization validation so we still have some wiggle room to make some changes- actually a lot of our packaging needs some minor redesign- this is one switch I'll hopefully be able to get to.

Failed a natural product sterility test

One part of the ETO sterilization validation we're performing involves testing the natural product sterility (NPS). This entails sterilizing the medical device and then immersing the device in a media (you can also run the media through the device). Then removing the media and waiting around to see if it grows anything. We had 40 samples tested, which is standard, I'm not sure if they mix the media together or keep it separate while waiting for stuff to grow. By testing the sterility this way you're ensuring that the product is at least as easy to sterilize as known spore strips. Once your sterilization is fully validated you can skip the NPS testing.

Anyway, our natural product sterility sample failed on day 12 of 14, looks like a do-over with some more aggressive sterilization conditions. Even if it is a false positive (day 12!!), it doesn't matter, its a non-sterile load. Resterilization (or actually now just sterilization) is a tricky mix of old full cycles becoming the new partial cycles and the sample requirements cascade from that.

There is a silver lining, we did pass the bacteriostasis/fungistasis test! Actually, while a bit of a downer we had planned for something like this previously and we have to push some things a bit harder- we need to make up some samples, but overall it is not too bad and our timeline is largely intact. My boss has had these things happen with sterilization before so he had us prepared.

Medical device questions asked

I thought I'd answer some questions that people have attempted to find answers for on this blog, keep in mind that I'm no expert- and looking at everything from a USA point of view, you should double check everything I say.

If you validate a medical device with one sterilization method (ETO), do you have to revalidate if you change methods (to gamma)?

Yes, you will almost certainly have to revalidate almost everything. I can't think of any concrete exceptions now, if I do think of some or hear of some I'll add them at a later date. I think you may be able to justify your way out of redoing some performance studies depending on what you had to show.

Do you have to sterilize all medical devices?

No, the term "medical device" covers a wide range of products including things like defibrillators, ECG machines, and external pumps. Some classifications don't require sterilization, find your classification on the FDA website starting here and go from there. A good rule of thumb is if you're going to contact something not normally exposed to outside air, then you have to sterilize it.

What do I need to get a medical device ready for clinical trials?

Medical devices manufactured to GMP and a 510(k) if you're going down a 510(k) path. If you're following a PMA path in my experience you'll need to convince the FDA that you have a quality system and manufacture to GMP, biocompatibility validation, safety validation which may include a few animal studies, and a some decent test results- along with whatever else the FDA and the hospital review board say you need.

What is the accepted standard deviation for medical devices?

I have no idea if this is related to lab results or what, but there is no standard accepted standard deviation for medical devices, however, if you go less than two, you should be prepared to justify it. This does not mean that two is required, you just have to justify it, please keep this in mind if you are transferring from the drug industry!

How can you tell if a medical device needs FDA approval?

Check the FDA web site, it really is very informative. Find your device classification on the FDA website starting here and go from there.

What is a typical day for a medical device representative?

I talk with these guys from time to time, it generally involves driving around to doctor's offices and hospitals to try to sell and then complaining that the company doesn't have any good products in the pipeline.

How many people to hire for a medical device start up?

I think I've covered this before, but I'll go for it again, 1 QA, 1 manufacturing, 1 engineer and 1 management is a starting point to build from. You really do want all of your departments covered from the start or you'll have a big mess on your hands when you try to finalize things.

Are medical devices good or bad?

They are good!

How much money to start a medical device company?

If you have a cheap, simple, 510(k) device and are somewhat knowledgeable about the field, I bet you could do it for less than $1 million. If you have some drug coated, ground breaking, research intensive device you'll need many times that.

What is the medical device standard expiration date?

There is no standard expiration date, but unless there is a good reason otherwise, you can label for 6 whole months without validating the packaging and saying you'll "hand carry" everything to the site. Hand carrying involves someone flying on the plane with the boxes. This is useful because you don't want to validate your packaging until you have a final product. On the other side of things, it used to be you tried to label for a 5 year shelf life, but I think lately a lot of products and companies are content with less, 2 or 3 years is fine.

What is a sample IQ/OQ/PQ?

I think I'll do a post on this later, until then search the MDI archives.

Update and approved vendor list chatter

It was a rather slow week at the medical device factory, our sterilization load was finished up and was delivered on Friday, management has now moved on to the next crisis- the hardware and software, which I don't directly work on, just test and criticize- so the sterilization load is sitting quietly all weekend until QA finalizes a procedure or form or something. My initial post concerning sterilization was on Aug 2, so it took about 2 months from start to finish, we actually shipped to the sterilizer mid August. Also not news, the company's board did approve moving the company, but someone else picked up the place they were looking at, so that is at least a temporary reprieve.

We did have a contentious meeting regarding the approved vendor list (AVL). My opinion regarding the AVL is that engineers should not have to worry about it. There have been complaints that we're ordering things from vendors not on the list. My thought is the vendor should get approved (or disqualified) before the ECN (or ECO or whatever you call it) with the component or supply on it is finalized. They've actually been waiting until the part has been received in from the vendor before checking if the vendor is on the list and then putting it on the list. Don't ask me what QA/QC is checking on ECNs before signing off on them- it seems as though checking to make sure that what we're planning on doing actually follows quality policy should be high on the list however. I think we have it straightened out now, but its one of many details a startup has to work its way through. Its fine if one of my vendors is disqualified, but telling me about it (or starting the process) after the part is in doesn't help out.

Full speed ahead

It is full speed ahead here, after a considerable amount of trouble the validation load is scheduled to be sterilized in about two weeks. Our company has only done gamma sterilization in the past, but this product requires ethylene oxide. So we get to learn a whole new world that we could happily ignore in the past. I never realized how great we had it with just gamma sterilized product.

Our original sterilizer, Steris, who we've been working with since at least January, completely dropped the ball. We were scheduled to sterilize with them in early to mid August, then about one weeks ago the rep says she can't write the protocol until the end of August because she is going on vacation and no one else is available to do it. This despite the fact that two weeks ago she was still confirming the early to mid August time frame for the actual sterilization. The customer service from them has been spotty all along and I should have paid more attention to it.

Luckily, the other big contract sterilizer, Sterigenics, is hitting it out of the park, a protocol in one week, reps who return calls the same day or the next at the latest, its a big breath of fresh air and the whole company is happier about the situation. Hopefully I didn't just jinx it, but small companies sometimes do have a hard time finding vendors that are interested enough to provide great customer service and we get excited when someone is on the ball.

UPDATE: Sterigenics has contacted me and are working to make sure things improve.