Finding Owners

More and more I'm learning one of the keys to making good devices that meet quality and regulatory standards is finding people who will take ownership. Lately I've been working in the packaging area a lot and almost every time I'm in there I find discarded labels without lines drawn through them. Of course these are always discarded by the other shift. Everyone already knows the labels need lined out when questioned, so the basic training is there.

If you're an owner, you walk into your area and you own it top to bottom. You don't not fix things because you weren't around. You correct the issue and take it up with the supervisor on shift change. These are the types of people you want, and why many large medical device companies pay way over what they could for manufacturing labor. Pointing out the same non conformance over and over to the same people is ridiculous.

I've been involved with contract manufacturing in China and they were excellent at following instructions. They picked up GDP about 3 times faster than anyone else and have maintained it. This is not to say everything is perfect, but the basics were taken care of. Some of the more complicated situations that came up with the contract manufacturer were really botched up before we were notified, but at least I know the easy stuff is covered.

I'm not sure that me telling the 19 year old putting labels on boxes that this is the era of global competition and she has to work smarter and harder than they are really sinks in. Hopefully, we have a chance to develop the skills necessary because you only get so many chances.

Heat sealing bags

In the comments, Mike asks:

I am trying to seal 4 x 6 3 mil poly bags and currently having some problems. The sealer that we have is a AIE 310FDA impulse sealer that can handle up to 20 mil. The problem we have seen is either the seal is too weak or melts when the sealing time is turned up. It is hard to regulate and get consistent seals. I just think this too much sealer for these bags. I like the looks of the Bocsh Dough Boy. Do you have any thoughts or advice to help?

Sorry, about the delay, but I don't always see the comments from old posts. I looked up your sealer here, and I don't know if is "too much" sealer for your bags, but I suspect, with never having used or seen this particular sealer that you need a fairly major upgrade in sealer if you want more consistent results. I've had much better results with sealers that use air pressure to seal (although its not clear to me how yours works). You might be able to use that sealer for some applications, but for medical devices I'm doubtful, ours cost $11,000 new, it is a base model, and I'm still not completely happy with it.

If you want to make sure that your sealer is the problem, the first thing I would do is call the bag manufacturer and get their settings and the test data for the lot you have, make sure you are getting a decent bag. The other thing to check is there is probably (again I'm not completely sure about your sealer) Teflon tape that goes over the heated metal of the sealer, make sure that is in good condition and replace it if not- that tape drives me crazy. Once the possibility of the those being problems is ruled out, make a grid of time/temp/pressure and see if you can find a suitable setting, one degree or 0.1 seconds can make a difference, use one inch peel tests to the ASTM standard to test the strength.

I am web published!

Medical device blogger addresses technical questions

The picture looked less geeky when I picked it out.

Our packaging design went fairly smoothly and was validated. There are couple cosmetic problems related to workmanship that need ironed out, and a few tweaks to the packaging could help that, but nothing serious. Of course, I blamed all of the problems on manufacturing not following the drawing precisely and QA for not inspecting correctly. Just kidding, I'll make the changes when I have time.

Anyway, I spent about 6 hours editing a software requirements document today and will spend about 6 more hours tomorrow because we thought it would be a good idea to let the software guy rewrite and make pretty the requirements before we submitted to the FDA. Instead of taking the already released document and editing it, he made a brand new one, and I get to reconcile the old with the new, both of which are missing major components. The joys.

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.

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.

Medical Device Labeling Control

As I mentioned previously, the hardest part of labeling medical devices is the control of the labels. This really only applies to labels for disposables and packaging labels. Permanent labels for devices are fairly easy, you get them in, you check them out, then use them as you need. Labels for disposables are a whole different animal, the FDA has some guidelines, but mostly its related to the general quality system. Keep in mind these are only my limited experiences, other companies might have brilliantly simple ways to do this.

On a label for disposable products, you want at least the lot number and expiration date (or "use by"- I've spent more hours than I care to debating if the FDA thinks the terms "expiration date" and "use by" are the same thing) - and usually a bar code, mfg date, and whatever else you want- you'll have to print those parts yourself. So the printers print the logos and any warnings on the label and you'll print the rest. This is where the first challenge comes in, the partial label requires its own identification number (id#), then another id# after you print it. You generally like to have the label id# printed on the label so you have to make sure you do that in the second step and tell QA to stuff it if they complain about it not being on the label as received from the vendor (you know who you are). This is all well and good but the first of many challenges. You'll have to keep the label print program under control, the files it prints from and who uses it, not to mention the printer itself along with the ink. You'll also need a procedure and fabrication order for printing and various drawings for label locations on the product. And don't go thinking you can print labels out ahead of time, thats a no no, you want to use those labels right after you (or hopefully someone not you) print them.

So, just keep your received labels, printed labels, printing program, files, printer, ink, how to use them, and who can use them all under control and you're well on your way. The last thing you need is some way to keep track of sterile and unsterile product, usually a tear away label on the box or carton. Once you have all of that in line, I believe you are good to go.

There is still one part of labeling which I haven't covered, the Instructions for Use, Operator's Manual and other such literature. I'll probably leave that alone for now.

Medical Device Labeling Design

The medical device company I work for has a hands off CEO who is also in charge of marketing, because of this I got put in charge of labeling. The text is mostly straightforward, just follow the FDA labeling guidance and requirements. The design is not so much straightforward, other company's labels provide inspiration, but I suspect if things get serious the labels will be redesigned quickly enough. In fact, a couple of the labels we sent out with the validation load for sterilization had the wrong product name, the company decided to rename the product four months before planned 510(k) submittal. This doesn't matter because they were samples and we are testing if the ink runs and do the labels stick through sterilization, things which are independent of the design. Although if push came to shove, the standard label materials have been through sterilization millions of times, so you could probably justify not sterilizing them for validation.

These labels aren't cheap and there are more of them around than you think. Most small medical device companies don't print their own labels and there are plenty of label printers around. I've used three label companies lately, all are fairly similar, the one not in California is a bit cheaper, but really they're all close. Save yourself some money and get a copy of Adobe Illustrator right off the bat, some label companies will do some (usually minimal) work for free, but others will charge you. Chances are if you can draw it in another program, you can draw it just as easy in Illustrator. For each label there is a setup fee that is about $35-$100 and maybe a dye charge of $50-$100. Each color adds cost, so make sure you really want the full color logo with the green and yellow star or whatever in it. Small quantities makes for some goofy pricing. For labels for disposables you'll end up with something like 1,000 labels for $600 or 10,000 labels for $650. Permanent labels for multiple use devices can also add up quickly and start at $20 each and you don't want to order less than ten or you'll pay the setup fee again later on. On the start up project I'm working on I'll probably end up spending more than $10,000 all told on the first batch of labels (not including the printer)- a cost that will probably be the same next year for things like moving and redesigns.

One of the complaints I have about labeling is that I can't get anyone to look at anything before the printing company sends a proof. I'll send around a label eight times and everyone will say its great, then once they get a proof in their hands its can we change that from "Battery Light" to just "Battery" and make everything in all capital letters. This is a style pet peeve of mine and I am in a constant war with the all caps people at my company. In some guidance document that I probably linked above it says one of the ways to make labeling stand out is to have it in all caps, however it is my belief that if EVERYTHING is in caps it negates this and thus only very important information should be all caps, plus I think it just looks bad. Anyway, caps rant aside, the label makers seem to understand, but I can change something in four minutes, waiting for a new proof takes more time.

The most challenging aspect of labeling is labeling control, which I'll save that for another post (now posted here).

Packaging problems

Here at the happy medical device factory we've run into a couple problems, but I think we've worked through them in not ideal ways, but the best we can hope for with limited time (sterilization date is quickly approaching) and money. As part of packaging validation we have decided to run dye penetration, burst and peel tests on our standard Tyvek/film pouches, once after sterilization and once after both sterilization and a shipping simulation (ASTM D4169). To hedge our bets we also sent some samples off for a preliminary shipping simulation and test before sterilization. This is all pretty standard, we're being a bit more careful than I think you have to, you could probably get away with not testing after sterilization, but we like to have the extra information in case of failure.

Our first snag was the burst test (ASTM F1140) results on one of the pouches, the burst test basically consists of filling the pouch with air and measuring the bursting point. We sent off 25 samples and the results were not wonderful. The samples were put through a shipping simulation, then we sent them on to a testing lab for burst strength tests. Two of the samples had rather low burst strengths, 2.5 and 4 psi, while the average was 13.5 psi and the standard deviation was 6 psi (all numbers ballparked). The good news was none of the seals that broke were our seals (we seal one side, vendor seals 3), and as expected the lowest numbers came from the peel away seal. The bad news is obviously no consistency and a couple very low results. As far as we can tell, neither the FDA or the standards set any pass/fail criteria on this test.

How did we solve this problem? After various discussions with QA and the testing lab we decided that since the burst test and the peel test are basically measuring the same thing (Tyvek to film seal bond), that we'd focus on the peel test. Like I said, not an ideal solution. The peel test is more reproducible and reliable, and we easily meet the generally accepted standard (greater than 1 lb per inch).

The second problem we ran into was more difficult and multifaceted. The companion disposable to the previously mentioned product first failed a carton (box) compression test (ASTM D642) during the shipping simulation, even after I lowered it to schedule III test. This alone is not that bad, we are using a stock carton and will design a custom box in the first year, the custom box we will obviously design to pass the standard. For now we are sticking in a reinforcing box liner that will hopefully give us good strength. Like I said, by itself this is not a huge problem, the FDA is not concerned about the outer box- it is more of a marketing issue, only the product packaging must remain intact. The rest of the shipping simulation we passed without incident.

However, the real problem came up when we got the sample back from the shipping simulation, remember where I said that the important thing is that the product packaging remain intact? Well on examination I discovered small wrinkles in the film of our bag seal on half of the pouches. When tested with the dye penetration test (ASTM F1929), which consists of timing the dye's travel through the seal, sure enough some of these samples failed at the wrinkle. Now I am 95% certain that these wrinkles were caused during our initial sealing of the bag, and not during the shipping simulation. I'm thinking that the film wasn't stretched completely tight during the heat sealing process. None of the vendor seals have the wrinkling.

The problem, the seals did not undergo inspection before the shipping simulation. Our company had a QA who would never let anything go out without his final inspection and approval. Unfortunately this QA no longer works for the company. Now, we have a QC in charge of inspections who sometimes doesn't inspect test samples. Even worse was that I actually sent three of the samples back for rework before I sent them because I saw at a glance that they had other unrelated problems, so I knew the samples had at least some problems before I shipped them. I should have inspected them better and insisted that they undergo a full QC check. I've definitely learned something from this.

Now I'm stuck with a couple not really great choices, redo the whole test ($1000+) with newly completely checked samples, or go ahead without the complete preliminary test results and hope everything is good enough to pass. I had thought to get manufacturing to seal a couple pouches and see if the wrinkle showed up in the new ones he sealed, but the manager has already told the guy about the problem, so hopefully its unlikely to happen again. No other seal on the pouch failed the dye penetration test. I'll probably retest, but its not making me happy tonight!