In the last few years the US FDA has been asking more
questions about color additives (colorants) in medical devices. A colorant is what makes your medical devices
a pretty color, and may be composed of several pigments. This is not so much a secret to endovascular
companies at this point, but if you have any colorant in your device you will
get questions from the FDA unless you address them beforehand. It is important to note, device
biocompatibility testing will not save you, you will not be able to hide behind
it, and you will have to do more. Unless
you want a delay in your submission processing, I suggest you include them with
your initial submission. Not so much EU
or Japan, but you may still get a question now and then. The FDA has issued guidance, but it is not really specific.
What are the questions from the FDA?
- What are the colorants? Identify by chemical name and CAS #.
- What are the colorant weight percent (wt%) in each component and total colorant weight per device?
- Submit colorant MSDS. (Hopefully it matches the answers to item 1…)
- Are the colorants are on 21CFR 73, 74, or 81?
- Have the colorants been used in any US approved predicate devices?
- If no to 4 or 5 they probably want to see a toxicological risk assessment.
I would stick all this information in the biocompatibility protocol / report you submit them with the materials list and hopefully that would head off any comments and delays in your submission. Alternatively you might create a separate report since other regulatory bodies don’t always ask and it may raise questions- don’t forget to submit the separate report to the FDA.
For items 1 through 4, you should be able to address those with a little help from your suppliers and a web search for your colorants on 21CFR73, 21CFR74, and 21CFR81.
You should create a table similar to this example:
If your colorants are listed on the approved colorant lists you don’t really need to worry so much about item 5, but I would complete it for thoroughness. If not… hopefully your company has used the colorant before, or you’re in for a bunch of meetings trying to figure it out. Maybe if you had someone else design the device they have used the colorant in other devices and well tell you, but otherwise it is probably impossible to figure this out. At this point, you want to find anything that has used the colorant, even if it is not the same use as your device.
If you have to go the toxicological risk assessment route (follow ISO 10993-17, Biological evaluation of medical devices – Part 17:Establishment of allowable limits for leachable substances), MDDI has an article on the details. Also ISO 10993-7 has an example of a toxicological risk assessment for ethylene glycol (EG) (take that Japan!).
I would just pay someone to do it, depending on your approach; you will be out about $20,000+ (with about half testing and the other half the risk assessment) and a couple months. The analysis usually involves using exaggerated extraction of your device in multiple solvents (saline, ethanol, hexane, etc.), using various chemistry techniques (GC-MS, HPLC, etc.) to analyze the extract, and then performing a risk analysis on the chemicals found. If that doesn't work out well, then repeat with leachables and write justifications. For example, justify why hexane extracts aren't relevant to the clinical use of your device.
NAMSA has a seminar this type of toxicological risk assessment, but your company probably lacks the tools to perform the risk assessment as you may need access to various toxicology databases. If your company does not have the expertise, most likely they will assign one person to do it, that one person will do it, then have to convince 3 or 4 other departments (regulatory, quality, clinical, etc.) that they did it right and teach them the method. Whereas if you hire the so called expert, most people accept the results, slap a cover page on it, and ship (unless they disagree with the results…). NAMSA, Toxikon, WuXi AppTec, and some chemistry labs will all do this for you.
For future medical device designs, I would stick to natural color or colors on 21CFR 73, 74, or 81, which really covers all of your standard colors. Certainly don’t take whatever your extruder has on hand. Although another blue catheter is not exciting, you’ll get to market quicker. These are medical devices, not electronic gadgets for 14 year old girls- your customers won't care.