MedTech Toxicologist Explains Biological Evaluation | Pressure Tested

Hello, I’m Sophie. I’m the biocompatibility specialist here at Test Labs, and I’m going to get pressure tested.

So what is biological evaluation and when is it required?
So biological evaluation is essentially a risk assessment, which assesses the potential for biological hazards to arise from the use of medical devices. It’s required for any medical devices that have either direct or indirect contact with a patient or a user.

So how do you start a biological evaluation?
Well, biological evaluation should be performed throughout the entire life cycle of a device, so even from inception of concept. So when you’re trying to decide on materials, when you’re trying to decide on manufacturing processes, all of these have the potential to cause biological risk. So it really should be performed at all times across the entire life cycle of the device.

What’s the most common mistake you see in biological evaluation plans?
This is using the ISO 10993-1 as a testing checklist. It’s designed to be a risk assessment, not a testing checklist. So by assessing the materials, the manufacturing processes, sterilisation processes, as well as the intended contact and use of the device, we don’t necessarily have to perform testing on every single device possible. There could be sufficient data to show that the risk is low. However, oftentimes there are gaps in the data, and that’s where the testing should be performed, not just every single time for every single device. I think people use it as a checklist for testing because they don’t fully understand what the document entails. I think people want it to be a simple, “I just have to do this,” and a check-off-the-boxes kind of situation. But really it involves a lot more effort and a lot more input from manufacturers to really, truly understand the materials and the manufacturing of their devices.

When should biological evaluations start in product development?
Well, this really does depend on different devices and the way that manufacturers are going through the process of getting their devices onto the market. Typically, you really want to be considering biological evaluation at least during design and development phases. So when you’re determining the materials, when you’re determining the design and the spec of the device, this is when you want to start considering biological evaluation concepts.

It helps to determine the specification of the materials so that we ensure that the potential risks of the device are limited from an early stage. How often are manufacturers underestimating material risk? I see this very often. A lot of material manufacturers will come to me and say, “Well, it’s just polypropylene.” And I’ll look at their device and say, “Well, it’s bright blue, so it’s definitely not just polypropylene.” There are additional materials in there, pigments, additives, plasticisers, a whole host of different things that could potentially leach from the product when it’s in use.

Additionally, I see a lot of manufacturers using medical grade materials and assuming that that means that they’re safe, but they’re forgetting that the
manufacturing processes, sterilisation, reprocessing, all can have an impact on biological safety.

What triggers additional biological testing?
Well, oftentimes this usually comes with a material change or a process change, or just at least some kind of change in the way that the medical device is developed. That means that we don’t necessarily understand the risk of the device anymore. We need to reevaluate materials and potentially retest if there are gaps in the data. What do regulators scrutinise most in biological evaluation reports? Well, I think what we’re really looking at here is why are people getting pushback, and the biological evaluations aren’t going through their submissions. And this is usually because they haven’t considered certain endpoints in testing, the materials haven’t been characterised fully, and therefore, the biological risks are not completely fully known.

Additionally, this can also be improper testing, so the wrong test method’s used, the wrong contact type determined, and so the wrong extraction condition’s decided. And then oftentimes, mostly it’s just the content of the report is not what the standard is requiring. There isn’t the full risk assessment and risk analysis. It’s oftentimes that these are just the results of testing that’s been performed and not a true integration into the risk management. What is a competent person in biological evaluation? Well, this again is another thing that notified bodies and regulators scrutinise.

A competent person has to have the experience in biological evaluation necessary for the device that they’re evaluating. Lower-risk devices do not require such a high level of competency as perhaps a class three implantable device, where the risks are much higher. However, a competent person at least has to have some scientific background and experience using the regulation.

What are the key changes in the new biocompatibility standard?
So this is the ISO 10993-1, the 2025 version, and this is quite a hot topic at the moment as it’s only just come out back in October. And with the way that submissions are running at the moment, we don’t have a huge amount of feedback from regulators.

But the main key changes here are there’s improved integration to ISO 14971, which is just going to make the risk management integration of these reports so much easier. In addition, there’s a real push to emphasise the life cycle requirements for medical devices and ensuring that biocompatibility risk is assessed throughout the entire life cycle of the device. In addition, we now have to consider reasonably foreseeable misuse of the device.

So could it be used for longer than it’s intended to?
Could it be used in a different area of the body than it’s intended to?
And what are the potential risks that come from those potential situations occurring?

We now need to consider additional testing or additional endpoint evaluation to cover reasonable foreseeable misuse. Additionally, the way that devices are characterised has now changed with the contact duration type changing with regards to repeated use. But we understand that it’s quite difficult to navigate all of these changes, so we advise that you speak to your biocompatibility specialist to determine how to go forward with the next steps to be in compliance with the new standard.

How do you avoid over-testing and unnecessary cost?
Well, this is something that we deal with quite regularly, and the main cause for needing to do additional testing is not planning properly. We have this all the time where our clients come to us when they’re at the end stage of development of their devices, and they’re ready for submission, and they’ve not considered biocompatibility at all until this point. And then we find that devices don’t pass because the materials haven’t been fully evaluated. And that then leads to having to retest, having to redesign, and actually increase cost in the long run than considering to look at biocompatibility way earlier in the process.

What’s the biggest red flag in a biological risk assessment?
Ah, so it depends on what point of view you’re coming from. From a regulator’s point of view, it’s that there’s missing data gaps. There is inadequate analysis. You’ve not considered manufacturing, you’ve not considered life cycle, all of these.

For me, when often I see red flags in biological evaluations is people thinking that it’s pure polypropylene when actually it’s bright blue. I often have an issue when it comes to green pigmented devices because these often times have issue in testing.

And also just really short evaluations that are maybe four or five pages long and just are very much a summary and not an in-depth analysis as they should be.

When do you need to do in vivo testing, and when can you avoid it?
Well, this really does depend on your device and the materials that it’s made of. There’s now a massive push to perform chemical characterisation before looking at doing any in vivo testing to see what testing you actually would need to do afterwards.

So are there any end points that need to be evaluated that can be covered through the chemical characterisation data, through in silico analysis, through in vitro data as well? Basically, in vivo data is only necessary when there is substantial enough of a gap or substantial enough of a risk that we need to look at an animal model to give us the data necessary.

What is NAM testing approach?
So this is the new approach methodologies. So this is basically looking at finding alternatives to in vivo testing to provide us with the data. So this is the chemical characterisation, so determining a full extractable and leachable profile for the device to basically determine if there’s any hazardous compounds that are leaching out, which could cause biological safety risks to the patient.

There’s also now been the introduction of the in vitro skin irritation test for intact skin contacting devices, so a move forward and away from in vivo testing for irritation for suitable devices. But essentially, it’s just trying to comply with the three Rs, the reduce, replace, and refine of animal testing.

So what slows down biological evaluation the most?
Well, I think this probably comes back to the planning issue again. Starting this at the beginning of the cycle of development of your device will always improve how quickly the actual biological evaluation process can go. Because oftentimes we’re having to wait for information from suppliers, so material data sheets, from contract manufacturers, so manufacturing processes and any processing aids. These are the kind of hold-ups that bottleneck the process where we’re unable to get all of the necessary data to complete a biological evaluation plan, and therefore, move into the next stage of testing.

And then once in the testing stage, if things haven’t been planned properly and the evaluation hasn’t been completed adequately, we can then lead to failures, which mean going back to the drawing board, amending device materials, and then having to ultimately retest.

So I have a lot of older biocompatibility data. Can I use it?
Well, you certainly can use it. It’s just a matter of whether it fills the gaps that we need to determine biological risk. Often, some of these methods haven’t been updated in many, many years, or the updates are considered so negligible that actually the data that’s already available is sufficient.

And this is one of the things that’s a real push in the new ISO 10993:2025 standard is to utilise available data from devices that are already on the market. And if you have sufficient post-market surveillance data alongside your testing, it’s likely that that may be enough. But it’s important to do a gap analysis and really determine whether everything is available for you to complete your biological risk assessment.

When should I update my BEP?
Well, I’m assuming this is probably in reference to the updated 10993:2025 version. You may not need to update it. This is the thing. It depends on the device, but what you really need to start off with doing is a gap analysis to the new standard. This is going to tell you what information you need to include additionally to your BEP. Do you need to make any changes to your device categorisation, which then means additional endpoints to be evaluated, or are you fine carrying on as you are? For the most part, a lot of devices don’t have the data on life cycle, so it’s more than likely that this information is going to be needed to update the BEP. But it’s not expected from regulators that you’ll have that data immediately. But by doing a gap analysis, you’re proving to them that you’re going in the right direction. Additionally, I suppose this could also be with regards to new data, so new post-market surveillance data, which might indicate risks that weren’t considered previously, any material changes, any supplier changes. All of these things can trigger biological evaluation update.

So what samples do I need, and how many samples do I need?
Well, this is a kind of question that’s going to come out of performing a biological evaluation plan.It’s going to depend on a number of things. Are there different variants of the devices which may have different properties which need to be tested separately, or can a worst case scenario sample be chosen? But ultimately, the devices that are used for testing need to be in their final finished form. So they’ve been through manufacturing, sterilisation, and in some cases reprocessing if you’re trying to evaluate the life cycle of the device.

Now, in terms of how many you need, well, this is again, very device dependent. It’s either based on the surface area of the device, the weight of the device, or the test that you’re performing. So really you need to have a conversation with the testing house or whoever’s writing your biological evaluation to get them to narrow that down for you.

What information do I need to provide to start writing a biological evaluation?
Well, obviously with biological evaluation being performed throughout the life cycle of device, it’s not really a specific set of instructions right at the beginning, but a starting point would be the materials, the design, and specification of the device, manufacturing processes need to be confirmed so that any processing aids and manufacturing additives can be evaluated. Sterilidation, if it’s applicable, needs to be confirmed as well, as well as the intended use of the device and any claims made because this could impact on the potential risk and how the device is used.

So how long does it take to write a biological evaluation plan?
Well, this really depends on the availability of data and where perhaps you’re in the development process.
So here at Test Labs, we say that if you have all of the information available to us, we’ll be able to write that within four to six weeks. But really it’s us getting that information that bottlenecks that time point. So it’s definitely best to plan early and consider when your submission date is expected to be.

Can I do biological evaluation myself? Do I need you to write it?
Well, it really depends on what your experience is. If you have experience in biological evaluation, experience in toxicology, or clinical experience with the device, then you may have the necessary competency to perform these. But if not, then it’s definitely necessary for you to reach out to somebody with biocompatibility expertise. For many manufacturers, they may not have somebody within their team that has the necessary experience, and it’s really important to reach out to somebody that you can trust to work with and make sure that you get over the line with your biological evaluation.

What is the most common question you get about biological evaluation?
Well, there are many. Some of them are, “Well, why do I even need one? My device has been on the market for 50, 75, 100 years. Why do I need to evaluate it when I know it’s safe?” Oftentimes, I’m asked exactly what testing is needed. But all of these questions really come back to, well, you need to do your biological evaluation plan to answer those questions. So why would you need one? Well, what materials are you using? Have you considered reprocessing? Do you have any data on the life cycle of your devices? All of this comes out within the biological evaluation plan, and while your device more than likely will be safe, you need to be able to document that and prove that to regulators.

Why is everyone obsessed with biocompatibility all of a sudden?
Well, it’s just great. No, it’s because the safety of devices has been called into question a lot recently. We’ve seen the concerns with the breast implants, with the surgical meshes that have caused all of these complications down the line, and it’s been through inadequate biological evaluation that has come out as one of the leading causes of these events happening. So now regulators are really pushing towards these documents being thoroughly, thoroughly investigated prior to devices going onto the market so we can avoid situations like that occurring again.

Okay. Wow. Those were some good questions. And I think the real takeaway from there is that people need support in performing biological evaluation. So please reach out to us at Test Labs. We’d be more than happy to help you.