Biocompatibility: Selection of worst-case device

#1
Hello,

I ran into an interesting discussion lately and would like to hear your opinions.

In my experience, orthopedic medical device manufacturers have been successful with regulatory bodies (EU notified bodies, as well as FDA) by evaluating product families for biocompatibility.
Example:
1. Bone screws that are manufactured in identical ways, have the same design and indication, but differ only in size (length) and shape (thread count).
2. Bone plates that are manufactured in identical ways and have the same design and indication, but differ only in size (length) and shape (amount of threaded holes that receive bone screws).

Regarding worst-case device selection for biocompatibility assessment, the largest device would have been chosen since it has the highest design complexity in regards of thread count (screws), as well as threaded holes (plates). The rational behind this was that the more threads a device has, the risk of effectively cleaning the device (and leaving residues from the manufacturing process behind adversely affecting biocompatibility) would increase.
Any toxicological data could therefore be applied to smaller device sizes since they are lower risk.

I was now wondering if anyone used the opposite approach by using the smallest device and scaling data up to larger devices?
Thinking about this, my concern would be that it might be hard to rationalize the cleanability (and therefore removal of any manufacturing residuals) of the larger devices which have more threads, especially since usually the thread count (screws) or hole count (plates) does not scale linearly to the device size.
Another issue would be if the largest device has been tested, but the manufacturer now wants to expand the product family with even larger devices. What approach to biocompatibility risk assessment would one use in such a case?

Happy to hear any insights!

Archi
 
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planB

Super Moderator
#2
Archi,

there are deliberate reasons why the term "worst case" does not appear in ISO 10993-1:2018; the standard only talks about - quote from section 6.3.1 (a):
[...] the final medical device, or representative samples from the final device or materials processed in the same manner as the final medical device [...]
One reason is that establishing biocompatibility is an _evaluation_ activity within a risk management system and not a _validation_ activity, such as e.g. the sterilization process validation for a product (family).

So building a case for "representativeness" may be a complex assessment process, in which actual device size as well as manufacturing aspects (where potential manufacturing residues could be one consideration of many more) play a role, as you correctly point out, but there might be a lot more relevant factors to consider.

Your example of a product family of identically manufactured devices of identical materials with identical intended use, but different size, implies that all involved manufacturing processes have been demonstrated to be safe and effective, including cleaning processes being capable of removing potential residues within allowable limits for all devices in your family, including the most challenging (small) ones. So scaling downwards, i.e. (small) device size should not be an issue in your biocompatibility evaluation when it comes to cleanability.

Scaling upwards, i.e. larger devices: your existing quantitative material characterization data accounting for leachables/ extractables might be the basis for your risk assessment, in which you could build a case by linearly scaling up the detected quantities by a factor corresponding to the increased surface and showing that you are still within allowable limits. A confirmatory cytotoxicity test might support your risk assessment even further.

HTH,
 
#3
The approach to biocompatibility risk assessment for orthopedic medical devices can vary depending on the product family and the specific devices within that family.
In the example you provided, the approach of selecting the largest device for biocompatibility assessment makes sense as it would have the highest design complexity in terms of thread count and threaded holes, thus presenting a higher risk for effectively cleaning the device and leaving residues from the manufacturing process behind. This approach would allow for the toxicological data to be applied to smaller device sizes as they would be considered lower risk.
Using the opposite approach of selecting the smallest device and scaling data up to larger devices could be challenging as it may be difficult to rationalize the cleanability of the larger devices with more threads. Additionally, if the manufacturer wishes to expand the product family with even larger devices, it may be difficult to apply the data collected from the smallest device to the larger devices.
In the case of expanding the product family with even larger devices, it would be important to conduct a new biocompatibility risk assessment specifically for the larger devices to ensure their safety and efficacy. This could include testing for cleanability, toxicity and other relevant parameters to ensure that the larger devices are safe for use. It's always good to consult with regulatory bodies (EU notified bodies, FDA) for guidance and to ensure that the process is compliant with regulations.
 
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