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Technical File Reviewer has requested more testing to ISO 10993

#1
Good morning,

The company I work for manufactures RGP (Rigid Gas Permeable) contact lenses which are usually used for a year (worn during the day and removed at night for cleaning). Our technical file contains the following biocompatility testing; Cytoxicity, Sensitisation, Ocular Irritation and Systemic Toxicity for our RGP contact lenses. These have been tested as contact lenses are a surface device (as per the ISO 10993 matrix) are contact duration A (<24 hours) within a mucosal membrane.

The technical file reviewer is stating that although the the contact lenses are within the eye for less than 24 hours, they have stated
"Due to the cumulative, multiple or repeated use of the lens the duration of contact will be >30d and hence additional biocompatibility testing will be required. The manufacturer need to complete the tests or provide a justification for not conducting the required tests"

Previously our biocompatibility data has been more than sufficient to meet this requirement... does anyone know of any change for this now to be the case?
 
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#2
The reviewer does have the current appropriate viewpoint, as based on ISo 10993-1:2018, section 5.3.1 states "medical device whose cumulative sum of single, multiple or repeated duration of contact is ...".
This standard came out 2018-08, was corrected in 2018-10 (on a nonrelated point iirc), and will be mandatory for the FDA by december 2020.
 
#3
Right you are, just referenced this version of the standard. This has serious cost implications for many small medical device companies...
 
#4
Cost implications is perhaps too generic to describe the obstacle. The changes also provide for opportunities. The core thing is that companies need to increase familiarity if not competence with regards to this entire series of standards, and specifically the chemical/material characterization that is the only mandatory item. The others have turned into 'E''s or endpoints, which explicitly allow rationalization (by for example a toxicologist) to not proceed with indepth testing (often based at least in part on the characterization). This was expected to reduce the load of 'tick-the-box' testing for those extended matrices.
 
#5
Thanks for the information.
So as an example;
We have completed the chemical/material characterization for our contact lens material. The data we receive from this characterization in conjunction with our bio-compatibility data that we have already completed can be used by (for example) a toxicologist to compile a report/justification on why a suite of tests may not be necessary?
Have I understood that correctly?
 
#6
Yes, it is an essential (but not necessarily sufficient) input for a toxicologist to decide on the necessary tests.
Note that this is not a guarantee that testing can always be rationalized away.
They will evaluate that information for risk as controlled versus the benefits that the available tests can provide in assuring future problem-free use of the device. They will select the ones based on the confidence gained (taking into account for which costs (i.e. suffering of test subjects, not necessarily economical) are justifiable). If a test provides no additional confidence, they should not select it either as it is redundant or useless.

Key take-away: build a good relationship with a toxicological firm you work well with, and align your design change process (especially include adjuvants in their scope, a single word in the EU MDR but very important with respect to this topic).

[Note: I'm not a toxicologist, i'm a systems guy who knows all of these Risk management, QMS and design interactions well]
 

Ronen E

Problem Solver
Staff member
Super Moderator
#7
Cost implications is perhaps too generic to describe the obstacle. The changes also provide for opportunities. The core thing is that companies need to increase familiarity if not competence with regards to this entire series of standards, and specifically the chemical/material characterization that is the only mandatory item. The others have turned into 'E''s or endpoints, which explicitly allow rationalization (by for example a toxicologist) to not proceed with indepth testing (often based at least in part on the characterization). This was expected to reduce the load of 'tick-the-box' testing for those extended matrices.
Just a quick note to say that most (if not all) those concepts and pathways were already in the 2009 version. IMO a lot of difficulty has stemmed from manufacturers rushing to the Annex A test matrix without thoroughly reading the normative text (let alone really taking the concepts in).
The key is (and was) running a biocompatibility risk evaluation by/with a toxicologist with expertise in this.
Added in edit: I am not a toxicologist.
 
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#8
Just a quick note to say that most (if not all) those concepts and pathways were already in the 2009 version. IMO a lot of difficulty has stemmed from manufacturers rushing to the Annex A test matrix without thoroughly reading the normative text (let alone really taking the concepts in).
The key is (and was) running a biocompatibility risk evaluation by/with a toxicologist with expertise in this.
Indeed, and the same held for the cumulative aspect as it was logical that exposures to materials that do not dissipate but stack should be summed to match reality.
However, such things used to be implicit, or in external guidance. If you do not or could not spend time it was easy to overlook. This happened both on the industry side as well as the oversight side. Many a company would go the right way, but be overridden by auditors or reviewers who were required to act out of their competence zone. A discussion might ensue, but one end holds the market access approval card so the company would yield in extended debate, thus perpetuating the wrong interpretation in case study.
This happens a lot. Standards are written by the foremost experts on a topic (that have the time to do so), but expected to be applied by less than foremost companies. Small ones might not even have the time to understand them well under market or investor pressure.
Thus explicitly clarifying something that was implicitly clear (to experts) so lesser professionals do not need to interpret levels the playing field such that intent is achieved more easily is something I applaud.
There is an irony in that we expect medtech to address usability of devices, but with standards and their framework we do not endeavour to systematically improve them based on general feedback (mandatory guidance y'all). We only do so based on expert filtered preferential feedback (no comprehension study on standards that takes into account the user groups "small company", "plucky startup", "time strapped department") .
 

Ronen E

Problem Solver
Staff member
Super Moderator
#9
I generally agree with you but don't fully accept the argument about lack of time or lack of resources. "If you do it, do it right". Besides, saying "we don't have time for that" is actually saying "this is not important enough for us".

With specific regard to cumulative contact duration, it was mostly spelled out in the 2009 version (s. 5.3, last para.):
With multiple exposures to the device, the decision into which category a device is placed shall take into account the potential cumulative effect, bearing in mind the period of time over which these exposures occur.
The "devices whose cumulative single, multiple or repeated use or contact is..." wording was also already there in the 3 duration categories.
 
#10
I generally agree with you but don't fully accept the argument about lack of time or lack of resources. "If you do it, do it right". Besides, saying "we don't have time for that" is actually saying "this is not important enough for us".

With specific regard to cumulative contact duration, it was mostly spelled out in the 2009 version (s. 5.3, last para.):

The "devices whose cumulative single, multiple or repeated use or contact is..." wording was also already there in the 3 duration categories.
You are correct. It was already present. I'd wager that the previous classification rationale was built on it not being the same physical device and the file focusing on representing the product as singular. This could pass cursory inspection for reviewers unexperienced or time-pressed. Silly argument if you look at it with common sense, but under constraints things can go wrong.

I also agree that the principle you should follow is "If you do it, do it right". But importance assigned to something is built on adequate prior experience or knowledge with a matter. It is not important to wear your seatbelt, until you've seen, were convinced or have lived the results of it. Counter to that you have simple unawareness (you don't know you need it until you've had it), things that prevent persons from being convinced (typical biases, overreliance on rockstar employees outside of their speciality, HIPPO's) or plain things that we cannot imagine/simulate accurately.
That then leads to not spending the time on it. Even when this is not the case, they might not be able to spend a competent person's time on it because they were not available (pre-occupied or simply all taken outside of reach). Yet something needs to be handed in (market pressure, HIPPO's) so use the most proficient person you have, and rely on the (unverified) competence of the authority that will be checking you hoping for an old-school teacher dynamic of being taught through trial-and-error. Just keep in mind that an authority faces the same constraints when it comes to sourcing competent people, allocating training budgets, meeting response time targets etc. Some may even have perverse incentives.

We may not like it, but we live in a world of constraints and try to make the best of it. I don't know a company which is not like this [and if there is, I (believe I) am competent in my areas of expertise, and as they wouldn't have resource restrictions to facilitate my transfer so get them to give me a call ; ) ].
 
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