Summary from a year with Limulus Bio Coffee Breaks - 2022

January The first coffee Break in 2022 was January 20 on the topic “READ ACROSS – what is it?” Our guest was Joel Cohen, Sc.D., DABT (Board Certified Toxicologist and Principal at Gradient). Joel clarified that READ ACROSS is a technique to fill gaps in toxicity data for an untested chemical constituent by use of data from similar tested chemical(s) for a particular adverse health effect (cancer, reproductive toxicity, etc.). The technique is often applied within groups of similar chemical constituents assembled for assessment using either?an?analogue approach (grouping based on a very limited number of chemical constituents, often data for a single source substance is "read across" to a single target substance) or?a?category approach (grouping based on a larger number of?structurally similar?chemical constituents).

?February The following Coffee Break in February was with?several guests Arthur Brandwood , Lars Magnus Bjursten and Sherry Parker discussed?“What is cooking in ISO/TC 194”.

• Lars Magnus told us about what is going on, at top level, within ISO 10993 series
• Arthur pointed out the necessity of a revised Part 1 and that it needs to be more clearly risk related
• Sherry continued with discussing the Part 17 revision and all in all it was another epic event

?Quoting Lars Magnus: “The tox concepts from drugs and food have limited relevance to implanted devices. The parts that matter are sensitization, irritation and cytotoxicity in the current series. With this in mind are the resources in industry and with regulators well spent? It is easy to check the evaluations according to 10993 but much harder to address clinical evaluations that have proved to be essential when selecting e.g. orthopedic implants.?With the advent of tissue engineered constructs, immunotoxicology will become important, especially when you introduce cells and immunologically modifying compounds”.

?March The March Coffee Break was with?Thomas Hartung, MD PhD, the inventor of the whole blood pyrogen test, as our guest,?discussing on the topic in vitro pyrogenicity.?To summarize, further discussions are needed, is there scientifically justifiable to continue using the rabbit pyrogenicity test? Articles by among others,?Kelly Coleman,?point at the opposite.

• ?Rabbit pyrogen test would not pass a current test validation?
• The required extraction?means that any pyrogens would be?highly diluted if extractable at all
• The use of rabbits for pyrogenicity test has been decreasing, and the Med Tech industry has to follow the trend
• No known material, except biologics, are known to have the potential to cause?material mediated pyrogenicity (MMP); the materials within Annex G lack scientific justification

?Positive results in?Rabbit pyrogen test?have been connected to biological contamination (e.g. lipopolysaccharides) or effects from biological materials rather than a true pyrogenic response from regular materials.

?The Monocyte Activation Test (MAT) is in general more sensitive. The drive to change to a more sensitive method is low from some stakeholders, however,?it?should be better that any risk is detected than products causing pyrogenicity are released to the market. To do a recall is very costly.

TTC for?pyrogenicity??The validation study shows that tests are quantitative and thus could be converted to, e.g., ug/device or EU/cm2 and used in a toxicological risk assessment.

?April The guest in April was Robert A. Allen, PhD (Biocompatibility Consultant and Associate Director at MCRA) who gave a recap with key takeaways from?the Society of Toxicology (SOT)?Annual Meeting.?Robert pointed particularly on two trends at the SOT meeting:

???Trend 1 -?extractables datasets are getting ever larger which is leading to increasing number of equivocal tox risk assessments.

???Trend 2 - the increasing availability of in vitro alternative methods for biological endpoints, especially irritation and sensitization. Some with predictive ability even greater than established in vivo models (surprisingly).

?Another observation was that there is an undersupply of toxicologists in the medical device field and more work needs to be done to build awareness and recruit, train and mentor early career scientists and toxicologists in the area.?

?May Limulus Coffee Break May 26 had two guests, Alan Hood (Convenor of ISO TC194/WG 11) and Sherry Parker .

?We got some insight in the Part 17 revision:

• The current version of Part 17 was published back in 2002 based on toxicological principles from the 80s?and?considered?to represent the state of the art at that time
• Goal with the update is to?align?with ISO 14971 principles
• A goal has been to lessen the burden of deriving TRAs
• TSL?(Toxicological Screening Limit)?– where does it come from??Already used principle, but with a new name for it
• AL (allowable limit)?for Part 17 – do you need to revise old data??Likely not

?June Arthur Brandwood (project leader of the revision of ISO 10993-1) stopped in at the Limulus Coffee Break June 29 to give us an update on the work to revise and update ISO 10993-1.

?Why the revision?

• ?Better alignment with ISO 14971?
• ?Fundamental review of some key parts

?Key Issues:

• Alignment with ISO 14971
• Table A1/Evaluation process
• Definitions
• Annexes
• Specific Technical Issues

?Arthur described the challenge of updating the evaluation process, to drive a systematic and scientifically justified?approach to?the evaluation of biological risk for medical devices.

Another engaging and wide-ranging discussion ensued?especially around how a simpler version of the Table A1 may drive users to better plan their evaluations in a staged way.

September For us in Scandinavia the theme of Limulus Bio Coffee Break September 14 would probably be a perfect match for any Coffee Break between November and March: “ISO 10993 - finding light and dark in the world of grey”.

Michelle Kelly (toxicologist?at?NAMSA and formally?head of biological safety?at?UK regulator MHRA) expressed her experiences and thoughts about how biological evaluations are performed following the ISO 10993 standard series. Are we focusing too much on what may go wrong? And with that said are we excluding innovations that could be beneficial for patients from the market? Regulator / competent authority are very much focused on adverse events. Not surprisingly since MHRA (& other regulators) do not have a list of all marketed medical devices and their clinical benefits. First contact is often after an adverse event.

?A question that was brought up by Michelle is if we really are able to predict all adverse events seen during clinical use by preclinical testing. Lots of adverse events have some immune element coupled to them and the ISO 10993-20 needs to be revised to better reflect how to evaluate for immuntox reactions. Another area that needs to be explored is with regard to neurotoxicity which can be an issue especially when it comes to bioabsorbable materials.

In conclusion, it′s all about weighing the risk with the clinical benefit!

October Ulrika Carlander , Toxicologist and investigator at Swedish MPA and Associate researcher in Nanotoxicology at Karolinska Institute was our guest at the October Limulus Coffee Break, she summarized highlights from Biocompatibility Matters 2022.

?Ulrika mentioned that there were new young people that participated and presented their work, and that together with the development of new alternative methods, looks really promising for the future to come.

“As a researcher and regulator, I feel trust when I see that new developing standards are based on science and that results are published.?My belief is that standard test methods must be validated and built on science otherwise it is difficult to build trust among regulators. Methods must also address specific requirements in regulation to facilitate regulators’ market surveillance.”

November The year’s last Limulus Bio Coffee Break was in November with Emanuela Corsini , Professor of Toxicology at the University of Milano. We learned that many things could contribute to immunotoxicity reactions, dose/frequency/route of exposure/genetics/gender/age. The immune system and its response may be tightly connected to other organ systems, e.g. CNS, endocrine system.?The AOP (Adverse Outcome Pathway) for skin sensitization is well understood. As medical devices become increasingly complex, it is not possible to have one test approach that is suitable for all medical devices. Instead, the decision on additional immunotoxicity testing should be taken on a case-by-case basis.??

How to proceed with NAMs for immunotoxicity? Build confidence and prove that the system is working and eligible for validation. There are existing methods that can be adapted to use also for mixtures/extractables. In order to facilitate in vitro work on mixtures/extractables for immunotoxicity testing, alternative non-polar solvents may need to be developed/validated.?

?Systemic immunotoxicity, where e.g. autoimmunity and immunosuppression were discussed, can in some cases be tested using already available in vitro methodologies (e.g. whole blood assay, in vitro immunoglobulin/antibody production), but may also pose a challenge. These effects are however anticipated to be rare, and again, a case-by-case approach may be warranted.?

There is lots going on in the field, and it was concluded that more research is needed within the medical device sector.?

We would like to end by thanking everyone who has joined Limulus Bio Coffee Breaks for the great discussions that we have had during 2022 and hope that you too are looking forward to the upcoming discussions in 2023.

With best wishes for 2023

The Limulus Bio team