Regulatory Open Forum

This message was posted by a user wishing to remain anonymous

Good morning

The company I am working with are interested in moving to a terminally sterilized product (gamma).
The product is a human tissue (demineralized bone matrix and bone chips) with a dessicated hydrogel carrier (purchased), currently aseptically processed.  The hydrogel carrier is currently EO sterilized prior to processing.

Original testing for the 510(k) included extensive biocompatibility testing on the hydrogel carrier, including:
USP Biological Reactivity In Vitro <87> Agar Diffusion
Skin Sensitization Test, Guinea Pig Assay Maximization test
Ames Salmonella Microsome Mutagenesis Assay
USP Biological Reactivity In Vivo Systemic Injection Test
USP Biological Reactivity In Vivo Intracutaneous Test
Subconronic Toxicity
LAL Pyrogenicity

My question is what biocompatibility testing should I consider repeating?  I will be performing a dose range study.
Knowing that gamma radiation may alter certain linking properties of the hydrogel carrier, I will be repeating functional testing.  But how will gamma impact biocompatibility.

Look forward to the responses.
Thanks.

Unfortunately, in many cases, regulators stick close to the book on this one and want to see all of the biocompatibility redone as a result of the change in sterilization. I have had success in arguing against some of the more complex and longer term animal studies using an argument based on ethical use of animals.

------------------------------
Lisa Olson
RCRI
Minneapolis MN
United States
------------------------------

Original Message:
Sent: 28-Nov-2017 09:01
From: Anonymous Member
Subject: Bicompatibility testing after gamma radiation

This message was posted by a user wishing to remain anonymous

Good morning

The company I am working with are interested in moving to a terminally sterilized product (gamma).
The product is a human tissue (demineralized bone matrix and bone chips) with a dessicated hydrogel carrier (purchased), currently aseptically processed.  The hydrogel carrier is currently EO sterilized prior to processing.

Original testing for the 510(k) included extensive biocompatibility testing on the hydrogel carrier, including:
USP Biological Reactivity In Vitro <87> Agar Diffusion
Skin Sensitization Test, Guinea Pig Assay Maximization test
Ames Salmonella Microsome Mutagenesis Assay
USP Biological Reactivity In Vivo Systemic Injection Test
USP Biological Reactivity In Vivo Intracutaneous Test
Subconronic Toxicity
LAL Pyrogenicity

My question is what biocompatibility testing should I consider repeating?  I will be performing a dose range study.
Knowing that gamma radiation may alter certain linking properties of the hydrogel carrier, I will be repeating functional testing.  But how will gamma impact biocompatibility.

Look forward to the responses.
Thanks.

I agree totally with Lisa - the "lazy" answer is to redo the testing and this is usually the default of regulators and auditors, but a much better answer in line with ISO 10993-1 and imho the RAPS Code of Ethics is to take a risk based approach (or risk-benefit approach if you don't like seeing a benefit as a negative risk) and then use utility theory to demonstrate that the often marginal benefit is outweighed by suffering and death of numerous animals and to conduct the testing would therefore be unethical. It is worth the fight. FYI changing to gamma, I would consider embrittlement (both quickly and then over the shelf-life/product-life and potential damage to molecular links - there are bench testing ex-vivo alternatives to animal testing.

Good luck!

Neil

------------------------------
Neil Armstrong FRAPS
CEO
MeddiQuest Limited
Peterborough
United Kingdom
------------------------------

Original Message:
Sent: 29-Nov-2017 08:37
From: Lisa Olson
Subject: Bicompatibility testing after gamma radiation

Unfortunately, in many cases, regulators stick close to the book on this one and want to see all of the biocompatibility redone as a result of the change in sterilization. I have had success in arguing against some of the more complex and longer term animal studies using an argument based on ethical use of animals.

------------------------------
Lisa Olson
RCRI
Minneapolis MN
United States

Original Message:
Sent: 28-Nov-2017 09:01
From: Anonymous Member
Subject: Bicompatibility testing after gamma radiation

This message was posted by a user wishing to remain anonymous

Good morning

The company I am working with are interested in moving to a terminally sterilized product (gamma).
The product is a human tissue (demineralized bone matrix and bone chips) with a dessicated hydrogel carrier (purchased), currently aseptically processed.  The hydrogel carrier is currently EO sterilized prior to processing.

Original testing for the 510(k) included extensive biocompatibility testing on the hydrogel carrier, including:
USP Biological Reactivity In Vitro <87> Agar Diffusion
Skin Sensitization Test, Guinea Pig Assay Maximization test
Ames Salmonella Microsome Mutagenesis Assay
USP Biological Reactivity In Vivo Systemic Injection Test
USP Biological Reactivity In Vivo Intracutaneous Test
Subconronic Toxicity
LAL Pyrogenicity

My question is what biocompatibility testing should I consider repeating?  I will be performing a dose range study.
Knowing that gamma radiation may alter certain linking properties of the hydrogel carrier, I will be repeating functional testing.  But how will gamma impact biocompatibility.

Look forward to the responses.
Thanks.

Hi,
as above you need to take a risk based approach.

i would determine what if any will be the effects of the gamma radiation on the material.  Is there any information within the scientific literature, is there any studies that can be done to demonstrate it has no effect?
Once i have this information i would then approach each biocompatibility test independently and determine if it could be impacted by the change. Documenting all rationals and conclusion.
Remember as per ISO 10993, a biocompatibility assessment does not necessarily need to have testing. We need to assess based on what data we have already and then determine the need.

------------------------------
Sebastian Clerkin
GMP Advisory Services
Ballincollig
Ireland
------------------------------

Original Message:
Sent: 28-Nov-2017 09:01
From: Anonymous Member
Subject: Bicompatibility testing after gamma radiation

This message was posted by a user wishing to remain anonymous

Good morning

The company I am working with are interested in moving to a terminally sterilized product (gamma).
The product is a human tissue (demineralized bone matrix and bone chips) with a dessicated hydrogel carrier (purchased), currently aseptically processed.  The hydrogel carrier is currently EO sterilized prior to processing.

Original testing for the 510(k) included extensive biocompatibility testing on the hydrogel carrier, including:
USP Biological Reactivity In Vitro <87> Agar Diffusion
Skin Sensitization Test, Guinea Pig Assay Maximization test
Ames Salmonella Microsome Mutagenesis Assay
USP Biological Reactivity In Vivo Systemic Injection Test
USP Biological Reactivity In Vivo Intracutaneous Test
Subconronic Toxicity
LAL Pyrogenicity

My question is what biocompatibility testing should I consider repeating?  I will be performing a dose range study.
Knowing that gamma radiation may alter certain linking properties of the hydrogel carrier, I will be repeating functional testing.  But how will gamma impact biocompatibility.

Look forward to the responses.
Thanks.

​Hi,

I have quite a bit of experience with Change Control of Medical Devices and I agree with Neil and Sabastian.  You should be taking a risk based approach as outlined in ISO 10993-1.  I would suggest that you start by completing a chemical characterization of the device per ISO 10993-18. Using this approach you will conduct exhaustive extraction testing of the gamma irradiated device vs the current device.  From this you should be able to tell if the gamma irradiation impacted the extraction profile of the device.  If it did, you will then have to assess any newly identified extractables and any elevated extractables.  If it did not, you may not need to do any testing at all, it depends on if you identify any other risks unrelated to the extraction profile.  Whatever you decide, be sure to document your decisions and your rationale.   You may want to consider drafting both a strategy document and a biological evaluation report.  Again this depends in part on the risks you identify.

Best regards,

Dan O'Mara
Principal Scientist - Nonclinical Safety
Bausch+Lomb
US

------------------------------
Dan O'Mara
Rochester NY
United States
------------------------------

Original Message:
Sent: 30-Nov-2017 08:18
From: Sebastian Clerkin
Subject: Bicompatibility testing after gamma radiation

Hi,
as above you need to take a risk based approach.

i would determine what if any will be the effects of the gamma radiation on the material.  Is there any information within the scientific literature, is there any studies that can be done to demonstrate it has no effect?
Once i have this information i would then approach each biocompatibility test independently and determine if it could be impacted by the change. Documenting all rationals and conclusion.
Remember as per ISO 10993, a biocompatibility assessment does not necessarily need to have testing. We need to assess based on what data we have already and then determine the need.

------------------------------
Sebastian Clerkin
GMP Advisory Services
Ballincollig
Ireland

Original Message:
Sent: 28-Nov-2017 09:01
From: Anonymous Member
Subject: Bicompatibility testing after gamma radiation

This message was posted by a user wishing to remain anonymous

Good morning

The company I am working with are interested in moving to a terminally sterilized product (gamma).
The product is a human tissue (demineralized bone matrix and bone chips) with a dessicated hydrogel carrier (purchased), currently aseptically processed.  The hydrogel carrier is currently EO sterilized prior to processing.

Original testing for the 510(k) included extensive biocompatibility testing on the hydrogel carrier, including:
USP Biological Reactivity In Vitro <87> Agar Diffusion
Skin Sensitization Test, Guinea Pig Assay Maximization test
Ames Salmonella Microsome Mutagenesis Assay
USP Biological Reactivity In Vivo Systemic Injection Test
USP Biological Reactivity In Vivo Intracutaneous Test
Subconronic Toxicity
LAL Pyrogenicity

My question is what biocompatibility testing should I consider repeating?  I will be performing a dose range study.
Knowing that gamma radiation may alter certain linking properties of the hydrogel carrier, I will be repeating functional testing.  But how will gamma impact biocompatibility.

Look forward to the responses.
Thanks.

​
To the OP, you've gotten good feedback from all so far.  In particular, I agree with Dan's suggestion to consider a materials equivalence approach.  In addition to the chemical equivalence he suggests, I would recommend considering the potential for any changes in surface properties (ISO 10993-19).  Such changes (if any) can potentially affect the local biological response.

Good luck with this change!

Ted

------------------------------
Theodore Heise PhD RAC
VP Regulatory and Clinical Services
MED Institute
West Lafayette IN
United States
------------------------------

Original Message:
Sent: 30-Nov-2017 17:32
From: Dan O'Mara
Subject: Bicompatibility testing after gamma radiation

​Hi,

I have quite a bit of experience with Change Control of Medical Devices and I agree with Neil and Sabastian.  You should be taking a risk based approach as outlined in ISO 10993-1.  I would suggest that you start by completing a chemical characterization of the device per ISO 10993-18. Using this approach you will conduct exhaustive extraction testing of the gamma irradiated device vs the current device.  From this you should be able to tell if the gamma irradiation impacted the extraction profile of the device.  If it did, you will then have to assess any newly identified extractables and any elevated extractables.  If it did not, you may not need to do any testing at all, it depends on if you identify any other risks unrelated to the extraction profile.  Whatever you decide, be sure to document your decisions and your rationale.   You may want to consider drafting both a strategy document and a biological evaluation report.  Again this depends in part on the risks you identify.

Best regards,

Dan O'Mara
Principal Scientist - Nonclinical Safety
Bausch+Lomb
US

------------------------------
Dan O'Mara
Rochester NY
United States

Original Message:
Sent: 30-Nov-2017 08:18
From: Sebastian Clerkin
Subject: Bicompatibility testing after gamma radiation

Hi,
as above you need to take a risk based approach.

i would determine what if any will be the effects of the gamma radiation on the material.  Is there any information within the scientific literature, is there any studies that can be done to demonstrate it has no effect?
Once i have this information i would then approach each biocompatibility test independently and determine if it could be impacted by the change. Documenting all rationals and conclusion.
Remember as per ISO 10993, a biocompatibility assessment does not necessarily need to have testing. We need to assess based on what data we have already and then determine the need.

------------------------------
Sebastian Clerkin
GMP Advisory Services
Ballincollig
Ireland

Original Message:
Sent: 28-Nov-2017 09:01
From: Anonymous Member
Subject: Bicompatibility testing after gamma radiation

This message was posted by a user wishing to remain anonymous

Good morning

The company I am working with are interested in moving to a terminally sterilized product (gamma).
The product is a human tissue (demineralized bone matrix and bone chips) with a dessicated hydrogel carrier (purchased), currently aseptically processed.  The hydrogel carrier is currently EO sterilized prior to processing.

Original testing for the 510(k) included extensive biocompatibility testing on the hydrogel carrier, including:
USP Biological Reactivity In Vitro <87> Agar Diffusion
Skin Sensitization Test, Guinea Pig Assay Maximization test
Ames Salmonella Microsome Mutagenesis Assay
USP Biological Reactivity In Vivo Systemic Injection Test
USP Biological Reactivity In Vivo Intracutaneous Test
Subconronic Toxicity
LAL Pyrogenicity

My question is what biocompatibility testing should I consider repeating?  I will be performing a dose range study.
Knowing that gamma radiation may alter certain linking properties of the hydrogel carrier, I will be repeating functional testing.  But how will gamma impact biocompatibility.

Look forward to the responses.
Thanks.

Hi all,

I agree with Dan: Chemical characterization can be a great tool to assess design or process change impact on Biocomp..
One further really big advantage: You learn a lot about your product when you deep dive into it's chemical profile.
Since I am not familiar with the device type & category in scope I do not know which analytical method could work out. This may be something to discuss with your test lab.
I have gained some good experiences with polymer devices with short term patient contact (skin & external communicating).
ISO 10993-17 provides a step by step guidance how to assess the extractable/leachable compounds you find in your characterization.
Principally you could perform the assessment on your own, because there is plenty of literature available online and the databases are partly free to access (TOXNET, Toxline, ECHA Website...).
Depending on your products complexity and the kind of extractables/leachables you find it may be more efficient to get it done by the test lab (especially if you find a lot of compounds and you do not have a toxicologist in your company).
If you need I basic introduction it is worth to watch the following webinar:
The Power of Chemical Characterization to Assess Changes webinar

YouTube		remove preview
The Power of Chemical Characterization to Assess Changes webinar Uploaded by Nelson Labs on 2014-12-18. View this on YouTube >

Another point to consider are your internal stakeholders: Some people still treat Annex A of ISO 10993-1 (and the corresponding FDA guidance table) as a checklist, or are afraid that regulatory bodies may see it as a checklist.
For this reason I recommend to write down a Biological Evaluation Plan that points out what (analytical) testing you aim to do and why you see it as appropriate to mitigate all potential biological risks.
What may be helpful for you is 'ISO/TR 15499:2016 Biological Evaluation of medical devices - Guidance on the conduct of biological evaluation within a risk management system'. Section 6.3.1 points out the you should do in-vitro testing before considering any in-vivo tests.
Section 6.5.1 gives guidance how to deal with changes (e.g. sterilization) and again points out "[...]followed by animal testing only if the materials characterization or in-vitro tests do not provide sufficient information".

Best wishes,
Michael

------------------------------
Michael Hottner
Straight Forward Medical Device Consulting Gmbh
Cologne
Germany
------------------------------

Original Message:
Sent: 28-Nov-2017 09:01
From: Anonymous Member
Subject: Bicompatibility testing after gamma radiation

This message was posted by a user wishing to remain anonymous

Good morning

The company I am working with are interested in moving to a terminally sterilized product (gamma).
The product is a human tissue (demineralized bone matrix and bone chips) with a dessicated hydrogel carrier (purchased), currently aseptically processed.  The hydrogel carrier is currently EO sterilized prior to processing.

Original testing for the 510(k) included extensive biocompatibility testing on the hydrogel carrier, including:
USP Biological Reactivity In Vitro <87> Agar Diffusion
Skin Sensitization Test, Guinea Pig Assay Maximization test
Ames Salmonella Microsome Mutagenesis Assay
USP Biological Reactivity In Vivo Systemic Injection Test
USP Biological Reactivity In Vivo Intracutaneous Test
Subconronic Toxicity
LAL Pyrogenicity

My question is what biocompatibility testing should I consider repeating?  I will be performing a dose range study.
Knowing that gamma radiation may alter certain linking properties of the hydrogel carrier, I will be repeating functional testing.  But how will gamma impact biocompatibility.

Look forward to the responses.
Thanks.

You've received excellent advice on the biocompatibility front. I agree with the poster who said the bigger concern would be the mechanical changes. Particularly with plastics, gamma can cause significant changes in performance and stability. You should make sure and assess those risks as well. In my experience, gamma is much more likely to cause performance problems rather than  biocompatibility changes.

g-

------------------------------
Ginger Glaser RAC
Chief Technology Officer
MN
------------------------------

Original Message:
Sent: 28-Nov-2017 09:01
From: Anonymous Member
Subject: Bicompatibility testing after gamma radiation

This message was posted by a user wishing to remain anonymous

Good morning

The company I am working with are interested in moving to a terminally sterilized product (gamma).
The product is a human tissue (demineralized bone matrix and bone chips) with a dessicated hydrogel carrier (purchased), currently aseptically processed.  The hydrogel carrier is currently EO sterilized prior to processing.

Original testing for the 510(k) included extensive biocompatibility testing on the hydrogel carrier, including:
USP Biological Reactivity In Vitro <87> Agar Diffusion
Skin Sensitization Test, Guinea Pig Assay Maximization test
Ames Salmonella Microsome Mutagenesis Assay
USP Biological Reactivity In Vivo Systemic Injection Test
USP Biological Reactivity In Vivo Intracutaneous Test
Subconronic Toxicity
LAL Pyrogenicity

My question is what biocompatibility testing should I consider repeating?  I will be performing a dose range study.
Knowing that gamma radiation may alter certain linking properties of the hydrogel carrier, I will be repeating functional testing.  But how will gamma impact biocompatibility.

Look forward to the responses.
Thanks.