Overview
Often times, following the completion of biocompatibility testing, or a portion thereof, if there may be surprising results. With proper planning and associated biological risk assessment of the entire device down to the individual materials, the amount of surprises can be reduced to a minimum. The biological risk assessment will identify both potential physical and toxicological risks of the device and it’s critical to perform this step prior to initiating testing. Within this paper are a few examples of pitfalls that are commonly seen in the lab as well as a few recommendations based on actual testing and notified body feedback. Most older and larger labs have extensive experience with a wide range of devices and material types and can help manufacturers develop a test plan. Manufacturers should keep these notes in mind in order to help avoid potential issues and ultimately lead to a successful testing program and submission to notified bodies.
Sample Preparation
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Often times, following the completion of biocompatibility testing, or a portion thereof, if there may be surprising results. With proper planning and associated biological risk assessment of the entire device down to the individual materials, the amount of surprises can be reduced to a minimum. The biological risk assessment will identify both potential physical and toxicological risks of the device and it’s critical to perform this step prior to initiating testing. Within this paper are a few examples of pitfalls that are commonly seen in the lab as well as a few recommendations based on actual testing and notified body feedback. Most older and larger labs have extensive experience with a wide range of devices and material types and can help manufacturers develop a test plan. Manufacturers should keep these notes in mind in order to help avoid potential issues and ultimately lead to a successful testing program and submission to notified bodies.
Sample Preparation
- Test the final finished product - ISO requirement!
- Prototype or engineering builds may not be representative of the final materials, manufacturing process (including manufacturing aids like mold release agents), or sterilization. Changes to these can have a profound effect on the chemical characterization of the device.
- Sample preparation
- Selection of extraction condition
- The Device should not degrade or deform during the extraction process
- Review the entire bill of materials for physical properties
- Melting points
- Are all the materials stable in the extraction vehicles?
- Did you use the highest grade materials?
- Assess the clinical environment the device may be used in
- i.e. heated vapor through a nebulizer
- Extraction ratio
- Use surface area to volume ratios
- FDA expects that if you have a CAD drawing you can determine the surface area
- During extraction
- Rust, dissolution of materials, changes in the color or clarity of the vehicle or unanticipated particulates are events that will require further investigation.
- Absorptive materials need to be extracted beyond their absorptive capacity
- Alert lab if any materials fit this case
- Selection of extraction condition
- Good for initial material screening
- Most common failing materials
- Rubber, natural or artificial latex, silver (or other antimicrobials), glue, gels, liquids, PVC, silicone, coating, fabrics, electronics
- Check with labs about a test plan
- Rubber, natural or artificial latex, silver (or other antimicrobials), glue, gels, liquids, PVC, silicone, coating, fabrics, electronics
- What do you do If you have a failure
- Any of the above materials present?
- Perhaps try a different sample/extract preparation
- Is the test method used appropriate to address patient exposure
- NOTE: a failed cytotox does not necessarily mean any other tests in the battery will have problems
- This is an opportunity to not waste time and money qualifying a product that will fail more expensive and tests and expose animals to unnecessary testing.
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In-Vivo Thrombogenicity (Non-Anticoagulated Venous Implant)
Implantable Devices
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- Can thrombogenicity be assessed as a part of a large animal implant study?
- As part of this assessment anticoagulants are not to be used, regardless of whether the IFU indicated their use or not
- If there are coatings that need to be activated or rehydrated they need to be followed during this evaluation?
- If significant thrombus levels are seen, notified bodies may request the following:
- Material/surface characterization (descriptive or testing)
- Review for manufacturing defects - old molds etc.
- 40X microscopy
- Is the thrombus associated with a particular material or geometric formation/junction?
- Potential device labeling
- Only use with anticoagulants
- Summary of preclinical NAVI findings for physician risk determination
- Potentially repeat study under heparinization
Implantable Devices
- All individual components which enter the body should be evaluated by implantation
- An assessment on the microscopic level between the implanted material and the adjacent cells
- The test samples may require special machining depending on the hardness of the material
- It is imperative to use an appropriate or predicate control, particularly for woven, braided or degradable products
- Degradable Materials
- Knowing the degradation profile will prevent unnecessary testing or carpet bombing the timepoints in the In Vivo implantation tests
- In-vitro assessment – e.g. ASTM F1635
- Review similar materials/devices
- ISO 10993-6 - Evaluate out to the point of stable tissue reaction
- Multiple time points
- Tissue reactivity assessments need to occur before complete degradation, at expected degradation and past degradation when the tissue has returned to condition of stasis
- Biologically active ingredients
- Determine where byproducts go (accumulation? where?)
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Hemostatic Products
Closing Thoughts
It is impossible to cover every potential device or test type but the biggest takeaway is to never underestimate your device. This should start your thought process and provide a structure to take forward to your particular device type. Take the time upfront to develop a solid test plan in which a deep biological risk assessment of all materials is performed. The biological risk assessment is not only required by ISO 10993-1, but can save you significant time, sample requirements, and associated costs of rework or if you determine if you can exempt out of certain testing. When setting your test plan and thoughts on extraction conditions, don’t forget how shipping conditions may affect your device. Shipping your device over the Pacific Ocean by boat (warm and humid) versus flying it in the cargo hold of a plane (cold) are very different environments. All of the individual components or materials may have passed individual testing or have historical use, but the testing is on the final finished sterilized product. This is because in the manufacturing of this specific product, it may be unknown what other materials get on, or are formed, during the build. What release agents, polishing compounds, sterilants or cleaners that remain on the product after completion are all of concern and are the reason that the product made with “well characterized historical” still need to be evaluated. Finally, if you’re unsure of anything, talk to your test lab or a trusted, experienced consultant because they most likely have the experience with specific devices like yours and know the risks and benefits of certain testing plan strategies.
- Some products elicit an exothermic reaction
- pH changes to extracts - can cause reactions
- Particulates or suspension
- By design these products will effect and consequently cause findings in hemocompatibility evaluations
- Have the potential of causing necrosis or systemic toxicity when implanted
- IV-dosed in-vivo tests will likely require a change to the dosing route or post extraction manipulation
- If they are soluble in aqueous solutions or oils, then the extract is not an extract but should be viewed as dosing solution.
- Consideration to dosing neat should be given based upon patient exposure
- Are they too viscous to dose with a syringe or pipette?
- Dilute keeping in mind clinical dose with associated safety factor
- Consider alternative test methods e.g. Agar vs. NRU
- Characterization of liquids
- Is it isotonic?
- What is the pH?
- Compatible with cell media?
- Safety Data Sheets
- Intended use
Closing Thoughts
It is impossible to cover every potential device or test type but the biggest takeaway is to never underestimate your device. This should start your thought process and provide a structure to take forward to your particular device type. Take the time upfront to develop a solid test plan in which a deep biological risk assessment of all materials is performed. The biological risk assessment is not only required by ISO 10993-1, but can save you significant time, sample requirements, and associated costs of rework or if you determine if you can exempt out of certain testing. When setting your test plan and thoughts on extraction conditions, don’t forget how shipping conditions may affect your device. Shipping your device over the Pacific Ocean by boat (warm and humid) versus flying it in the cargo hold of a plane (cold) are very different environments. All of the individual components or materials may have passed individual testing or have historical use, but the testing is on the final finished sterilized product. This is because in the manufacturing of this specific product, it may be unknown what other materials get on, or are formed, during the build. What release agents, polishing compounds, sterilants or cleaners that remain on the product after completion are all of concern and are the reason that the product made with “well characterized historical” still need to be evaluated. Finally, if you’re unsure of anything, talk to your test lab or a trusted, experienced consultant because they most likely have the experience with specific devices like yours and know the risks and benefits of certain testing plan strategies.
