Nick Hibbard, In-Vitro Scientific Research Fellow at WuXi AppTec Medical Device Testing07.22.21
The publication of ISO 10993-23:2021 in January 2021 marks a paradigm shift in prioritizing in-vitro testing alternatives within the medical device biocompatibility space. Drafting for ISO 10993-23 has been in progress for years and its debut has been anticipated for many reasons—chief among them is the potential to reduce in-vivo irritation test methods.
In 2003, a validation study from the European Centre for the Validation of Alternative Methods (ECVAM) laid the groundwork for ISO 10993-23. The Centre focuses on safety assessments for chemical, agricultural, and cosmetic products with the goal of reducing, refining, and replacing in vivo testing wherever possible. The skin irritation assay ECVAM initially used as part of a cosmetic directive evolved to become ISO 10993-23 within the medical device space. And, publishing the new standard means ISO officially recognizes in-vitro irritation testing as an approved method for understanding, predicting, and classifying the potential for skin irritation risk in medical devices.
But that does not mean regulatory bodies worldwide have completely followed suit. ISO 10993-23 is relatively new, and regulators are still interpreting it according to their individual mandates. It’s critical to stay informed about what guidance comes from which regulatory body and ensure medical device submissions are aligned accordingly. Keeping a pulse on the regulatory landscape is important, as evolving guidance could impact test programs.
Unpacking ISO 10993-23:2021
The standard represents a split from ISO 10993-10—an assessment of irritation and sensitization. As a part of the ISO 10993 family of standards that assesses biological risks in medical devices, ISO 10993-23 includes new language that will require in-vitro testing for skin irritation, but only for specific contact points.
The standard’s approved in-vitro methods are limited to contact points located on epidermal tissue. At the time of publication, ISO 10993-10 still contained language relating to irritation and sensitization. But as ISO 10993-23 becomes a more popular standard for testing irritation, ISO 10993-10 will eventually focus exclusively on sensitization. Until that happens, however, two standards exist to evaluate the irritant potential in medical devices, with ISO 10993-23 being the preferred method.
ISO created a step-by-step directive to maximize thoroughness and outline how to use the two standards in concert. The five steps include:
The Business Case for In-Vitro Skin Irritation Assays
One of the most valuable characteristics of ISO 10993-23 is the robustness of the in-vitro assay. Part of the development included a large round-robin study that tested two types of RhE. The study demonstrated that in-vitro models can detect irritant chemicals extracted from PVC and silicone—two materials commonly used in medical device production. The study was conducted across different geographies and laboratory environments and found the assay to be equally sensitive in detecting low concentrations of some potent irritant compounds. Previous methods for this type of detection were limited to human patch testing and other in vivo methods.
Because the assay is robust and repeatable, it can also be a valuable safeguard. Cytotoxicity testing helps assess the potential for a test article to inhibit cell growth or cause cell death. Likewise, pyrogenicity testing determines the presence of foreign substances that may trigger a fever response. Used together, an in-vitro skin irritation, pyrogenicity, and cytotoxicity panel of tests may provide a formidable battery of biocompatibility testing that could enable researchers to proactively remove problematic test articles early in their development. Depending on manufacturers’ regulatory strategy and the market they would like to enter, this biocompatibility trifecta could also serve as a proactive measure before moving into any in-vivo testing the local regulatory agency may require.
Manufacturers hoping to leverage the in-vitro skin irritation test as a screening method must understand their product’s origins and components, down to the coatings, packaging, materials, and products or methods used for sterilization. A coating, for example, might not be central to a device’s design and functionality, but it can still be a source of irritation that gets flagged during testing. Put simply, any combination of these variables could create an irritation that has the potential to undermine a regulatory application and require revisiting a completed design.
Emerging In-Vitro Modalities
As the use of in-vitro modalities increases, in-vitro skin irritation testing could conceivably become the preferred approach. Regulatory bodies will take some time to interpret the test method and issue guidance and, as such, there will still be a time and place for in vivo methods for the foreseeable future. But the primary appeal of in-vitro modalities will always be their adherence to the scientific tenets of the three Rs: replacement, reduction, and refinement.
The publication of ISO 10993-23 has bolstered the case for using in-vitro assays to assess skin irritation whenever possible. In fact, regulatory bodies in parts of Asia and the European Union have already deemed in-vitro testing as the preferred method for assessing skin irritation. But companies should always consider the market in which they plan to launch their products and ensure the regulatory guidance in those locations matches their testing processes. In the past, medical devices that tested negative or inconclusive for irritation would still require an in vivo evaluation, but under the ISO 10993-23 revisions, regulators can now accept both positive and negative results, should they choose to do so.
The bottom line is, ISO 10993-23 is still in its infancy and applying it can be confusing. This might make it challenging for manufacturers to fully understand the regulatory guidance that applies to the particular products in each region. Manufacturers that collaborate with testing partners can gain a better understanding of how regulatory bodies interpret ISO standards. Engaging the right testing partner can also build confidence in facing an evolving regulatory landscape and it can help manufacturers build the best and safest device possible.
Prioritizing Safety
The ISO 10993-23 guidance is just the beginning. It is unlikely that in biological evaluations overall, in-vitro methods will totally replace in vivo methods, but the journey has begun. In vivo skin irritation testing is a robust and repeatable complement to the ISO 10993 guidance that can add efficiency to manufacturing processes and preserve valuable resources along the way. The standard offers a trustworthy alternative to in vivo testing that can, in some cases, help reduce, refine, and replace the use of test articles in skin irritation assessments.
Managing risk and prioritizing patient safety will always be the central goals in evaluating medical device biocompatibility. The ISO 10993 standard is continuously evolving to support this endeavor. Collaborating with a qualified laboratory testing partner with expert knowledge of the shifts and changes within the guidance documents will help ensure successful submissions.
Nick Hibbard earned a bachelor of science degree from Bowling Green State University and a master of science degree from the University of Liverpool, where he wrote his dissertation, “Accuracy and precision of liver based in-vitro models relating to pre-clinical drug screening.’’ Hibbard has more than 10 years of direct experience within the field of in-vitro sciences, ranging from standard guideline driven assays to complex novel assay development. Currently he is the in-vitro Scientific Research Fellow at WuXi AppTec Medical Device Testing in St. Paul, Minn. Within this position he is responsible for troubleshooting assay deviations, novel assay development, and validating current approved assays for service.
In 2003, a validation study from the European Centre for the Validation of Alternative Methods (ECVAM) laid the groundwork for ISO 10993-23. The Centre focuses on safety assessments for chemical, agricultural, and cosmetic products with the goal of reducing, refining, and replacing in vivo testing wherever possible. The skin irritation assay ECVAM initially used as part of a cosmetic directive evolved to become ISO 10993-23 within the medical device space. And, publishing the new standard means ISO officially recognizes in-vitro irritation testing as an approved method for understanding, predicting, and classifying the potential for skin irritation risk in medical devices.
But that does not mean regulatory bodies worldwide have completely followed suit. ISO 10993-23 is relatively new, and regulators are still interpreting it according to their individual mandates. It’s critical to stay informed about what guidance comes from which regulatory body and ensure medical device submissions are aligned accordingly. Keeping a pulse on the regulatory landscape is important, as evolving guidance could impact test programs.
Unpacking ISO 10993-23:2021
The standard represents a split from ISO 10993-10—an assessment of irritation and sensitization. As a part of the ISO 10993 family of standards that assesses biological risks in medical devices, ISO 10993-23 includes new language that will require in-vitro testing for skin irritation, but only for specific contact points.
The standard’s approved in-vitro methods are limited to contact points located on epidermal tissue. At the time of publication, ISO 10993-10 still contained language relating to irritation and sensitization. But as ISO 10993-23 becomes a more popular standard for testing irritation, ISO 10993-10 will eventually focus exclusively on sensitization. Until that happens, however, two standards exist to evaluate the irritant potential in medical devices, with ISO 10993-23 being the preferred method.
ISO created a step-by-step directive to maximize thoroughness and outline how to use the two standards in concert. The five steps include:
- Performing a chemical characterization of medical device materials, residue, and additives.
- Conducting a literature review to evaluate a device’s chemical and physical properties, as well as the irritation potential of any extracts or constituents.
- Conducting in-vitro testing using reconstituted human epidermis (RhE).
- Conducting in vivo testing when device materials cannot be characterized and risk assessments cannot be undertaken.
- Performing non-invasive clinical studies only after irritancy potential is established using one of the aforementioned methods.
The Business Case for In-Vitro Skin Irritation Assays
One of the most valuable characteristics of ISO 10993-23 is the robustness of the in-vitro assay. Part of the development included a large round-robin study that tested two types of RhE. The study demonstrated that in-vitro models can detect irritant chemicals extracted from PVC and silicone—two materials commonly used in medical device production. The study was conducted across different geographies and laboratory environments and found the assay to be equally sensitive in detecting low concentrations of some potent irritant compounds. Previous methods for this type of detection were limited to human patch testing and other in vivo methods.
Because the assay is robust and repeatable, it can also be a valuable safeguard. Cytotoxicity testing helps assess the potential for a test article to inhibit cell growth or cause cell death. Likewise, pyrogenicity testing determines the presence of foreign substances that may trigger a fever response. Used together, an in-vitro skin irritation, pyrogenicity, and cytotoxicity panel of tests may provide a formidable battery of biocompatibility testing that could enable researchers to proactively remove problematic test articles early in their development. Depending on manufacturers’ regulatory strategy and the market they would like to enter, this biocompatibility trifecta could also serve as a proactive measure before moving into any in-vivo testing the local regulatory agency may require.
Manufacturers hoping to leverage the in-vitro skin irritation test as a screening method must understand their product’s origins and components, down to the coatings, packaging, materials, and products or methods used for sterilization. A coating, for example, might not be central to a device’s design and functionality, but it can still be a source of irritation that gets flagged during testing. Put simply, any combination of these variables could create an irritation that has the potential to undermine a regulatory application and require revisiting a completed design.
Emerging In-Vitro Modalities
As the use of in-vitro modalities increases, in-vitro skin irritation testing could conceivably become the preferred approach. Regulatory bodies will take some time to interpret the test method and issue guidance and, as such, there will still be a time and place for in vivo methods for the foreseeable future. But the primary appeal of in-vitro modalities will always be their adherence to the scientific tenets of the three Rs: replacement, reduction, and refinement.
The publication of ISO 10993-23 has bolstered the case for using in-vitro assays to assess skin irritation whenever possible. In fact, regulatory bodies in parts of Asia and the European Union have already deemed in-vitro testing as the preferred method for assessing skin irritation. But companies should always consider the market in which they plan to launch their products and ensure the regulatory guidance in those locations matches their testing processes. In the past, medical devices that tested negative or inconclusive for irritation would still require an in vivo evaluation, but under the ISO 10993-23 revisions, regulators can now accept both positive and negative results, should they choose to do so.
The bottom line is, ISO 10993-23 is still in its infancy and applying it can be confusing. This might make it challenging for manufacturers to fully understand the regulatory guidance that applies to the particular products in each region. Manufacturers that collaborate with testing partners can gain a better understanding of how regulatory bodies interpret ISO standards. Engaging the right testing partner can also build confidence in facing an evolving regulatory landscape and it can help manufacturers build the best and safest device possible.
Prioritizing Safety
The ISO 10993-23 guidance is just the beginning. It is unlikely that in biological evaluations overall, in-vitro methods will totally replace in vivo methods, but the journey has begun. In vivo skin irritation testing is a robust and repeatable complement to the ISO 10993 guidance that can add efficiency to manufacturing processes and preserve valuable resources along the way. The standard offers a trustworthy alternative to in vivo testing that can, in some cases, help reduce, refine, and replace the use of test articles in skin irritation assessments.
Managing risk and prioritizing patient safety will always be the central goals in evaluating medical device biocompatibility. The ISO 10993 standard is continuously evolving to support this endeavor. Collaborating with a qualified laboratory testing partner with expert knowledge of the shifts and changes within the guidance documents will help ensure successful submissions.
Nick Hibbard earned a bachelor of science degree from Bowling Green State University and a master of science degree from the University of Liverpool, where he wrote his dissertation, “Accuracy and precision of liver based in-vitro models relating to pre-clinical drug screening.’’ Hibbard has more than 10 years of direct experience within the field of in-vitro sciences, ranging from standard guideline driven assays to complex novel assay development. Currently he is the in-vitro Scientific Research Fellow at WuXi AppTec Medical Device Testing in St. Paul, Minn. Within this position he is responsible for troubleshooting assay deviations, novel assay development, and validating current approved assays for service.
