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Regulatory Development Indicates Shift Toward In Vitro

Jul 30, 2021 | Biocompatibility, Medical Device Testing

After several years of waiting, the International Organization for Standardization (ISO) approved the release of ISO 10993-23 in January 2021. The standard officially recognizes in vitro as an approved method for understanding, predicting and classifying skin irritation risk in medical devices.

The skin irritation assay uses reconstituted human epidermis (RhE) tissue to detect irritant chemicals extracted from polymeric materials—PVC and silicone—in medical devices. It can also identify low concentrations of strong irritants previously only detectable through in vivo or human patch testing.

One of the most interesting parts of ISO 10993-23’s history is that it almost never saw the light of day. Its unusual origin played a role in why approvals took so long.

“The current in vitro testing guidelines in ISO 10993-23 are the result of the evolution of alternative testing methods initially guided by the European Centre for the Validation of Alternative Methods (ECVAM),” says Nick Hibbard, in vitro scientific research fellow at WuXi AppTec Medical Device Testing. “The initiative outlined the need to develop alternatives to in vivo testing in areas like chemicals and cosmetics. Ultimately, skin irritation testing designed to reduce in vivo testing in the chemical and cosmetic industries found its way to being appropriately applied to the medical device industry.”  

Why is ISO 10993-23 significant?

ISO 10993-23 evolved out of ISO 10993-10—an assessment of irritation and sensitization. ISO 10993-10 still contains language around skin irritation, but it will eventually be updated to focus on sensitization. One of ISO 10993-23’s most significant advantages is its potential to reduce in vivo irritation testing. It’s a clear nod to the basic tenets of responsible scientific methodology, the three Rs—replacement, reduction and refinement.   

Another advantage of ISO 10993-23 is reliability. It is a reproducible, round-robin-validated assay that can be trusted to deliver scientifically valid results across multiple laboratory settings. Its robustness is also what makes the in vitro assay a valuable safeguard.

When combined with pyrogenicity and cytotoxicity testing, the skin irritation assay is an effective complement to biocompatibility testing manufacturers might perform in the early stages of development. The results of these assessments can help weed out potentially unsuccessful test candidates before they get too far down the manufacturing path.  

What do manufacturers need to know about ISO 10993-23?

For the time being, manufacturers should plan to prepare studies for in vitro and in vivo testing. ISO 10993-23 is still very new and it’s unclear how the standard will be interpreted by different regulatory bodies. Parts of Asia and the European Union have already determined in vitro to be the preferred method for skin irritation testing, but even that guidance is applied inconsistently throughout those regions. Other markets have yet to issue guidelines on 10993-23 at all.   

But, manufacturers who are still wondering if the in vitro method is appropriate for their device can exercise due diligence by asking themselves four questions:

  1. Do we know where in vitro methods are fully accepted? Skin irritation assessments in the U.S. and elsewhere still require in vivo assays. Regulatory agencies around the world are working to incorporate the guidance and approve it for use as they see fit. Partnering with a reputable laboratory testing partner can help clarify regulatory guidance for a particular market.
  2. Do we understand our device’s intended contact point? The approved in vitro methods listed in 10993-23 only detect dermal irritation. Contact points must be located on the skin, not on or in mucosal regions. Alternative methods for mucosal and subcutaneous testing are outlined in ISO 10993-10 under the irritation and sensitization guidance.
  3. Have we considered every component of our device? It is crucial to understand all the design and development factors present in your device. For example, do you know how the device was sterilized? Do you know details about its coating? Do you know how the device was packaged and what materials were present? Any of these factors could cause an irritant by themselves and undermine your device or, at least, cause delays.

What should manufacturers consider when selecting a testing partner?

Choosing the right laboratory testing partner comes down to a few basic questions. Of course, manufacturers should try working with a partner who understands each regulatory body. They’ll also want someone who stays on top of regulatory updates. But there are a few other factors to consider that will ensure a successful partnership. Ask yourself:  

  1. Does our partner have the proper credentials? The ISO 10993-23 guidance recommends testing under GLP conditions, so make sure your testing partner can follow that directive. ISO certification provides an additional quality standard that ensures a testing partner maintains and improves its business processes.
  2. Are we prepared to approach potential laboratory testing partners? Being prepared to enlist the help of a testing partner goes back to understanding the device. It is crucial manufacturers consider every component of their devices, especially if they are not planning to undergo a separate sterilization testing program. Unplanned irritants can cause delays and frustration.

What is the future of ISO 10993-23?

It’s unlikely in vitro testing will fully replace in vivo assessments for skin irritation. But ISO 10993-23 gets us a step closer to realizing that vision. As a screening method, however, ISO 10993-23 is a great way to identify small issues with test articles before they become big problems. At the end of the day, evaluating biocompatibility in medical devices is critical to managing risk and keeping patients safe. And ISO 10993-23 is an exciting and effective step in that direction. 

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WuXi AppTec provides a broad portfolio of R&D and manufacturing services that enable companies in the pharmaceutical, biotech and medical device industries worldwide to advance discoveries and deliver groundbreaking treatments to patients. As an innovation-driven and customer-focused company, WuXi AppTec helps our partners improve the productivity of advancing healthcare products through cost-effective and efficient, socially responsible and sustainable solutions. With industry-leading capabilities such as R&D and manufacturing for small molecule drugs, cell and gene therapies, and testing for medical devices, WuXi AppTec’s open-access platform is enabling more than 4,400 collaborators from over 30 countries to improve the health of those in need – and to realize our vision that “every drug can be made and every disease can be treated.”

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