Interpreting ISO Standards to streamline testing and submissions

Kimberly Ehman, from WuXi AppTec & Bob Przygoda, from Adventure Biocompatibility Consulting, explain how ISO 10993 Standards impact on biocompatibility evaluations for global submissions.

ISO 10993 standards provide guidance and requirements for the biological evaluation of medical devices, but their application and interpretation can vary between regulatory bodies and reviewers. 

Currently, regulatory agencies within the European Union accept ISO standards without exception. Notified Bodies (NBs) review submissions for CE mark for regulatory agencies. However, the specifics of each NB’s submission requirements differ slightly. 

The EU Medical Device Regulation (MDR) has an arguably more complex interpretation of ISO 10993. Substances that are carcinogenic, mutagenic or toxic to reproduction, or have endocrine-disrupting properties at a concentration above 0.1% by weight, a justification for the continued use of the material and assessment of the potential risk is required. This applies to any invasive device, even if exposure is for less than 24 hours.  

MDR requires that any device sold in the EU shall meet current standards. Any evaluations following older ISO standards require a gap analysis and, if needed, supporting justifications. While performing new testing procedures is not technically required to satisfy the requirements of all new standards, complying to EU MDR may prompt additional evaluations to fill gaps in data or meet testing parameters. 

While NBs have broad acceptance of the ISO 10993 standards, the intricacies of their acceptance still require attention to small variances. These NBs use ISO 10993 as a baseline, where others have a more selective means of acceptance.

As of February 2020, the Japanese MHLW wholly recommends using ISO 10993 standards and further expands upon them – holding biocompatibility tests to a high standard. Officials require separate extraction strategies for sensitisation and genetic toxicity testing; an attempt to deliver sufficient extractable chemicals to represent the whole device or to deliver more extractable chemicals that could be administered by standard extraction procedures. 

The U.S. Food and Drug Administration (FDA) and China’s National Medical Products Administration (NMPA) do not recognise all current ISO 10993 standards. When submitting under either jurisdiction, manufacturers should dedicate time to understanding the acceptance criteria of each part to the standard.

With submissions in the U.S., many parts of ISO 10993 are only partially accepted, meaning manufacturers should review the agency’s latest guidance documents and database of recognised consensus standards. Devices containing novel materials will likely be subjected to greater scrutiny than those containing well-established materials, and additional testing may be necessary.

The NMPA does not universally accept current versions of ISO standards and may prefer conformance to previous versions. It is essential to reference the Chinese standards and the equivalent versions of the ISO standards with every submission. Still, subject to an individual reviewer’s discretion, risk-based evaluations are accepted based on the reviewer’s perspective. Additionally, the regulatory body evaluates medical devices with CE mark or 510(k) clearance using alternative procedures. Thus, device submissions already holding EU and U.S. clearance can streamline the review process by taking alternative regulatory pathways when submitting a device to the NMPA.

Whichever governing body a manufacturer plans to submit to, they should review their submissions closely. The acceptance of 10993 varies from regulator to regulator and standards continue to evolve. 

With each new version of the ISO 10993 series of standards, manufacturers can begin to see where regulators hope to push biological evaluations in the future. Short-term perspectives might focus on the additional test methods and evaluation procedures, but in the long-term, experts are aiming to gain a better understanding of each specific device and tailor evaluations accordingly. 

Guidance outlined in ISO 10993-1 and EU MDR increased the importance of materials characterisation, physical and/or chemical information, and risk assessments. Regulators expect detailed chemical information supporting biocompatibility test plans and additional testing like extractables and leachables (E/L) studies to identify all chemicals of potential toxicologic concern. 

Recent updates to ISO 10993-18 include advanced chemical characterisation requirements and the exposure dose estimation. First, manufacturers must submit multiple replicates during chemical characterisation testing. Then during study development, toxicological data and exposure assumptions must inform chemistry study design and execution. The extraction protocol is defined by the duration and type of contact, with prolonged and long-term contact being subject to the most rigorous extraction procedures. Part 18 has revamped how manufacturers understand their device’s chemical constituents, setting a baseline for other sections of ISO 10993.

With regulatory expectations for increasingly complex chemical characterisation study designs, the toxicological risk assessments (TRAs) based on these data follow suit. Experts are required to navigate the large datasets and prepare for the changes coming in the new version of ISO 10993-17.