The release of ISO 10993-1:2025 represents an important evolution in the biological evaluation of medical devices. While the structure of the standard remains familiar, the updates reinforce a clear regulatory direction. Biological evaluation must be risk-based, scientifically justified, and aligned with real-world device use.

For manufacturers, this revision is less about new testing requirements and more about strengthening the logic behind evaluation decisions.

Several terminology updates reflect a broader move toward clarity and outcome-focused thinking.

“Biological endpoints” are now referred to as “biological effects,” emphasizing observable impact rather than checklist-style categories. Similarly, “implantation effects” has been updated to “local effects after tissue contact,” broadening the framing of how tissue interactions are considered.

The standard also consistently formalizes the use of the Biological Evaluation Plan (BEP) and Biological Evaluation Report (BER). This serves to reinforce that biological evaluation is a structured, documented process rather than a series of disconnected tests.

Additional language is added on the importance of minimizing in vivo animal testing and using animals only where strictly necessary. Animal testing should be performed only if suitable data cannot be obtained in the literature or from prior clinical use, cannot be generated by chemical or physical testing, and there are no alternative in vitro or in silico methods that can produce equally (or more) relevant information.

These refinements may seem subtle, but they signal a meaningful shift: regulators expect thoughtful evaluation strategies, not automatic testing pathways. The need for animal use should be carefully considered, and minimized or avoided as much as possible without compromising data quality

One of the most significant additions in ISO 10993-1:2025 is the explicit requirement to evaluate “reasonably foreseeable misuse.”

Manufacturers must now assess not only intended use, but also foreseeable ways a device might be used outside its instructions, based on predictable human behavior, whether accidentally or intentionally. This aligns biological evaluation more closely with ISO 14971

risk management principles and strengthens the expectation that risk assessments reflect real-world conditions of device use.

In practice, this means evaluation strategies should account for how devices are handled and utilized, not just how they are described in labeling.

The updated standard simplifies body contact classifications into four streamlined categories:

· Intact skin

· Intact mucosal membranes

· Breached /compromised surfaces or internal tissues (excluding circulating blood)

· Circulating blood

This clarification reduces ambiguity and helps manufacturers more confidently determine appropriate evaluation strategies. While categorization has always been central to ISO 10993-1, the updated framework improves consistency and simplifies interpretation.

Perhaps the most important theme in ISO 10993-1:2025 is its reinforced emphasis on risk management.

The standard strengthens its linkage to ISO 14971 and continues moving away from prescriptive, automatic testing matrices. Biological testing is no longer viewed as the default response to every device scenario. Instead, manufacturers are expected to determine whether testing is scientifically necessary based on material characterization, exposure assessment, existing data, and risk evaluation.

For example, certain low-risk, limited-contact skin devices may not require biological testing if sufficient scientific justification demonstrates minimal risk.

The expectation is clear: biological evaluation must be justified — not automatic.

Material-mediated pyrogenicity has been removed from the summary tables in ISO 10993-1:2025. However, this does not eliminate the need to evaluate materials for pyrogenic risk.

Instead, it creates flexibility in how that risk is addressed. Alternative approaches — such as in vitro assays like the Monocyte Activation Test (MAT), screening materials of

construction or chemical characterization data against a list of known material pyrogens, or other scientifically justified methods — may be appropriate depending on device type and exposure.

As always, alignment with regulatory expectations remains essential, particularly while agencies finalize their interpretations of the updated standard. In particular, manufacturers intending to submit to FDA should verify that their specific reviewer is willing to accept alternative methods to rabbit pyrogen testing, if such methods are planned to address this biological effect.

At this time, the FDA is developing guidance related to ISO 10993-1:2025. Until formal guidance is published, FDA’s acceptance of certain new provisions (for example, non-animal methods to address material mediated pyrogenicity) is not yet clear.

Manufacturers considering changes to their biological evaluation strategies — especially those involving reduced testing or alternative methods — may benefit from early agency engagement. Proactive alignment can help avoid unnecessary testing, delays, or regulatory challenges.

ISO 10993-1:2025 reinforces a direction the industry has been moving toward for years: biological evaluation should be strategic, science-driven, and integrated into overall risk management, with continued emphasis on alternatives to animal testing whenever such methods can produce data of equivalent or better quality.

For manufacturers, the opportunity is to build evaluation programs that are both compliant and efficient — grounded in material science, toxicology, and documented risk assessment rather than routine testing alone.

As regulatory expectations continue to evolve, thoughtful planning and strong scientific justification will remain central to successful device development and submission.

If you’re assessing how ISO 10993-1:2025 impacts your device portfolio, a proactive, risk-based approach can help ensure both compliance and confidence.