---
title: "Where Biological Evaluations Fall Short, and How to Close the Gaps"
description: "Five common gaps in medical device biological evaluations, from unjustified endpoints to weak chemical characterization, and how to close each one."
url: https://qbdgroup.com/en/blog/biological-evaluation-gaps-how-to-close
type: "Blog post"
language: en
published: 2026-11-13
author: "Paola Vitellio & Mae Ann Belandres"
category: "Toxicology"
publisher: "QbD Group"
citation: "QbD Group, \"Where Biological Evaluations Fall Short, and How to Close the Gaps\", https://qbdgroup.com/en/blog/biological-evaluation-gaps-how-to-close"
---
# Where Biological Evaluations Fall Short, and How to Close the Gaps
> Five common gaps in medical device biological evaluations, from unjustified endpoints to weak chemical characterization, and how to close each one.

A biological evaluation can contain every report a reviewer might ask for and still fail to convince. The problem is rarely a missing test; more often, it is a missing link between the data and the conclusion. Reviewers want to understand why each biological risk is acceptable, and a stack of laboratory reports does not answer that question on its own.

**In This Blog Post**

- Why a complete set of test reports can still fail to convince reviewers
- How ISO 10993-1:2025 and ISO 10993-3:2026 shift the focus from testing to evaluation
- Five common gaps, from unjustified endpoints to unsupported equivalence claims
- How chemical characterization (ISO 10993-18) and toxicological risk assessment (ISO 10993-17) work together
- Why better reasoning often matters more than new studies

## The Standards Point in the Same Direction

The standards point in the same direction. ISO 10993-1:2025 frames biological evaluation as part of the ISO 14971 risk management process, and the revised ISO 10993-3:2026 places more emphasis on evaluation than on testing alone, which ISO describes as helping organizations avoid unnecessary testing. In practice, this shifts the weight of the file toward chemistry, toxicology and clear reasoning. These are the gaps we see most often, and how each one can be closed.

## Five Common Gaps and How to Close Them

### Gap 1: Endpoints Listed, but Not Justified

Many evaluations reproduce the endpoint table for the device category and attach a test report, or a short waiver, for each line. What is missing is the rationale: why an endpoint is relevant for this device, given its materials, contact type and duration, and why the chosen approach is sufficient.

**How to close it:** build the evaluation from the risk analysis outward. For each endpoint, state the hazard being considered, the evidence used and the reasoning that connects them; where an endpoint is addressed without testing, explain why the available information is enough.

### Gap 2: Chemical Characterization That Does Not Fit Its Purpose

Extractables studies are sometimes run with generic conditions and a fixed reporting limit, without checking whether that limit is low enough for the patient exposure in question. Unidentified peaks are reported and left there.

**How to close it:** design the study around ISO 10993-18, setting extraction conditions that reflect the device and its clinical use, and deriving the analytical evaluation threshold from a toxicological threshold and the expected exposure. The 2022 amendment to ISO 10993-18 adds guidance on the uncertainty factor applied in that calculation. The resulting chemical characterization should be sufficient to support the toxicological risk assessment of identified constituents according to ISO 10993-17. In the US, FDA guidance on chemical analysis for biocompatibility gives detailed recommendations on extraction, analysis and reporting.

### Gap 3: Chemical Data Without a Toxicological Assessment

A complete extractables report is not, by itself, a safety conclusion. When detected substances are listed without being assessed, the file shows what is in the device but not whether it matters.

**How to close it:** carry out a toxicological risk assessment according to ISO 10993-17:2023. That means establishing a tolerable intake or tolerable contact level for each relevant constituent, comparing it with the estimated exposure and documenting the margin of safety. The standard is designed to work with chemical characterization data obtained in line with ISO 10993-18, so the two activities should be planned together rather than in sequence.

### Gap 4: Tests Added Without a Defined Question

When a standard is revised, adding tests can look like the prudent choice. Without a clear question behind each one, though, extra results can raise new issues instead of settling existing ones, and they add cost, time and animal use.

**How to close it:** before commissioning any study, write down what it is meant to show and whether existing data, chemical characterization or a toxicological assessment could answer the same question. If testing is still needed, the protocol can then be designed around that specific purpose.

### Gap 5: Equivalence Claimed, but Not Demonstrated

Statements such as "same materials as the previous version" or "equivalent to a marketed device" appear often, and are supported less often. Small differences in formulation, processing or sterilization can change what leaves the device.

**How to close it:** document the comparison explicitly. ISO 10993-18 describes how chemical equivalence can be established with a device that is already shown to be biocompatible or clinically established; when that case can be made, it can remove the need for further testing.

## What These Gaps Have in Common

None of them is solved by generating more data. Each one is closed by interpretation: choosing the right evidence, assessing it with toxicological methods and explaining the conclusion in a way a reviewer can follow. A focused gap analysis, done endpoint by endpoint, usually shows that the file needs better reasoning far more than it needs new studies. Getting that reasoning right is what turns a biological evaluation from a compliance document into a defensible one.

## Close the Gaps in Your Biological Evaluation

QbD Group's regulatory toxicology experts help medical device manufacturers run endpoint-by-endpoint gap analyses, design fit-for-purpose chemical characterization studies and carry out toxicological risk assessments according to ISO 10993-17, so your file rests on clear reasoning rather than extra testing.

Not sure where your evaluation stands? Start with [the questions every manufacturer should ask](/en/blog/biological-evaluation-iso-10993-1-questions), or [get in touch with our experts](https://qbdgroup.com/en/services/regulatory-toxicology) to discuss a gap analysis.

## Main Sources

- [ISO 10993-1:2025, Biological evaluation of medical devices, Part 1](https://www.iso.org/standard/10993-1)
- [ISO 10993-3:2026, Evaluation of genotoxicity, carcinogenicity, reproductive toxicity and developmental toxicity](https://www.iso.org/standard/10993-3)
- [ISO 10993-17:2023, Toxicological risk assessment of medical device constituents](https://www.iso.org/standard/75323.html)
- [ISO 10993-18:2020, Chemical characterization of medical device materials](https://www.iso.org/standard/64750.html)
- [FDA guidance: Chemical Analysis for Biocompatibility Assessment of Medical Devices](https://www.fda.gov/regulatory-information/search-fda-guidance-documents/chemical-analysis-biocompatibility-assessment-medical-devices)
- [FDA guidance: Use of International Standard ISO 10993-1](https://www.fda.gov/regulatory-information/search-fda-guidance-documents/use-international-standard-iso-10993-1-biological-evaluation-medical-devices-part-1-evaluation-and)
---
Source: https://qbdgroup.com/en/blog/biological-evaluation-gaps-how-to-close — © QbD Group. Quote freely with attribution and a link back.