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Short answer
ISO 10993-4 is the part of the ISO 10993 series that guides how to select tests for a medical device’s interactions with blood (hemocompatibility). The test families depend on how the device touches blood: direct contact with circulating blood calls for consideration of hemolysis, complement activation and thrombogenicity, while indirect contact generally calls for hemolysis alone. This page is general information, not medical advice.
What ISO 10993-4 covers
ISO 10993-4, “Biological evaluation of medical devices – Part 4: Selection of tests for interactions with blood,” is prepared by ISO/TC 194 with CEN/TC 206. The current third edition dates from April 2017 and was amended by Amendment 1 (Amendment 1 text carries a 2024 date). It is one part of the wider biocompatibility series, which the FDA biocompatibility guidance explainer covers as a whole. Searches for “iso 10993 4” and “iso 10993 hemocompatibility” refer to this part. The standard itself is sold by ISO and national bodies; this page summarizes the amendment text and FDA’s published guidance.
A device is a “medical device” in the regulatory sense before any of this applies; see what is a medical device for that definition.
Direct vs indirect blood contact and Amendment 1
The standard sorts blood-contacting devices into categories, and the category drives test selection. Amendment 1 moved several device types between the indirect and direct lists.
What changed in Amendment 1
| Device type | Before Amendment 1 | After Amendment 1 |
|---|---|---|
| Blood collection devices | Listed under external communicating devices, indirect blood contact (5.2.2) | Listed under direct blood contact (5.2.3) |
| Cannulae | Listed under indirect (5.2.2) | Listed under direct (5.2.3) |
| Cell savers | Listed under indirect (5.2.2) | Listed under direct (5.2.3) |
| Devices for storage and administration of blood and blood products (for example tubing and bags) | Storage and administration bullet referred to “blood and blood product” under indirect (5.2.2) | Listed under direct (5.2.3); the indirect bullet now reads “saline and/or therapeutics” |
| Intravascular catheters | Listed under indirect (5.2.2) | Bullet deleted from 5.2.2 |
| Blood monitors | Direct-contact entry for blood monitoring devices also read “or indirect” | “Or indirect” removed from the direct entry; “blood monitors with indirect blood contact” added to 5.2.2 |
Source: ISO 10993-4:2017/Amd.1:2024 (proof text), https://standards.iteh.ai/catalog/standards/iso/4e679ad5-1bc3-44dc-b553-cbee179a50c9/iso-10993-4-2017-amd-1, checked 2026-11-01. Related supplies are covered in what is blood tubing.
The test-article rule
Under clause 6.1.2 as amended, direct-contact tests (direct hemolysis, complement activation, coagulation, platelet activation, hematology, in vitro or ex vivo thrombosis) “should be conducted using only the direct blood contacting components.” Extract-based testing, such as indirect hemolysis, uses both direct and indirect blood-contacting components. If the test article includes components with different tissue contact, the amendment says a justification shall be provided. For externally communicating devices or components with indirect blood contact, “only an indirect contact haemolysis test is generally recommended.”
Hemolysis, complement and thrombosis: what each test asks
Hemolysis (iso 10993-4 hemolysis)
Hemolysis testing asks whether a device or its extract damages red blood cells. FDA’s guidance points to ASTM F756 or an equivalent method. For direct-contact devices FDA recommends both direct and indirect (extract) methods; for indirect-contact devices, the extract method only.
Complement activation
For direct-contact devices FDA recommends testing the device itself rather than an extract, using an established ELISA for the SC5b-9 fragment. FDA states that there are no established pass/fail criteria for a clinically acceptable level of complement activation, so a legally marketed comparator may help interpretation. Results are generally satisfactory if there is no statistically significant difference from the negative control. ASTM F1984 is named as an equivalent static method.
Thrombogenicity
FDA recommends assessing thrombogenicity within a relevant animal safety or functional study where one is generally conducted (for example, stents). For devices such as oxygenators, an in vitro or ex vivo battery (platelets, TAT, PTT) may substitute. FDA quotes ISO 10993-4:2017 on the activated PTT test: it “is rarely useful in the in vitro evaluation of the thrombogenic properties of blood-contacting devices/materials because the activating substances mask any activation caused by the device or its component materials.”
What FDA says about blood-contact testing
In its guidance “Use of International Standard ISO 10993-1” (issued 8 September 2023, nonbinding), FDA recommends that for devices with direct contact with circulating blood, regardless of contact duration, you consider hemolysis, complement activation and thrombogenicity testing, if not otherwise addressed in the risk assessment. For indirect contact, FDA recommends considering only hemolysis, since complement activation and in vivo thrombogenicity testing are generally not needed. Exceptions: novel materials not previously used in legally marketed cardiac or vascular devices, and devices intended to release a chemical into circulating blood, may need some in vitro thrombogenicity assessment.
Where the risk assessment concludes hemocompatibility testing is unnecessary, FDA asks for a summary of that assessment, which may compare materials and geometry to a legally marketed device with similar blood-contact duration and an acceptable history of use. Devices with no direct or indirect circulating-blood contact generally do not need hemolysis testing, unless components could reach blood (a sealant is the example given).
Questions to ask about a hemocompatibility report
This checklist turns the sources above into questions a lab, clinic or supply team can raise when reading a manufacturer’s test summary. It is a reading aid, not a pass/fail rule.
| Question | Why it is asked | Source |
|---|---|---|
| Is the device classed as direct or indirect blood contact, and does that match its listed category? | Category determines which tests are considered; Amendment 1 moved several device types to direct. | ISO 10993-4 Amd.1:2024 (proof); FDA 2023 |
| Which components were in the test article? | Direct tests use only direct blood-contacting components; extract tests use direct and indirect components; differing tissue contact needs a justification. | ISO 10993-4 Amd.1:2024 (proof), 6.1.2 |
| Was hemolysis tested by direct and extract methods (direct contact) or extract only (indirect)? | FDA recommends these method sets by contact type. | FDA 2023 |
| Does the report show blank, positive and negative controls, absorbance and percent hemolysis? | FDA lists these as items a hemolysis report should describe (ASTM F756). | FDA 2023 |
| Was complement tested on the device itself, and compared with a negative control or comparator? | No pass/fail criterion exists, so interpretation relies on controls or a legally marketed comparator. | FDA 2023 |
| If a test was waived, is there a risk-assessment summary? | FDA asks for a summary and comparison to a legally marketed device. | FDA 2023 |
| Has the manufacturing process or manufacturer changed since testing? | Changes affecting surface properties or chemistry of the finished sterilized device “can also impact haemocompatibility.” | ISO 10993-4 Amd.1:2024 (proof), 6.1.4 Note 1 |
Common misunderstandings
- “ISO 10993-4 is a pass/fail checklist.” It guides test selection; FDA itself says there is no established pass/fail criterion for complement activation.
- “Every blood-contact device needs every test.” FDA recommends considering tests by contact type and allows a documented risk-based rationale.
- “aPTT is a standard thrombogenicity test.” The standard, as quoted by FDA, calls it rarely useful for in vitro evaluation of device thrombogenicity.
- “Hemolysis on agar plates is the same thing.” Culture-plate hemolysis, such as alpha hemolysis on a blood agar plate, is a microbiology observation and unrelated to device blood-compatibility testing.
FAQ
What is ISO 10993-4?
It is Part 4 of the ISO 10993 series, covering the selection of tests for interactions of medical devices with blood. The third edition is from 2017, with Amendment 1 dated 2024.
What does ISO 10993 hemocompatibility testing include?
Test families named in the sources are hemolysis, complement activation, coagulation, platelet activation, hematology and thrombosis. Which apply depends on contact type and the risk assessment.
What is ISO 10993-4 hemolysis testing?
It examines whether a material or its extract damages red blood cells. FDA points to ASTM F756 or an equivalent method, and recommends extract testing for indirect-contact devices.
Does an indirect-contact device need thrombogenicity testing?
FDA says complement activation and in vivo thrombogenicity testing are generally not needed for indirect blood-contacting devices, with exceptions for novel materials and devices releasing a chemical into circulating blood.
Sources
- FDA, “Use of International Standard ISO 10993-1, Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process,” issued 8 September 2023: https://www.fda.gov/media/142959/download (checked 2026-11-01).
- ISO 10993-4:2017/Amd.1:2024 (proof), Biological evaluation of medical devices – Part 4: Selection of tests for interactions with blood, Amendment 1 (proof preview): https://standards.iteh.ai/catalog/standards/iso/4e679ad5-1bc3-44dc-b553-cbee179a50c9/iso-10993-4-2017-amd-1 (checked 2026-11-01).
- Related CASRAI guides: FDA guidance on biocompatibility, blood bank supply checklist, sterility assurance level.
