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ISO / ISO 10993-4:2017/Amd 1:2025 Biological evaluation of medical devices — Part 4: Selection of tests for interactions with blood — AMENDMENT 1

ISO 10993-4:2017/Amd 1:2025 Biological evaluation of medical devices — Part 4: Selection of tests for interactions with blood — AMENDMENT 1

Foreword

ISO (the International Organization for Standardization) is a worldwide federation of national standards bodies (ISO member bodies). The work of preparing International Standards is normally carried out through ISO technical committees. Each member body interested in a subject for which a technical committee has been established has the right to be represented on that committee. International organizations, governmental and non-governmental, in liaison with ISO, also take part in the work. ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of electrotechnical standardization.

The procedures used to develop this document and those intended for its further maintenance are described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the different types of ISO documents should be noted. This document was drafted in accordance with the editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives).

ISO draws attention to the possibility that the implementation of this document may involve the use of (a) patent(s). ISO takes no position concerning the evidence, validity or applicability of any claimed patent rights in respect thereof. As of the date of publication of this document, ISO had not received notice of (a) patent(s) which may be required to implement this document. However, implementers are cautioned that this may not represent the latest information, which may be obtained from the patent database available at www.iso.org/patents. ISO shall not be held responsible for identifying any or all such patent rights.

Any trade name used in this document is information given for the convenience of users and does not constitute an endorsement.

For an explanation of the voluntary nature of standards, the meaning of ISO specific terms and expressions related to conformity assessment, as well as information about ISO's adherence to the World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT), see www.iso.org/iso/foreword.html.

This document was prepared by Technical Committee ISO/TC 194, Biological and clinical evaluation of medical devices, in collaboration with the European Committee for Standardization (CEN) Technical Committee CEN/TC 206, Biological and clinical evaluation of medical devices, in accordance with the Agreement on technical cooperation between ISO and CEN (Vienna Agreement).

A list of all parts in the ISO 10993 series can be found on the ISO website.

Any feedback or questions on this document should be directed to the user’s national standards body. A complete listing of these bodies can be found at www.iso.org/members.html.

 

3.4

Replace “ISO/TR 10993-20” with “ISO/TS 10993-20” in Note 1 to entry.

 

5.2.2

Replace the subclause heading with:

Biological evaluation of medical devices — Part 4: Selection of tests for interactions with blood — AMENDMENT 1

5.2.2   External communicating devices indirectly contacting blood

 

Delete the bullet points “cannulae”, “cell savers”, “intravascular catheters” and “blood collection devices”.

 

Replace “blood and blood product” with “saline and/or therapeutics” as follows:

  — devices for the storage and administration of either saline or therapeutics, or both (e.g. tubing and bags);

 

Add the bullet point “blood monitors with indirect blood contact” as the second bullet point.

 

5.2.3

Add “blood collection devices” as a second bullet point, “cannulae” as a fourth bullet point, “cell savers” as a sixth bullet point and “devices for the storage and administration of blood and blood products (e.g. tubing and bags)” as an eighth bullet point.

 

Delete “or indirect” in the third bullet point as follows:

  — blood monitoring devices with direct blood contact;

 

6.1.2

Add the following text to the second paragraph after the sentence “Only direct or indirect blood-contacting parts should be tested.”:

For direct contact haemocompatibility testing (e.g. direct haemolysis, complement activation, coagulation, platelet activation, haematology, in vitro or ex vivo thrombosis), testing should be conducted using only the direct blood contacting components of the device to minimize interference of non-direct blood contacting components on the results. For extract-based haemocompatibility testing (e.g. indirect haemolysis), testing should be conducted using only the direct and indirect blood-contacting components of the device. The test article shall be described and a justification shall be provided if the test article includes device components that include different tissue contact than described above.

 

Replace the fourth paragraph with:

As many tests for haemocompatibility are recognized to be generally surface-contact dependent (e.g. direct contact haemolysis, complement activation, coagulation, platelet activation, haematology, and in vitro or ex vivo thrombosis), such tests do not apply to indirect contact applications. For externally communicating medical devices or components that have indirect blood contact, only an indirect contact haemolysis test is generally recommended.

 

6.1.4

Replace NOTE 1 with:

 

NOTE 1

Changes in the manufacturing process (e.g. change in manufacturer), the use of different manufacturing aids that can affect the surface properties or the chemistry of the complete sterilized device can also impact haemocompatibility.

 

6.1.6

Replace Table 1 with:

Table 1
Devices or device components and categories of appropriate testing for consideration
Device examples Test category
Haemolysis Thrombosisc
In vitro In vivo or
ex vivoa
Material-induced Mechanically-induced Coagulation Platelet activation Complementd Haematology
External communicating devices indirectly contacting bloode
Blood monitors with indirect blood contact X            
Devices for storage and administration of saline and/or therapeutics (e.g. tubing and bags), extension sets X            
External communicating devices directly contacting circulating bloodb
Blood collection devices X   X X   X  
Blood administration sets and extension sets X Xf X X   X  
Catheters in place for less than 24 h (e.g. atherectomy devices,
intravascular ultrasound catheters, antegrade or retrograde coronary perfusion catheters, guide wires); cannulae		 X   X X   X X
Catheters in place for more than 24 h (e.g. parenteral nutrition
catheters, central venous catheters); cannulae		 X   X X   X X
Cell savers X X X X      
Devices for adsorption of specific substances from blood X X X X X    
Donor and therapeutic aphaeresis equipment and cell separation systems X X X X X    
Cardiopulmonary bypass system and components X X X X X X X
Haemodialysis or haemofiltration equipment X X X X X X X
Leukocyte removal filter X   X X X X X
Percutaneous circulatory support devices X X X X X X X
Implant devices
Annuloplasty rings, mechanical heart valves X X         X
Embolization devices X           X
Endovascular grafts X           X
Implantable defibrillator and cardioverter leads X           X
Intra-aortic balloon pumps X X         X
Pacemaker leads X           X
Prosthetic (synthetic) vascular grafts and patches, including
arteriovenous shunts		 X           X
Stents (vascular) X           X
Tissue heart valves, vascular grafts and patches and AV shunts X           X
Total artificial hearts X X         X
Vena cava filters X           X
Ventricular-assist devices X X         X

a Thrombosis is an in vivo or ex vivo phenomenon but can be simulated with in vitro conditions. In vivo or ex vivo testing is not always unnecessary if clinically relevant in vitro thrombosis testing is performed.

b Some examples can contain other components with indirect blood contact. For device components that only have indirect blood contact, direct contact material-induced haemolysis, mechanical haemolysis, thrombosis and complement activation are not always necessary. For components with indirect blood contact, generally only an indirect contact haemolysis test is recommended.

c It is recognized that coagulation, platelet and leucocyte responses are primarily involved in the process of thrombosis. Therefore, in vitro thrombogenicity methods can be acceptable in place of in vivo testing if scientifically justified. The manufacturer should justify which specific testing in the coagulation, platelet and haematology test categories is appropriate for their devices.

d Complement activation testing is also requested by certain regulatory authorities to address other end points such as anaphylaxis for all devices with direct blood contact.

e Except for devices composed of novel materials, each test in the category of thrombosis is generally not necessary for indirect blood contact devices.

f For blood administration sets without using mechanical pumps, mechanically induced haemolysis testing is generally not necessary.

 

6.1.11

Delete “(see also ISO 10993-2)” at the end of the second paragraph.

 

6.1.12

Replace the paragraph with:

The use of antithrombotics in in vivo and ex vivo tests should be avoided unless the device is designed to perform in their presence. Even if the device is designed to perform in their presence, the completion of studies without antithrombotics can also be required in order to properly assess the thrombosis risk to patients that cannot receive antithrombotics. The type and concentration of antithrombotic(s) used influence(s) blood/device interactions and their selection shall be justified. Devices that are used with antithrombotics should be assessed using them in the range of concentrations specified clinically and/or described in the product IFU or other appropriate literature. Species differences should also be considered when determining the appropriate level of antithrombotic(s).

 

Add the following NOTE at the end of this paragraph:

 

NOTE

Antithrombotics can consist of any combination of either antiplatelet drugs (e.g. acetylsalicylic acid, clopidogrel and glycoprotein IIb/IIIa receptor antagonists) or anticoagulants (e.g. unfractionated or low molecular weight heparin, warfarin and direct thrombin inhibitors), or both.

 

6.1.14

Delete "see ISO 10993-2" and add the following NOTE after the paragraph:

 

NOTE

For more information on animal welfare, see ISO 10993-2.

 

6.3.1

Replace “Alternatives to the latter may be feasible if validated.” with:

The use of blood older than 4 h may be feasible for certain tests, if validated alongside freshly obtained blood or by other scientifically sound methods.

 

A.1.1

Delete “of non-contact-, externally communicating and implant devices” from the sentence as follows: “and a list of tests for evaluating blood/device interactions.”

 

A.1.4

Replace the first sentence of the third paragraph with:

The classical Chandler loop in vitro test model[43] or modifications thereof[193][194][195][199][200][203] are examples of models used to test for general material or device haemocompatibility under physiological and/or quasi-physiological flow conditions.

 

Add the following sentence at the end of the third paragraph:

Recent publications that describe and apply alternative in vitro methods are References [243] to [249].

 

Clause A.3

Add “(or an alternative surface treatment intended to have anti-thrombotic properties)” in the second sentence of the second paragraph as follows:

For example, following simple dose-response kinetics, the thromboresistance of a medical device heparin coating (or an alternative surface treatment intended to have anti-thrombotic properties) can be completely masked by normal (clinical) levels of solution heparin anticoagulant.

 

Replace the third sentence with:

However, under a reduced/challenging level of solution heparin or in a non-anticoagulated model, the effectiveness of the heparin coating (or alternative anti-thrombotic surface treatment) to reduce thrombus formation becomes more apparent.

 

Bibliography

Add the following references:

[238]   ISO 10993-2, Biological evaluation of medical devices — Part 2: Animal welfare requirements1

1 This reference will be added to the Bibliography under the heading “International Standards” in the next revision.

[239]   ISO 10993-6, Biological evaluation of medical devices — Part 6: Tests for local effects after implantation1)

[240]   ISO/TS 10993-20, Biological evaluation of medical devices — Part 20: Principles and methods for immunotoxicology testing of medical devices1)

[241]   ISO 18242, Cardiovascular implants and extracorporeal systems — Centrifugal blood pumps1)

[242]   ISO 18193, Cardiovascular implants and artificial organs — Cannulae for extracorporeal circulation1)

[243]   Grove K et al. Thrombogenicity Testing of Medical Devices in a Minimally Heparinized Ovine Blood Loop. Journal of Medical Devices 2017, 11 (2).2

2 This reference will be added to the Bibliography under the heading “in vitro models” in the next revision.

[244]   Jamiolkowski MA et al. An In Vitro Blood Flow Loop System for Evaluating the Thrombogenicity of Medical Devices and Biomaterials. ASAIO J 2020, 66 (2), 183-189.2)

[245]   Jamiolkowski MA et al. Preclinical Device Thrombogenicity Assessments: Key Messages From the 2018 FDA, Industry, and Academia Forum. ASAIO J. 2021;67(2):214-219. doi: 10.1097/MAT.0000000000001226.2)

[246]   Wolf MF et. al. In vitro methodology for medical device material thrombogenicity assessments: A use condition and bioanalytical proof-of concept approach. J Biomed Mater Res B Appl Biomater. 2021 Mar;109(3):358- 376. doi: 10.1002/jbm.b.34705.2)

[247]   Lu Q et al. Platelet and leukocyte count assay for thrombogenicity screening of biomaterials and medical devices: Evaluation and improvement of ASTM F2888 test standard. J Biomed Mater Res B Appl Biomater. 2021 Dec;109(12):2259-2267. doi: 10.1002/jbm.b.34887.2)

[248]   Jamiolkowski MA et al, Comparison of animal and human blood for in vitro dynamic thrombogenicity testing of biomaterials. Artif Organs. 2022 Jul 22. doi: 10.1111/aor.14366.2)

[249]   Tim Schatz et al. Improved Method for the ASTM Platelet and Leukocyte Assay: Use of Minimal Heparinization in a Screening Test for Hemocompatibility of Blood-Contacting Medical Devices J. Med. Devices. Mar 2019, 13(1): 011004.2)