ISO/TR 8417:2024
(Main)Risk management of particulate contamination for devices with intravascular access
Risk management of particulate contamination for devices with intravascular access
This document — provides information on the determination of particulate loads; — reports on established methods for a comprehensive risk analysis on potential particle sources and related risks in design, manufacturing, and application of devices. This document is applicable to medical devices that are used to provide intravenous access to patients to deliver liquids. NOTE For routes of administration that are not intravenous, the information in this document might be relevant to assist in the identification of sources of potential particulate contamination.
Gestion des risques de contamination particulaire pour les dispositifs d'accès intravasculaire
General Information
Standards Content (Sample)
Technical
Report
ISO/TR 8417
First edition
Risk management of particulate
2024-10
contamination for devices with
intravascular access
Gestion des risques de contamination particulaire pour les
dispositifs d'accès intravasculaire
Reference number
© ISO 2024
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ii
Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
2 References . 1
3 Terms and definitions . 1
4 Risk management on particulate contamination . 1
4.1 Application of risk management .1
4.2 Determination of particulate contamination .2
Annex A (informative) Examples for hazards and risk control options related to particulate
matter . 3
Annex B (informative) Rationales and history of the development of this document . 7
Bibliography . 9
iii
Foreword
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This document was prepared by Technical Committee ISO/TC 76, Transfusion, infusion and injection, and
blood processing equipment for medical and pharmaceutical use.
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.
iv
Introduction
Medical devices, that are part of the fluid path for delivery directly into circulating blood or are connected
to those devices (such as administration or extension sets), include a risk of delivering particulate matter to
the patient’s body.
These particulates can be created or transferred to the devices during the production or application of those
devices and can cause a variety of severe and fatal harms to patients (such as phlebitis, pulmonary emboli,
pulmonary granulomas, immune system dysfunction, pulmonary dysfunction, infarction and death).
All parenteral products contain such particulate matter, as it is technically impossible to produce and use
these devices without creating or transferring these particles to the devices. This is considered in technical
standards and international pharmacopoeias that identify limits of particulate contamination, but these
limits can only be considered as a definition of the maximum particle load that is based on current technical
state of the art for various particle size ranges.
Several studies and publications imply, that no rationale for any tolerable number for the particulate
contamination exists. The occurrence rates of related severe and fatal complications in patients that receive
parenteral infusions is closely related to factors such as:
— route of administration;
— particle size and shape;
— number of particles injected;
— particle composition;
— patient population;
— exposure by multiple devices.
Additionally, the current specifications in standards and international pharmacopoeias are omitting the fact,
that medical devices and drug containers are typically used in combinations with each other (e.g. container,
infusion set, IV-catheter) and/or in parallel (e.g. several infusions running in parallel or in sequence) and/
or repeatedly (e.g. several containers/infusion sets being used consecutively). With any of these, the total
particulate load that patients receive is an addition of all those sources.
As the complexity of the number of influencing factors and their interrelations do not allow the derivation
of any safe level of particulate contamination, the current specifications in standards and pharmacopeia
can lead to an inappropriate assumption of safety by manufacturers, regulators, authorities, and clinical
practitioners when these levels are met.
This document is intended to provide alternative perspectives on how to control risks related to particulate
contaminations and to guide manufacturers, regulators, and authorities into a more comprehensive
assessment of the measures related to reducing particulate contaminations.
The leading concept behind this alternative perspective is to apply the general methodology of risk
management to identify, assess and control the risks that are related to particulate matter rather than
defining an unsubstantiated level of assumed safety.
v
Technical Report ISO/TR 8417:2024(en)
Risk management of particulate contamination for devices
with intravascular access
1 Scope
This document
— provides information on the determination of particulate loads;
— reports on established methods for a comprehensive risk analysis on potential particle sources and
related risks in design, manufacturing, and application of devices.
This document is applicable to medical devices that are used to provide intravenous access to patients to
deliver liquids.
NOTE For routes of administration that are not intravenous, the information in this document might be relevant
to assist in the identification of sources of potential particulate contamination.
2 References
The following documents are referred to in the text in such a way that some or all of their content constitutes
requirements of this document. For dated references, only the edition cited applies. For undated references,
the latest edition of the referenced document (including any amendments) applies.
ISO 14971, Medical devices — Application of risk management to medical devices
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 14971 and the following apply.
ISO and IEC maintain terminology databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at https:// www. iso. org/o bp
— IEC Electropedia: available at https:// www.e lectropedia. org/
3.1
particle
minute piece of matter with defined physical boundaries
[SOURCE: ISO 14644-1:2015, 3.2.1]
4 Risk management on particulate contamination
4.1 Application of risk management
Medical devices are designed and manufactured in such a way to eliminate or reduce the probability of
particulate contamination of the fluid path of the devices and other surfaces which are relevant for the
application of the devices.
To identify, assess and control the related risks, the general methodology of ISO 14971 is applied. Annex A
lists known sources of particulate contamination of medical devices.
It is expected that medical device manufacturers create or update risk management files to include all
relevant and applicable risks from Annex A and implement feasible control measures.
4.2 Determination of particulate contamination
The particulate contamination of infusion sets, and their components and accessories are determined by
quantitative testing to assess initial particle loads.
To be able to verify the effectiveness of risk control methods, before or after potential changes, quantitative
or qualitative methods are commonly used.
Some of the applicable related methods are described in:
— ISO 8536-4:2019, A.2;
— European Pharmacopoeia 2.9.19, 2.9.20;
— US Pharmacopoeia 787, 788, 790, 1790;
— Japanese Pharmacopoeia 6.07, 6.06;
— ISO/TR 19727.
Annex A
(informative)
Examples for hazards and risk control options related to
particulate matter
Table A.1 shows example for hazards and risk control options related to particle matter.
Table A.1 — Example for hazards and risk control options related to particle matter
Protective measures in the Protective measures
Source or nature of contam- Approaches for safe device Approaches for safe manu- Information for
Risk source group medical device itself or in in the manufacturing
ination design facture safety
the manufacturing process process
Moulding Metal parts from tools Design of moving parts, split Controlled environment Properly specified require- Mould preventative mainte- Cleaning instructions
line and gates (Clean room etc.) ments/limits for geometrical nance for equipment
Mould release agents
defects (flash, etc.)
Selection of materials and Unidirectional air flow over Tool design (i.e. sprue less
Flash
additives moving parts of mould or runner less designs/hot
sprues/gates
runners)
Parts demoulding (avoid Peripheral material supply
falling parts
drop parts) “Cleaning”, shaking, blow-
Validated moulding processes
Damaged parts (e.g. not fully
ing, vacuum, managing
Maintenance and cleaning of
ejected parts)
electro-static charge
moulding press/ machines
Visual checks/camera
Conveyer systems
control for ejection
Extrusion Water bath particulates Filtration system for the Cleaning and maintenance of Cleaning instructions
cooling water equipment, tools, extrusion for equipment
Chill roll for film extrusion
head
Material selection
Cutting of tube segments
Sharp, regularly maintained
Extrusion head
blades for cutting
Controlled environment (clean
room etc.) – separate areas
for the extrusion machine and
the post-extrusion processing
(cooling, coiling)
See applicable elements from
“moulding”
Purchasing/ in- Insufficient control over sup- Double bagging of compo- Incoming inspection on
coming goods pliers and goods nents particulate contamination (for
monitoring and comparison
“Contaminated” raw materials
between parts and suppliers)
Sampling (opening/ closing
Supplier audits
bags)
Quality agreements
Shipping/transportation from
vendor to manufacturer Technical specifications for
storage condition
Properly specified require-
ments/limits
Procedures for material
handling (where, by whom,
opening/ closing of bags, in
which state is material trans-
ported after incoming goods
inspection
...
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