1、BS ISO 18562-4:2017Biocompatibility evaluation of breathing gas pathways in healthcare applicationsPart 4: Tests for leachables in condensateBSI Standards PublicationWB11885_BSI_StandardCovs_2013_AW.indd 1 15/05/2013 15:06BS ISO 18562-4:2017 BRITISH STANDARDNational forewordThis British Standard is
2、the UK implementation of ISO 18562-4:2017. The UK participation in its preparation was entrusted to TechnicalCommittee CH/121/9, Lung Ventilators informative material appearing outside of tables, such as notes, examples and references: in smaller type. Normative text of tables is also in a smaller t
3、ype; test specifications: italic type; terms defined in Clause 3 of this document or as noted: small capitals type.In this document, the conjunctive “or” is used as an “inclusive or” so a statement is true if any combination of the conditions is true.The verbal forms used in this document conform to
4、 usage described in Annex H of the ISO/IEC Directives, Part 2. For the purposes of this document, the auxiliary verb:a) “shall” means that compliance with a requirement or a test is mandatory for compliance with this document;b) “should” means that compliance with a requirement or a test is recommen
5、ded but is not mandatory for compliance with this document;c) “may” is used to describe a permissible way to achieve compliance with a requirement or test. ISO 2017 All rights reserved vBS ISO 18562-4:2017ISO 18562-4:2017(E)An asterisk (*) as the first character of a title or at the beginning of a p
6、aragraph or table title indicates that there is guidance or rationale related to that item in Annex A.The attention of Member Bodies is drawn to the fact that equipment manufacturers and testing organizations may need a transitional period following publication of a new, amended or revised ISO publi
7、cation in which to make products in accordance with the new requirements and to equip themselves for conducting new or revised tests. It is the recommendation of the committee that the content of this publication be adopted for implementation nationally not earlier than 3 years from the date of publ
8、ication for equipment newly designed and not earlier than 5 years from the date of publication for equipment already in production.vi ISO 2017 All rights reservedBS ISO 18562-4:2017INTERNATIONAL STANDARD ISO 18562-4:2017(E)Biocompatibility evaluation of breathing gas pathways in healthcare applicati
9、ons Part 4: Tests for leachables in condensate1 ScopeThis document specifies tests for substances leached by liquid water condensing into gas pathways of a medical device, its parts or accessories, which are intended to provide respiratory care or supply substances via the respiratory tract to a pat
10、ient in all environments. The tests of this document are intended to quantify hazardous water-soluble substances that are leached from the medical device, its parts or accessories by condensate and then conveyed by that liquid to the patient. This document establishes acceptance criteria for these t
11、ests.This document addresses potential contamination of the gas stream arising from the gas pathways, which is then conducted to the patient.This document applies over the expected service life of the medical device in normal use and takes into account the effects of any intended processing or repro
12、cessingThis document does not address biological evaluation of the surfaces of gas pathways that are in direct contact with the patient. The requirements for direct contact surfaces are found in the ISO 10993 series.Medical devices, parts or accessories containing gas pathways that are addressed by
13、this document include, but are not limited to, ventilators, anaesthesia workstations (including gas mixers), breathing systems, oxygen conserving devices, oxygen concentrators, nebulizers, low-pressure hose assemblies, humidifiers, heat and moisture exchangers, respiratory gas monitors, respiration
14、monitors, masks, mouth pieces, resuscitators, breathing tubes, breathing systems filters, Y-pieces and any breathing accessories intended to be used with such devices. The enclosed chamber of an incubator, including the mattress, and the inner surface of an oxygen hood are considered to be gas pathw
15、ays and are also addressed by this document.This document does not address contamination already present in the gas supplied from the gas sources while medical devices are in normal use.EXAMPLE Contamination arriving at the medical device from gas sources such as medical gas pipeline systems (includ
16、ing the non-return valves in the pipeline outlets), outlets of pressure regulators connected or integral to a medical gas cylinder, or room air taken into the medical device is not addressed by ISO 18562 series.This document does not address contact with drugs or anaesthetic agents. If a medical dev
17、ice is intended to be used with anaesthetic agents or drugs, then additional testing can be required.This document is intended to be read in conjunction with ISO 18562-1.NOTE This document has been prepared to address the relevant essential principles of safety and performance as indicated in Annex
18、B.2 Normative referencesThe 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 (includin
19、g any amendments) applies. ISO 2017 All rights reserved 1BS ISO 18562-4:2017ISO 18562-4:2017(E)ISO 7396-1:2016, Medical gas pipeline systems Part 1: Pipeline systems for compressed medical gases and vacuumISO 10993-1, Biological evaluation of medical devices Part 1: Evaluation and testing within a r
20、isk management processISO 10993-5, Biological evaluation of medical devices Part 5: Tests for in vitro cytotoxicityISO 10993-10, Biological evaluation of medical devices Part 10: Tests for irritation and skin sensitizationISO 10993-12:2012, Biological evaluation of medical devices Part 12: Sample pr
21、eparation and reference materialsISO 14971:2007, Medical devices Application of risk management to medical devicesISO 18562-1:2017, Biocompatibility evaluation of breathing gas pathways in healthcare applications Part 1: Evaluation and testing within a risk management process3 Terms and definitionsF
22、or the purposes of this document, the terms and definitions given in ISO 7396-1, ISO 14971 and ISO 18562-1 apply.ISO and IEC maintain terminological databases for use in standardization at the following addresses: IEC Electropedia: available at h t t p :/ www .electropedia .org/ ISO Online browsing
23、platform: available at h t t p :/ www .iso .org/ obpNOTE For convenience, an alphabetized index of all defined terms and their sources used in this document are given in Annex C.4 General principles4.1 Type testsThe tests described in this document are type tests. Type tests are performed on the fin
24、al medical device, a component of the medical device or a representative sample of the medical device, part or accessory being evaluated. If representative samples are used, (i.e. manufactured and processed by equivalent methods), consideration should be made regarding whether or not the differences
25、 between the representative sample and the final medical device or component could affect the results of the test. Testing of representative samples (manufactured and processed by equivalent methods) instead of the final medical device should be supported by a description of any differences between
26、the representative sample and the final medical device, and a detailed rationale for why each difference is not expected to impact the biocompatibility of the final medical device.NOTE Some authorities having jurisdiction evaluate these differences and rationales.4.2 GeneralAll gas pathways from whi
27、ch the patient inspires gas shall be evaluated using the strategy detailed in ISO 18562-1.2 ISO 2017 All rights reservedBS ISO 18562-4:2017ISO 18562-4:2017(E)5 Leachable substances in condensate5.1 GeneralA medical device, part or accessory shall not add to the condensate leachable substances at lev
28、els that create an unacceptable risk to the patient. All gas pathways from which the patient inspires gas in normal condition, where gas in the gas pathway can reach 100 % saturation with water at some point in the gas pathway, condensate can form on the gas pathway surfaces, and liquid condensate c
29、an reach the patient,shall be evaluated for condensate emissions. The evaluation should use the risk management process to assess if testing is required.NOTE 1 Condensate can form in gas pathways and can take the form of liquid drops or a film of water on the gas pathway walls. This liquid water can
30、 extract substances from the materials of the walls that would not be extracted by the breathing gas alone. If this liquid condensate can reach the patient, it could potentially convey harmful substances to the patient.NOTE 2 The evaluation of some components, which are identical in formulation, pro
31、cessing and preparation for use to an existing component of a medical device that has been previously tested, might conclude that no further testing is required. Refer to ISO 18562-1:2017, Figure 2.Sections of the gas pathway from which the patient cannot be exposed to condensate need not be tested.
32、If the risk management process determines that testing is required, the tests of 5.2 shall be performed.If the medical device under evaluation has already been evaluated as an external communicating medical device with contact to tissue/bone/dentin according to ISO 10993-1, then the following tests
33、need not be performed.EXAMPLE A tracheal tube, because of its direct contact with the patient, is evaluated according to ISO 10993-1. In this case, the tests of this document are not required.NOTE 3 Some authorities having jurisdiction might require these tests if the medical device is intended for
34、use on particularly vulnerable patient populations, such as neonates.5.2 * Test methodTest for leachable substances in condensate is as follows.a) To collect a sample, either1) produce and collect condensate under clinically relevant conditions, or2) circulate the water over the surface of the sampl
35、e at a temperature representative of clinical use, or3) * perform an aqueous extraction on the internal gas contact surfaces according to the method of ISO 10993-12:2012, Clause 10, with the extract at clinically relevant temperatures, for a clinically relevant duration of time.EXAMPLE There is no c
36、linical relevance to performing a 24-h extraction on a medical device that is only intended to be used on a patient for 20 min. However, the underlying principle remains “what is the dose to the patient in 24 h”. If a medical device could be used multiple times in a 24-h period, then the maximum lik
37、ely cumulative time is considered. Additionally, if the medical device is consumable and replaced consecutively, the 24-h exposure can be higher due to additive effects.NOTE 1 See the rationale in Annex A for further considerations if performing an aqueous extraction. ISO 2017 All rights reserved 3B
38、S ISO 18562-4:2017ISO 18562-4:2017(E)This document is not intended to be prescriptive in the selection of medical device configuration, test method and conditions used to produce the sample. Choices should be justified and documented.b) * Determine the content of metal ions in the condensate or extr
39、act using the method of pharmacopeias (e.g. USP17) or another relevant method. Evaluate the results based on limits defined in USP18or other validated sources. If not all the metals listed in USP are screened for, then justify and document the rationale.NOTE 2 Similar analytical methods are useful t
40、o assess other metals of concern, such as nickel and chromium.If exposure limits are not available for specific metals identified in condensate, then derive a tolerable intake using the method of ISO 18562-1:2017, Clause 7.Convert the concentration of each metal ion to a total dose/day by considerin
41、g the total amount of liquid condensate that reaches the patient in a day as 1 ml.c) * If required in order to achieve detection of concentrations at the limits specified, enrich the organic impurities in the condensate or extract using established methods, such as stir bar sorptive extraction, soli
42、d phase microextraction, liquid-liquid extraction or a demonstrably equivalent method. Then identify and quantify organic impurities using GC-MS (gas chromatography-mass spectrometry) or an equivalent method.Convert the concentration of each substance to a total dose per patient per day by consideri
43、ng the total amount of condensate that reaches the patient per day as 1 ml.Confirm that the dose of each identified substance delivered to the patient in 1 ml of condensate or extract is less than the tolerable intake or threshold of toxicological concern derived from the method of ISO 18562-1:2017,
44、 Clause 7.The route of exposure is into the lung and therefore considered inhalational, not oral ingestion.d) * Perform a cytotoxicity test according to ISO 10993-5 on the condensate or extract. There are several different methods offered in ISO 10993-5. Select a method suitable for liquids.NOTE 3 T
45、he MEM elution method is a sensitive method, and is normally accepted by authorities having jurisdiction as an appropriate method.e) * Perform a sensitization test according to ISO 10993-10 on the condensate or extract. Select a method suitable for liquids.NOTE 4 The LLNA method is normally accepted
46、 by authorities having jurisdiction as an appropriate method. However, there are concerns that this particular test method might not be wholly suitable if the medical device includes nickel, the extract contains a mixture of substances, rather than a single leached substance, the aqueous extract doe
47、s not include a vehicle to ensure the extract is in contact with the skin, or novel materials that do not penetrate the skin are present (e.g. nanomaterials).4 ISO 2017 All rights reservedBS ISO 18562-4:2017ISO 18562-4:2017(E)Annex A (informative) Rationale and guidanceA.1 General guidanceThis annex
48、 provides rationale for the important requirements of this document and is intended for those who are familiar with the subject of this document, but who have not participated in its development. An understanding of the reasons for the main requirements is considered to be essential for its proper a
49、pplication. Furthermore, as clinical practice and technology change, it is believed that rationale for the present requirements will facilitate any revision of this document necessitated by those developments.The clauses and subclauses in this annex have been so numbered to correspond to the clauses and subclauses in this document to which they refer. The numbering is, therefore, not consecutive.A.2 Rationale for particular clauses and subclauses5.2 Test methoda) 3)Typically, the extraction ratio will be 3 cm2of inner gas pathway
