INTERNATIONAL STANDARD ISO 18562-1 First edition 2017-03 Biocompatibility evaluation of breathing gas pathways in healthcare applications — Part 1: Evaluation and testing within a risk management process Évaluation de la biocompatibilité des voies de gaz respiratoires dans les applications de soins de santé — Partie 1: Évaluation et essais au sein d’un processus de gestion du risque Reference number ISO 18562-1:2017(E) © ISO 2017 ISO 18562-1:2017(E) COPYRIGHT PROTECTED DOCUMENT © ISO 2017, Published in Switzerland All rights reserved Unless otherwise specified, no part o f this publication may be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting on the internet or an intranet, without prior written permission Permission can be requested from either ISO at the address below or ISO’s member body in the country o f the requester ISO copyright o ffice Ch de Blandonnet • CP 401 CH-1214 Vernier, Geneva, Switzerland Tel +41 22 749 01 11 Fax +41 22 749 09 47 copyright@iso.org www.iso.org ii © ISO 2017 – All rights reserved ISO 18562-1:2017(E) Contents Page Foreword iv Introduction v Scope Normative references Terms and definitions General principles applying to b io com pati b i lity evaluation of medi c al devi c es 6 4.1 4.2 4.3 4.4 4.5 4.6 4.7 General Type tests B iocompatibility hazard identification Extent of ris k assessment B iocompatibility evaluation plan Selection of tests 10 Subsequent evaluation 10 5.1 5.2 5.3 5.4 * Duration of use 11 Particulate matter (pm ) emissions 13 Volatile organic compound (voc ) emissions 13 Leachable substances in condensate 13 6.1 6.2 6.3 General considerations 13 Adjustment for body weight 13 * Deriving a permitted concentration from a tolerable exposure 14 7.1 7.2 7.3 7.4 General process 14 For medical devices intended for limited exposure use (≤24 h) 15 For medical devices intended for prolonged exposure use (>24 h but h but < d) For medi a For e ach identi fie d comp ound: — if possible, obtain prolonged exposure inhalational exposure limits for that compound from i nternationa l ly accep te d to x icolo gic a l datab as e s Us e th i s e x p o s u re l i m it i n the a s s e s s ment o f biocompatibili ty; — i f prolonge d e x p o s ure i n lationa l e x p o s u re l i m its a re no t d i re c tly avai lable, then s e e k data on p erma nent contac t i n lationa l to x ic ity or c arc i no gen icity, and derive a b o dy weight/d) — for i f no to x ic ity data are avai lab le, then a an adult NO TE tolerable inta k e For the fi rs t h p er io d , the ttc ttc ( prolonge d e x p o s u re) va lue o f µg/d may b e u s e d i s µg; for s ub s e quent h p er io d s , the Use the process described in 6.2 f k tolerable e posure (in µg/d) This process allowed dose-to-patient, in µg/d, of this substance (adj u s tment µg/ 7.4 (µg/kg th i s comp ou nd; g b o dy weight/d) i nto a or b o dy weight) to conver t the x ttc is 120 µg tolerable inta k e for (in re s u lts i n identi fyi ng an c l devi c es intended for p ermanent contact (≥30 d) For medi a For e ach identi fie d comp ound: — if possible, obtain permanent contact inhalational exposure limits for that compound from i nternationa l ly accep te d to x icolo gic a l datab as e s Us e th i s e x p o s u re l i m it i n the a s s e s s ment o f biocompatibili ty; — i f p erma nent contac t i n h a lationa l e x p o s u re l i m its a re no t d i re c tly ava i l able, then s e e k data on p erma nent contac t i n lationa l to x ic ity or c arc i no gen icity, and derive a b o dy weight/d) — for voc NO TE for tolerable inta k e (µg/kg th i s comp ou nd; s , i f no to x icity data are avai lable, then a For the fi rs t h p er io d , the ttc ttc i s µg; (permanent contact) value of 40 µg/d for may be used; the s ub s e quent twenty-n i ne h p er io d s , the ttc is 120 µg and thereafter 40 µg/d NOTE A ttc of 40 µg/d represents the current state-of-the-art measurement threshold for vocs It represents an increase in the excess cancer ris of in 2,7 × 10 as compared to in ×10 for shorter exposures −4 k — for le ach able subs tances o f , µg/d may b e u s e d NO TE for −5 , i f no to x ic ity data a re avai lable, then a ttc (permanent contact) value an adu lt For the fi rs t h p er io d , the is 120 µg and thereafter 1,5 µg/d ttc i s µg; for the s ub s e quent twenty-n i ne h p er io d s , the f Use the process described in 6.2 k tolerable e posure (in µg/d) This process allowed dose-to-patient, in µg/d, of this substance (adj u s tment µg/ g b o dy weight/d) i nto a Ris k b enefit analysis or b o dy weight) to conver t the x I f s ub s tance s are identi fie d, and thei r qua ntitie s a re i n e xce s s o f the b a s ic tolerable inta k e ttc (in re s u lts i n identi fyi ng an tolerable e x posure le vels derived above, then the m anu facturer should review the materials and manufacturing processes If f processes , then the medic al de vice f f f medic al de vice outweigh the ris s posed to the patien t from this substance being present is that review c a nno t identi y prac tic able a lternative materi a l s or may s ti l l b e s idere d s uitable i k 16 the b enefits a ri s i ng rom the u s e o R the k b enefit ana lys i s i s p a r tic u larly © ISO 2017 – All rights reserved ISO 18562-1:2017(E) applicable to critical life-saving medic al de vices without which the patient will die or for medic al de vices for which there are no alternatives EXAMPLE The residual ri s s of the medic al de vice are similar to the residual ris s of other similar k medic al de vices NOTE k th at a re le ga l l y m a r ke tab le ISO 14971:2007, 6.5 describes ris k/ b ene fit a n a l ys i s When the m anu facturer disclose the residual ris in the accompan ying document The m anu facturer shall document the results of ris de term i ne s th at the b enefit outweigh the ris k s , the m anu facturer shall k k b enefit a na lys i s NOTE Some authori ties h aving jurisdic tion evaluate this ris k b ene fit a n a l ys i s Check compliance by inspection of the r isk ma nagement plan and r isk ma nagement file Assess the b io om ati c p b i it l y of the medi c a l de i e v c A biocompatibili ty evaluation of a medic al de vice is part of an overall ris m anagement process The potential h az ards associated with the medic al de vice f the purposes of this document, the biocompatibilit y h az ards arising from the gas path ways shall ris s associated with those h az ards shall be assessed and a biocompatibilit y evaluation plan developed f f medic al de vice shall be k s l l b e identi fie d, and , i n p ar tic u lar b e identi fie d T he k I n ormation to relati ng the s ub s tance s rele as e d ob ta i ne d Po s s ibly, te s ts are re qu i re d to gather a th i s c ument for b y the fu l l materia l s o or the s e t o f i n formation Re fer to the s ub s e quent p ar ts o f p ar tic u lar te s ts and the a na lys i s o f re s u lts The dose that the patient f f medic al de vice shall be calculated for each substance of interest The tolerable e posure for each of these substances shall be derived, following the procedure in Clause of this document If the dose the patient f tolerable e posure for that compound, then the medic al de vice complies with this document If the dose to the patient of one or more compounds exceeds the tolerable e posure , but it is not practicable to alter the materials or manufacture, and the m anu facturer outweigh the ris s , then the medic al de vice complies with this document wou ld re ceive i n e ach day o use o the x re ceive s e ach day o e ach comp ou nd i s le s s th an the x x de term i ne s that the b enefit k NOTE Some authori ties h aving jurisdic tion assess the biocompatibili t y evaluation © ISO 2017 – All rights reserved 17 ISO 18562-1:2017(E) Annex A (informative) Rationale and guidance A.1 General guidance This annex 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 appl ic ation Fu r thermore, a s cl i n ic a l prac tice and te ch nolo g y cha nge, it i s b el ieve d that rationa le pre s ent re qu i rements wi l l faci l itate for the any revi s ion o f th i s c u ment ne ce s s itate d b y tho s e developments The clauses and subclauses in this annex have been so numbered to correspond to the clauses and s ub clau s e s i n th i s c u ment to wh ich they re fer T he nu mb eri ng i s , there fore, no t s e c utive A.2 Rationale for particular clauses and subclauses Subclause 5.1 — Duration of use T h i s c u ment cl as s i fie s e x p o s u re accord i ng to th re e du ration s o f u s e: — l i m ite d e x p o s u re: ≤ h; — prolonge d e x p o s u re: >2 h and < d; — p erma nent e x p o s ure: ≥ d These times have been chosen to be consistent with the ISO 10993 series categories A, B and C for duration of use Subclause 6.3 — Deriving a permitted concentration from a to l era b l e ex p os u re Data for minute ventilation in infants and children are found in Reference [9] It has reference data for 12] and f f [13] These data are summarized in Table A.1 re s pi rator y p a rame ters i n ch i ld ren, wh ich were re ference d rom two publ ic ation s , Re erence s [ T he de fau lt b o dy weight va lue s u s e d i n th i s c u ment a re , kg for ne onate, , kg for i n fa nt, 10 kg for paediatric and 70 kg for adult patient The default breathing volumes are 0,21 m3/d, m3/d, m3/d, and 20 m3 /d, re s p e c tively Table A.1 — Ventilation data by body size ati en t P size Neonate Infant Paediatric Adult (≥19 ye a rs old) 18 Body weight (BW) kg 0,21 3,5 10 70 Proposed total ventilation for o dose m 3/d v c 0,5 2,0 5,0 20 © ISO 2017 – All rights reserved ISO 85 62 -1 : 01 7(E) C lause — Deriving allowable limits The choice of a ttc k f k f exposure), 120 µg/d (prolonged exposure) and 1,5 µg/d (permanent contact) was discussed at length patients , a patient ttc value (µg/d) based on the patient f Table A.1 should be derived The inhalation ttc value for prolonged (24 h to 30 d) exposure to vocs released into the gas path way is based on: — the 5th percentile of a distribution of noncancer tolerable inta e (ti) values derived from inhalation NOAEL (no observed adverse effect level) and LOAEL (lowest observed adverse effect level (adu lt with 70 g b o dy weight) or u n b y the com m itte e For lower b o dy weight b o dy weight nown s ub s tance s o µg/d ( l i m ite d - s p e c i fic rom k level) va lue s (e x p o s u re du ration ≤ d) rep or te d i n the RepD o s e datab as e (1 µg/d) — the accep table i nta ke o f an i nd i vidua l mutagenic i mpu rity in a pharmaceutic a l [14] ; pro duc t with [15] (120 µg/d) exposure to the patien t f The lower of the two values, 120 µg/d, was selected as the inhalation ttc value for prolonged exposure and this value is intended to be protective for both cancer and noncancer effects Recognizing that exposure limits can be adjusted to permit higher levels of exposure for shorter durations, the prolonged inhalation ttc was adjusted upwards to derive a limited exposure duration ttc f f C × Tn = k) [16] x f n = 0.33 was used to estimate an airborne concentration (C) of a voc that produces an equivalent toxicological response in 24 h to that seen after inhalation exposure to 120 µg/d for 30 d The three-fold increase in the limited exposure duration ttc compared to the ttc for prolonged exposure is consistent with similar efforts to extrapolate exposure limits from longer to shorter durations or ≤ d , p er the IC H M gu idance o µg/d u s i ng a mo d i fic ation o H ab er ’s Ru le ( L a s tly, the com m itte e s idere d p ermanent e x p o s u re l i m its B riefly, a n e for adu lts (70 kg) p onent o and prop o s e d µg/d Ta k i ng a prac tic a l appro ach , the com m itte e d i s c u s s e d the level s at wh ich it wa s c u rrently p o s s ible to me as u re concentration s u s i ng e s tabl i s he d, s tandard i z e d lab orator y tech n ique s T he c u rrent de te c tion limit for voc s using standardized test methods is µg/m3 Thus, a proposed limit of µg/m3 as a concentration is as low as possible to measure A concentration of µg/m3 gives a total dose-to-patient for an adult (who breathes 20 m3 f f ttc limit below 40 µg/d were to be proposed, it would be meaningless, as it would not be possible to measure it It is recognized that these limits can be adjusted in the future as more knowledge becomes known and f felt that the proposed limits of 360 µg/d (limited exposure duration), 120 µg/d (prolonged exposure x expose patients to unacceptable ris s medic al de vice to gases supplied to patients The f patient exposure /d) o µg T hu s , i any ana lytic a l me as u rement te ch n ique s i mprove H owever, on the b a l ance o du ration) a nd µg/d ( p ermanent e prob abi l itie s , the com m itte e p o s u re du ration) were re a s onab ly s er vative and wou ld no t k T he s e l i m its apply on ly to s ub s tance s adde d by the prop o s e d l i m its a re no t relevant to any o ther typ e o © ISO 2017 – All rights reserved 19 ISO 18562-1:2017(E) Annex B (informative) Reference to the essential principles T h i s c ument s b e en prep are d to s upp or t the e s s enti a l pri nciple s o f s a fe ty a nd p er formance o f path ways gas as components of medic al de vices according to ISO 16142-1 [6] This document is intended to b e accep table for form ity as s e s s ment pu r p o s e s C ompl iance with th i s c u ment provide s one me an s o f demon s trati ng forma nce with the s p e c i fic essential principles of ISO 16142-1[6] Other means are possible Table B.1 maps the clauses and subclauses of this document with the essential principles of ISO 16142-1 Table B.1 — Correspondence between this document and the essential principles Essential principles of ISO 16142-1 [6] 8.1 a) 8.1 b) 8.2 8.4 8.5 20 Corresponding clause(s)/ subclause(s) of this document Clause 4, Clause 5, Clause 6, Clause 7, Clause 8, Clause Clause 4, Clause 5, Clause 6, Clause 7, Clause 8, Clause Clause 4, Clause 5, Clause 6, Clause 7, Clause 8, Clause Clause 4, Clause 5, Clause 6, Clause 7, Clause 8, Clause Clause 4, Clause 5, Clause 6, Clause 7, Clause 8, Clause Qualifying remarks/notes O n l y the p a r t re l ati n g to to x ic i t y i s addressed O n l y the p a r t r e l a ti n g to e g r e s s o f substances from the medic al de vice is addressed © ISO 2017 – All rights reserved ISO 18562-1:2017(E) Annex C (informative) T e r m i n o l gy o — A lph b a e t i z e d i n d e x o f d e f i n e d t e r m s T he I S O O n l i ne B rows i n g Pl at for m (O B P) a nd the I E C E le c trop e d ia p ro vide acce s s to m a ny o f the s e NO TE ter m s a nd de fi n ition s Term accessory accompan ying doc ument authori t y h aving jurisdic tion biocompatibili t y e x pec ted service li f e f orm ul ation gas path way h az ard in tended use le ach able subs tance m anu fac turer medic al de vice medic al gas pipeline s ys tem norm al condi tion norm al use partic ul ate m atter partic ul ates patien t pm process residual ris k ris k ris k analysis ris k assessmen t ris k m anagemen t ris k m anagemen t f ile te threshold o f to x icologic al concern ti til tolerable e x posure tolerable inta k e tolerable inta k e le vel ttc t ype tes t voc © ISO 2017 – All rights reserved Source 3.1 ISO 14971:2007, 2.1 ISO 16142-1:2016, 3.1 3.2 3.3 3.4 3.5 ISO 14971:2007, 2.3 ISO 14971:2007, 2.5 3.6 ISO 14971:2007, 2.8 3.7 ISO 7396-1:2016, 3.36 3.8 3.9 3.10 3.10 3.11 3.10 ISO 14971:2007, 2.13 ISO 14971:2007, 2.15 ISO 14971:2007, 2.16 ISO 14971:2007, 2.17 ISO 14971:2007, 2.18 ISO 14971:2007, 2.22 ISO 14971:2007, 2.23 3.13 3.12 3.14 3.14 3.13 3.14 3.14 3.12 3.15 3.16 21 ISO 18562-1:2017(E) Term volatile organic compound very volatile organic compound vvoc 22 3.16 3.17 3.17 Source © ISO 2017 – All rights reserved ISO 18562-1:2017(E) Bibliography [1] [2] [3] [4] [5] [6] [7] [8] ISO 10993-9, Biolo g ical evaluation o f m edical devices — Pa rt 9: Fra m ewo rk fo r identification and quantification o f potential degradation p roducts ISO 10993-13, Biolo g ical evaluation o f m edical devices — Pa rt 3: Identification and quantification of degradation products from polymeric medical devices ISO 10993-14, Biological evaluation of m edical devices — Part 14: Identification and quantification of degradation products from ceramics ISO 10993-15, Biolo g ical evaluation o f m edical devices — Pa rt 15: Identification and quantification of degradation products from metals and alloys ISO 13485:2016, Medical devices — Quality management systems — Requirements for regulatory purposes ISO 16142-1:2016, Medical devices — Recognized essential principles of safety and performance of m edical devices — Pa rt 1: General essential p rinciples and additional specific essential p rinciples fo r all non-IVD medical devices and guidance on the selection of standards ISO/IEC 17025, General requirements for the competence of testing and calibration laboratories IEC 60601-1:2005+AMD1: 2012, Medical electrical equipment — Part 1: General requirements for basic safety and essential performance [9] BS 5724-3.12, Medical electrical equipment — Particular requirements for performance — Method [10] Glossary, Scientific Committees o f the EU [accessed May 2016] Available from: http://ihcp jrc ec europa eu/glossary?search _letter= e [11] US FDA 510( k) Memorandum #K97-1, January 10, 1997 of declaring parameters for lung ventilators [12] G odf re y S Growth and development o f the respiratory system In: Scientific Foundations of Paediatrics, (D avis J.A., & D obbing J eds.) Heinemann, London, Second Edition, 1981, pp 432–50 [13] S toc ks J The functional growth and development of the lung during the first year of li fe Early Hum Dev 1977, pp 285–309 [14] Fraunhofer RepDose Database The database for the analysis of relationship between chemical function groups/categories and target organs in repeated dose studies [accessed 28 June 2016] Available from: http://fraunhofer-repdose de/ [15] International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use, Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk ICH M7 Step version, dated 23 June 2014 [16] M iller F.J., S chlosser P.M., J anszen D.B Haber’s rule: a special case in a family of curves relating concentration and duration o f e x posure to a fi xed level o f response for a given endpoint Toxicology 2000, pp 21–34 © ISO 2017 – All rights reserved 23 ISO 18562-1:2017(E) ICS 11.040.10 Price based on 23 pages © ISO 2017 – All rights reserved