natgillin/translations-raw huggingface dataset:
Given that a daily treatment of six capsules corresponds to 2 g, the quantity of lead ingested by patients could reach 30 μg per day, i.e. much more than the threshold of 5 μg per day.
Navaja zlasti, da navedena metoda, ki temelji na količini svinca v pripomočku, ni relevantna za ocenjevanje izpolnjevanja bistvenih zahtev, ki se nanašajo na snovi, ki uhajajo iz pripomočka, in da ni prilagojena pripomočku na podlagi gline, ki teh elementov ne sprošča.
The manufacturer has therefore not reduced as far as possible the risk associated with the presence of lead in the device by selecting batches of raw material which would have made it possible to manufacture a device containing a level of lead below the threshold set by Guideline ICH Q3D.
Vendar v okoliščinah obravnavane zadeve in ker ni študije in vivo, ki bi omogočala oceno količine svinca, ki se dejansko izluži iz pripomočka, metoda, ki temelji na količini strupene snovi v pripomočku, omogoča določitev količine, ki bi se lahko sprostila v organizem, in torej oceno tveganja zaradi snovi, ki se sprostijo iz pripomočka.
The above-mentioned essential requirements may also lead the manufacturer of a device to select, from different raw materials, the one which poses the fewest risks as regards the toxic substances which it contains.
Pojasniti je treba, da po eni strani določeno uhajanje svinca iz pripomočka ni sporno (izhaja med drugim iz preskusov samega proizvajalca), po drugi strani pa je kljub mnenju proizvajalca, da je to uhajanje majhno, sporna metoda, s katero je proizvajalec prišel do te ugotovitve (glej točko 47 in nasl. spodaj).
Indeed, Section 7.1 of Annex I to the Directive provides that ‘particular attention must be paid to the choice of materials used, particularly as regards toxicity […]’.
Proizvajalec navaja, da bi bila kljub morebitni uporabi smernice ICH Q3D količina sproščenega svinca (ki jo v svojem dopisu z dne 30. novembra 2016 ocenjuje na 3,126 μg na dan, v poročilu laboratorija NAMSA iz februarja 2017 pa je ocenjena na 3,96 μg) nižja od mejne vrednosti iz smernice ICH Q3D (ki je 5 μg na dan).
In the present case, other raw materials — such as, for example, activated charcoal, simeticone or dimeticone — have properties similar to clay and are likely to achieve the medical purpose claimed by the manufacturer for its device, namely ‘to prevent digestive problems’.
Vendar je metoda, ki jo je uporabil proizvajalec za ugotavljanje količine svinca, ki uhaja iz pripomočka (glej točko 47 in nasl. spodaj), sporna in torej ne omogoča potrditve, da je s to metodo ugotovljena količina tako nizka, da ne pomeni nobenega tveganja, ob upoštevanju smernice ICH Q3D in drugih referenčnih dokumentov.
These other raw materials are not known to contain lead and are therefore unlikely to pose the risks associated with the device in question.
Proizvajalec navaja, da so bila (kardiovaskularna, nevrološka in nefrotoksična) tveganja, ki so jih opredelili francoski organi, upoštevana v navedbah navodila za uporabo pripomočka, zato pripomoček izpolnjuje bistveno zahtevo iz točke 1 Priloge I k Direktivi.
The manufacturer did not, however, try to find an alternative raw material uncontaminated with toxic substances (see its email of 30 March 2018).
Navaja tudi, da se je mogoče pretirani izpostavljenosti svincu izogniti z ukrepi proizvajalca, kakršni so navedeni v navodilu za uporabo, zato je ukrep organov, s katerim se med drugim prepoveduje dajanje pripomočka na trg in določa njegov umik s trga, v nasprotju z načelom sorazmernosti.
It has therefore not reduced as far as possible the risk associated with the presence of lead in the device in this way.
Vendar navedbe, ki jih je proizvajalec dodal v navodilo za uporabo in s katerimi se omejuje uporaba pripomočka za določene paciente (otroke, nosečnice in osebe z nefrotoksičnimi boleznimi), ne omogočajo zmanjšanja tveganja zastrupitve s svincem, ki zadeva celotno prebivalstvo.
In view of this, the French authorities were able to conclude that the device did not comply with the essential requirements of the Directive with regard to minimising risk.
Raziskava in vivo, ki bi pokazala, da je dejanska količina svinca, ki se izluži iz pripomočka, nižja od mejne vrednosti iz smernice, bi prispevala k odpravi tveganja za pretirano izpostavljenost svincu.
Objections raised by the manufacturer concerning failure to comply with essential requirements
Člen 8(1) Direktive 93/42/EGS upošteva načelo sorazmernosti s tem, ko določa, da je treba na podlagi ugotovitve tveganja za zdravje in/ali varnost ljudi sprejeti ustrezne začasne ukrepe za umik s trga ali prepoved ali omejitev dajanja na trg.
The manufacturer calls into question the use of Guideline ICH Q3D.
Iz navedenega v obravnavani zadevi sledi, da je ukrep prekinitve dajanja pripomočka na trg in umik pripomočka pri distributerjih do uskladitve s predpisi, če francoski organi dokažejo tako tveganje, skladen tako s členom 8(1) Direktive kot načelom sorazmernosti.
It argues in particular that the Guideline is not applicable ratione materiae — it applies to medicinal products — and ratione temporis — it applies to new applications for authorisation to place medicinal products on the market as of June 2016 and to existing authorisations to place medicinal products on the market as of December 2017 — and that its application runs counter to the principles of legality and legal certainty.
Ob upoštevanju navedenega ugovori proizvajalca ne morejo ovreči ugotovitve francoskih organov, da pripomoček ne izpolnjuje nekaterih bistvenih zahtev Direktive.
However, use of Guideline ICH Q3D is in keeping with Article 8(1) of the Directive, which requires a Member State to take certain interim measures if it notices that a medical device poses a risk to safety and/or health, and which does not limit the information which the Member State may draw on to show that such a risk exists.
Nepravilna uporaba standardov
Moreover, for the reasons mentioned above (point (24), while being formally applicable to medicinal products, the Guideline is relevant in identifying the risk associated with the presence of lead in a medical device whose situation is similar to that of a medicinal product.
Iz člena 8(1) Direktive 93/42/EGS izhaja, da lahko tveganje, zaradi katerega morajo države članice ukrepati, med drugim izhaja iz nepravilne uporabe standardov iz člena 5 Direktive, katerih uporaba se zatrjuje.
It follows that use of the Guideline appears to have a legal basis and be predictable.
Proizvajalec navaja, da je bil pripomoček ocenjen in potrjen kot skladen z nekaterimi harmoniziranimi standardi v zvezi z biološkim ovrednotenjem medicinskih pripomočkov (zlasti s standardi EN ISO 10993-1 2009/AC: 2010, EN ISO 10993-12 2012, EN ISO 10993-17 2009 in EN ISO 10993-18 2009), ki ustrezajo nekaterim bistvenim zahtevam Direktive in katerih sklic je bil objavljen v Uradnem listu Evropske unije, zato je treba za pripomoček domnevati, da je skladen z zadevnimi bistvenimi zahtevami.
The manufacturer calls into question the method used to evaluate the risk.
Navedeni standardi za biološko ovrednotenje medicinskih pripomočkov med drugim določajo, da je treba pri uporabljeni metodi poustvariti dejanske pogoje uporabe medicinskega pripomočka in da je morda treba izvesti druge preskuse od tistih, ki so opisani v standardih, na kar kažejo določbe v nadaljevanju.
It argues, in particular, that this method, based on the quantity of lead contained in the device, is not relevant in assessing compliance with the essential requirements which refer to substances released by a device and that it is not suitable for a device based on clay, which does not release its elements.
Standard EN ISO 10993-1 2010: biološko ovrednotenje medicinskih pripomočkov – ocena in preskušanje znotraj procesa obvladovanja tveganja
However, in the circumstances surrounding the present case, in the absence of an in vivo study making it possible to assess the quantity of lead actually released by the device, the method based on the quantity of the toxic substance contained in the device makes it possible to determine the quantity likely to be released into the body and thus to assess the risk posed by substances released by the device.
V uvodu standarda je navedeno, da je ta pristop kombinacija analize in vrednotenja vseh obstoječih podatkov, po potrebi z izbranimi in izvedenimi dodatnimi preskusi, kar omogoča celovito ovrednotenje bioloških odzivov vsakega medicinskega pripomočka v povezavi z varnostjo njegove uporabe, da biološko ovrednotenje med drugim temelji na preskusnih metodah in vitro ter in vivo ter na živalskih modelih, da ISO 10993 ni namenjen zagotavljanju toge zbirke preskusnih metod z merili za sprejem ali zavrnitev in da ga je treba uporabljati ob upoštevanju vseh dejavnikov v zvezi s pripomočkom, njegove predvidene uporabe in sodobnih spoznanj o medicinskem pripomočku s pregledom znanstvene literature in predhodnih kliničnih izkušenj.
It should also be pointed out, first, that the fact that the device releases a certain amount of lead is not disputed (as shown by tests carried out by the manufacturer itself) and, second, that while the manufacturer considers the amount of lead released to be small, the method used by the manufacturer to reach this conclusion is disputable (see points 47 et seq. below).
V točki 4.4 standarda je med drugim navedeno, da je treba pri izbiri preskusov ter potrebnih podatkih za biološko ovrednotenje in njihovi razlagi upoštevati kemično sestavo materiala, vključno s pogoji izpostavljenosti ter vrsto, stopnjo, pogostostjo in trajanjem izpostavljenosti človeškega telesa pripomočku ali njegovim sestavinam, da se omogoči razvrščanje pripomočkov za lažjo izbiro ustreznih preskusov.
The manufacturer argues that even if Guideline ICH Q3D were used, the amount of lead released (which it assesses at 3,126 μg per day in its communication of 30 November 2016, and which is estimated at 3,96 μg per day in the report of February 2017 by the NAMSA laboratory) would be below the threshold mentioned in Guideline ICH Q3D (which is 5 μg per day).
Potrebna strogost biološkega ovrednotenja je odvisna predvsem od vrste, stopnje, trajanja in pogostosti izpostavljenosti ter opredeljenih nevarnosti materiala.
However, the method used by the manufacturer to determine the quantity of lead released by the device is disputable (see points 47 et seq. below) and therefore does not make it possible to tell whether the quantity determined using this method is so low that it does not pose a risk, taking into consideration Guideline ICH Q3D and other reference documents.
V točki 6.1 standarda je med drugim navedeno, da se na podlagi ocene tveganja lahko [sic] ugotovi, da je potrebno dodatno preverjanje materiala, na primer kadar meja varnosti ni ocenjena kot zadostna, če bi se izlužila celotna kemikalija.
The manufacturer argues that the (cardiovascular, neurological and nephrotoxic) risks identified by the French authorities were taken into account through the indications the instructions for use of the device, with the result that the device complies with the essential requirement of Section 1 of Annex I to the Directive.
V takem primeru je mogoče stopnjo klinične izpostavljenosti kemični sestavini oceniti s preskusom ekstrakcije, s katerim se simulira klinična izpostavljenost.
It also argues that excessive exposure to lead may be avoided through measures taken by the manufacturer such as indications in the instructions for use, with the result that a measure taken by the authorities which, among other things, prohibits the device from being placed on the market and requires it to be withdrawn from the market, runs counter to the principle of proportionality.
V točki 6.2.2 standarda v zvezi z opisom preskusov je med drugim navedeno, da je pri preskusih nujno, da se vsak pripomoček obravnava ločeno.
However, the indications added to the instructions for use by the manufacturer restricting use of the device with regard to certain patients (children, pregnant women and individuals with kidney disease) do not eliminate the risk of lead poisoning for the population as a whole.
Lahko so potrebni dodatni preskusi, ki niso našteti v preglednici [Priloge A] (točka 6.2.2.1), da so lahko preskusi in vivo potrebni za ovrednotenje biorazgradnje materiala (točka 6.2.2.13) in da je treba predvideti toksikokinetične raziskave, če obstaja gotovost ali verjetnost sproščanja znatnih količin potencialno toksičnih ali reaktivnih razgradnih produktov in izluženih snovi iz medicinskega pripomočka v telo med klinično uporabo (6.2.2.14).
An in vivo study showing that the quantity of lead actually released by the device is lower than the threshold indicated in the Guideline would help to eliminate the risk of excessive exposure to lead.
Priloga A k standardu (informativna), ki vsebuje preglednico z opisom preskusov za biološko ovrednotenje, ki jih je treba upoštevati glede na vrsto stika s človeškim telesom in trajanjem stika, se ne nanaša izrecno na medicinske pripomočke, ki se zaužijejo.
Article 8(1) of Directive 93/42/EEC takes the proportionality principle into account by providing that where a risk to the health and/or safety of persons is ascertained, appropriate interim measures must be taken to withdraw the devices in question from the market or prohibit or restrict their being placed on the market.
V njej je navedeno, da je preglednica A.1 okvir za pripravo programa ovrednotenja in ne kontrolni seznam ter da je treba poleg okvira na podlagi preglednice A.1 upoštevati tudi to [torej preskuse, ki jih je treba izvesti], kar izhaja iz ocene tveganja.
It follows in the present case that where the French authorities show that a risk of this kind exists, a measure consisting in suspending the placing on the market of the device and withdrawing the device from the distributors until it is brought into line with the regulations is in keeping with Article 8(1) of the Directive and with the principle of proportionality.
Standard EN ISO 10993-12 2012: biološko ovrednotenje medicinskih pripomočkov – priprava vzorcev in referenčni materiali
In view of this, the objections raised by the manufacturer are not such as to call into question the French authorities' observation that the device does not comply with certain essential requirements of the Directive.
V točki 10.3.2 standarda, ki se nanaša na pogoje in metode ekstrakcije, je med drugim navedeno, da je treba izvesti ekstrakcijo z uporabo ustreznega ekstrakcijskega topila ter v časovnih/temperaturnih pogojih, ki omogočajo simulacijo pretirane izpostavljenosti, kadar je to mogoče.
Incorrect application of standards
Morda je primerno popolno raztapljanje.
It follows from Article 8(1) of Directive 93/42/EEC that the risk requiring the Member States to take measures may result from the incorrect application of the standards referred to in Article 5 of the Directive which the manufacturer claims to have applied.
Priloga C k standardu (informativna) v zvezi z načeli ekstrakcije vzorca v točki C.1 med drugim določa, da je najbolje, če pogoji ekstrakcije in uporaba ekstrakta v sistemih preskušanja odražajo ne samo dejanske pogoje uporabe proizvoda, ampak tudi namen in pričakovane neželene učinke preskusov, ter da se biološki preskusi izvajajo za opredelitev nevarnosti in ocenitev tveganja v pretiranih in/ali dejanskih pogojih uporabe.
The manufacturer argues that the device was assessed and deemed compliant with certain harmonised standards concerning the biological evaluation of medical devices (in particular standards EN ISO 10993-1 2009/AC: 2010, EN ISO 10993-12 2012, EN ISO 10993-17 2009 and EN ISO 10993-18 2009), which correspond to certain essential requirements laid down in the Directive and a reference to which has been published in the Official Journal of the European Union, with the result that the device must be presumed to comply with the essential requirements in question.
Pretirana ekstrakcija ali popolna ekstrakcija se prilagodi za opredelitev nevarnosti.
These standards concerning the biological evaluation of medical devices provide in particular that the method used must reproduce the actual conditions of use of the medical device and that it may be necessary to conduct tests in addition to those described in the standards, as indicated by the provisions below.
Standard EN ISO 10993-18 2009: biološko ovrednotenje medicinskih pripomočkov – kemična opredelitev lastnosti materialov
Standard EN ISO 10993-1 2010: biological evaluation of medical devices – evaluation and testing within a risk management process
V točki 5 standarda je med drugim navedeno, da pa je treba za oceno tveganja, ki izhaja iz sestavnih elementov proizvoda, zbrati podatke, ki omogočajo prikaz obsega razpoložljivosti sestavnih elementov v dejanskih pogojih uporabe končnega proizvoda.
The introduction to the standard states that ‘this approach combines the review and evaluation of existing data from all sources with, where necessary, the selection and application of additional tests, thus enabling a full evaluation to be made of the biological responses to each medical device, relevant to its safety in use’; that ‘biological testing is based upon, among other things, in vitro and ex vivo test methods and upon animal models’; that ‘it is not intended that ISO 10993 provide a rigid set of test methods, including pass/fail criteria’; that it must be used ‘taking into consideration all the factors relevant to the device, its intended use and the current knowledge of the medical device provided by review of the scientific literature and previous clinical experience’.
V obravnavani zadevi je proizvajalec uporabil preskusno metodo, ki ne odraža dejanskih pogojev uporabe pripomočka.
Point 4.4 of the standard states in particular that ‘the choice of tests and the data required in a biological evaluation, and their interpretation, shall take into account the chemical composition of the materials, including the conditions of exposure as well as the nature, degree, frequency and duration of exposure of the medical device or its constituents to the body, enabling the categorisation of devices to facilitate the selection of appropriate tests (…).
Natančneje, metoda, ki jo je uporabil za določanje količine izluženega svinca ter zajema uporabo samo 12 ml vode kot količine za ekstrakcijo ter uporabo samo nakisane vode brez bolusa ob obroku in brez primernega (dinamičnega) okolja, ne odraža dejanskih pogojev uporabe pripomočka, tj. zaužitja z večjo količino tekočine, prisotnosti bolusa ob obroku in njegove prebave skozi prebavni trakt.
The rigour necessary in the biological evaluation is principally determined by the nature, degree, duration and frequency of the exposure and the hazards identified for the material’.
Proizvajalec poleg tega ni uporabil nobene druge preskusne metode, zlasti preskusov pri ljudeh (in vivo), s katerimi bi se ugotovila raven svinca, ki je dejansko prisotna v krvnem obtoku.
Point 6.1 of the standard states in particular that ‘the results of the risk assessment can lead to the conclusion that additional material characterization is necessary, for example, where the margin of safety is not considered adequate if the entire amount of a particular chemical were to leach out.
Iz navedenega sledi, da proizvajalec ni dokazal, da je količina izluženega svinca majhna in/ali nižja od referenčne mejne vrednosti iz smernice ICH Q3D.
In such cases, appropriate extraction testing, simulating clinical exposure, can be used to estimate the degree of clinical exposure to the chemical constituent’.
Na podlagi navedenega je mogoče skleniti, da je prišlo do nepravilne uporabe standardov iz člena 5 Direktive, katerih uporaba se zatrjuje, zato tveganje zaradi prisotnosti svinca v pripomočku ni bilo odpravljeno.
Point 6.2.2 of the standard, concerning test descriptions, states in particular that ‘it is indispensable for testing that each device be considered on its own merits. Additional tests not indicated in the table [in Annex A] may be necessary’ (point 6.2.2.1), that ‘in vivo tests may be required to assess biodegradation of a material’ (point 6.2.2.13) and that ‘toxicokinetic studies shall be considered if (…) substantial quantities of potentially toxic or reactive degradation products and leachables are likely or known to be released from a medical device into the body during clinical use’ (6.2.2.14).
Sklep
Annex A (informative) of the standard, which includes a table describing the biological evaluation tests to be taken into consideration with regard to the nature and duration of contact with the human body, does not explicitly cover ingestible medical devices.
Iz podatkov v priglašeni odločitvi francoskih organov, posvetovanj z zainteresiranimi stranmi in ob upoštevanju vseh navedenih ugotovitev je razvidno, da so francoski organi upravičeno menili, da pripomoček lahko škoduje zdravju in/ali varnosti ljudi, in so zato upravičeno sprejeli začasen ukrep, da se pripomoček ne daje več na trg in se umakne s trga na ravni distributerjev –
It states that ‘Table A.1 is a framework for the development of an assessment programme and is not a checklist’ and that ‘In addition to the framework set out in Table A.1, the following [i.e. the tests to be carried out] should be considered based on a risk assessment (…)’.
SPREJELA NASLEDNJI SKLEP:
Standard EN ISO 10993-12 2012: Biological evaluation of medical devices – Sample preparation and reference materials
Člen 1
Point 10.3.2 of the standard, which deals with extraction conditions and methods, indicates that it is necessary to ‘perform extraction using the appropriate extraction vehicle and time/temperature conditions to simulate exaggerated exposure wherever possible.
Ukrep francoskih organov z dne 16. avgusta 2016 v zvezi z medicinskima pripomočkoma Terrafor in Defiligne, s katerim je bilo prekinjeno dajanje navedenih pripomočkov na trg in določen njun umik s trga, je upravičen.
Complete dissolution may be appropriate’.
Člen 2
Annex C (informative) of the standard, concerning the principles of test sample extraction, point C.1, indicates that ‘extraction conditions and application of the extract to test systems should therefore ideally reflect not only actual conditions of use of the products but also the purpose and predictability of the tests’ and that ‘biological tests are carried out to identify hazards and estimate the risks of the hazards occurring in exaggerated use and/or in actual conditions of use […] exaggerated and exhaustive extraction is appropriate for hazard identification’.
Ta sklep je naslovljen na države članice.
Standard EN ISO 10993-18 2009: Biological evaluation of medical devices – Chemical characterisation of materials
V Bruslju, 25. oktobra 2018
Point 5 of the standard states ‘However it is necessary to obtain information demonstrating the extent to which the constituents will be available under the actual conditions of use of the finished product to estimate the risk arising from them’.
Za Komisijo
In the present case it would appear that the manufacturer has used a testing method which does not reflect the actual conditions of use of the device.
Članica Komisije
In particular, the method used to determine the quantity of lead released, which involves using an extraction volume of only 12 ml of water and using only acidified water without a bolus or an adequate (dynamic) environment, is not representative of the actual conditions of use of the device, namely ingestion with a greater quantity of liquid, the presence of a bolus and the progress of it all through the digestive tract.
UL L 169, 12.7.1993, str. 1.
Moreover, it would appear that the manufacturer did not use another testing method, in particular tests in humans (in vivo), making it possible to determine the level of lead actually found in the bloodstream.
Navedeno poročilo je naslovljeno „Addendum to risk assessment No 164726 from 17 February 2017“.
It follows that the manufacturer does not show that the quantity of lead released is low and/or less than the reference threshold in Guideline ICH Q3D.
V zvezi z zaščitno klavzulo iz Direktive 2006/42/ES Evropskega parlamenta in Sveta z dne 17. maja 2006 o strojih in spremembah Direktive 95/16/ES (UL L 157, 9.6.2006, str. 24) glej zlasti sodbo Splošnega sodišča z dne 15. julija 2015, CSF/Komisija, T-337/13, ECLI:EU:T:2015:502, točke 46, 79 in 80.