The approval of a medical technology device requires absolute transparency - at least as far as the critical parts are concerned. You will become particularly aware of this when your RA department, the ladies and gentlemen dealing with the approval requirements, will reach out with their questions. Does the product contain phthalates? Or SVHC substances? What about biological substances? The list of possible choices is long and they vary in their probability of occurrence depending on the product. It's only natural that one person does not know all of them.
In order to provide a better overview of the various inquiries of relevant substances, we now want to dedicate some time to the small things in life, to be precise, we want to take a look at the particle level of medical devices. Some of the following terms have been in use for years, others are newly introduced by the MDR
1. The inquiries known so far
The term "Substances of very high concern" was established within Regulation 1907/2006, better known as the REACH Regulation.
These substances are chemical compounds with particularly hazardous properties. According to article 57 these are:
- CMR substances: carcinogenic (cancer-causing), mutagenic (genotype changing) and reprotoxic (influencing normal reproduction - also known as teratogenic) substances
- PBT substances: persistent, bio accumulative and toxic substances
- vPvB substances: very persistent and very bio accumulative substances
- substances suspected by scientific evidence of having serious effects on human health or the environment and of being as worrying as the substances listed above
The European Chemicals Agency publishes a list with substances that are affected by the regulation. This list is updated twice a year and can be found here.
The candidates on this list will be subject to further review and may eventually end up in Annex XIV "List of substances subject to authorisation" of the REACH Regulation. This then makes the substances subject to authorisation, with the following obligations for their suppliers:
- providing a safety data sheet
- information on safe use of the product
- response to consumer enquiries within 45 days, and
- notifying ECHA if the article they manufacture contains a substance of very high concern in quantities exceeding 1 tonne per producer/importer per year and if the substance is present in the articles concerned in a concentration exceeding 0,1 % by mass (w/w)
And this is the final element of the inquiry of the approving authority or your customers for a so-called "REACH declaration" or "SVHC declaration". They would like to receive a confirmation whether your product contains candidates or substances that are actually subject to authorisation in accordance with the Regulation. If you gain new knowledge, e.g. through your supplier, it is your responsibility to inform your customers about it. ECHA also provides information on this.
Did you know: this also applies in case your product does not contain any substances subject to authorisation, but contains substances that are subject to a restriction in accordance with Title VIII of the Regulation. The current list can be found on the ECHA homepage as well.
Phthalates are a subgroup of plasticizers used in particular in the manufacture of plastic products. They belong to the most commonly used group of plasticizers, however, for some phthalates it is feared and even proven that they feature properties harming health and the environment. The following phthalates are attributed to carcinogenic, mutagenic and reprotoxic properties as already described in the REACH Regulation and are therefore also listed in this Regulation:
- DEHP = di(2-ethylhexyl)phthalate
- DBP = dibutylphthalate
- DiBP = Diisobutylphthalate
- BBP = benzyl butyl phthalate
In addition, there are restrictions on the use of the following phthalates in products used with infants:
- DEHP, DBP and BBP as well as diisononyl phthalate (DINP), diisodecyl phthalate (DIDP) and di-n-octyl phthalate (DNOP)
The presence of carcinogenic, mutagenic or reprotoxic phthalates has become a mandatory labelling requirement under Directive 93/42/EEC, introduced in 2007 by Regulation 2007/47/EC.
- "If parts of a device […] contain phthalates which are classified as carcinogenic, mutagenic or toxic to reproduction, of category 1 or 2, in accordance with Annex I to Directive 67/548/EEC, these devices must be labelled on the device itself and/or on the packaging for each unit or, where appropriate, on the sales packaging as a device containing phthalates.”
In addition to DIN EN ISO 15223-1, DIN EN 15986 should be applied for product labelling.
Article 10.4 "Substance" is important for the regulation of phthalates by the MDR. Explicitly, 10.4.3 states that the "relevant scientific committee" has to be delegated by the Commission and must submit a guideline on phthalates by 26 May 2020. This does not yet indicate how the EU will continue to deal with phthalates, but a relaxation is hardly to be expected. Therefore, as a manufacturer it is already recommended to be aware of the presence of any phthalates in your products.
That way, the next declaration can be created, stating whether your product contains phthalates or not, without big question marks.
Here, it will be easier for most manufacturers to decide whether their product contains a so-called biological substance or not. These are either "tissues of animal origin" or "human blood derivatives". Since these are exceptional components, usually every person in charge knows whether they are affected by this regulation or not, nevertheless we would like to devote some time to this confirmation for the sake of completeness.
For medical devices manufactured using non-viable animal tissue or products derived from non-viable animal tissue, Directive 2003/32/EC must be followed, if the device has body contact which goes beyond contact with intact skin. The directive specifies the requirements for this particular product category and therefore applies in addition to 93/42/EEC.
If a medical device contains substances or derivatives derived from human blood (medicinal products or components derived from human blood or human plasma) as defined in Directive 2001/83/EC, the European Medicines Agency shall be involved in the authorisation process in addition to the notified body.
According to section 6.2 of Annex II of the MDR on the structure of technical documentation, in the case of products utilising “tissues or cells of human or animal origin or their derivatives”, the relevant information shall be attached. However, it may also be assumed that some authorities (domestic or foreign) expect as a matter of principle a statement at this section as to whether such substances are contained or not.
2. The new inquiries introduced by the MDR
Nanomaterial according to MDR
For many years, the term "nanoparticles" has been commonly used in advertising as a general term for very small particles which are also being said to have magical powers. The reasoning of the MDR, however, includes the following statement: "The risks and benefits of using nanomaterials in products have not been scientifically clarified". First of all, it is therefore necessary to introduce a common definition in accordance with the Commission Recommendation 2011/696/EU.
This then reads in §2 point 18 as follows:
"Nanomaterial" means a natural material resulting or produced during processes, containing particles in an unbound state, as an aggregate or as an agglomerate and in which at least 50 % of the particles in the number size distribution have one or more external dimensions in the range from 1 nm to 100 nm. Fullerenes, graphene flakes and single wall carbon nanotubes with one or more external dimensions below 1 nm should also be considered as nanomaterials;
The possible states in which nanomaterials can be found are also defined in more detail:
- (19) 'Particle' as defined in point 18 means a tiny particle of a substance with defined physical boundaries;
- (20). agglomerate as defined in point 18 means a collection of weakly bound particles or aggregates in which the resulting surface is similar to the sum of the surfaces of the individual components;
- (21) aggregate' as defined in point (18) means a particle of firmly bound or fused particles
If products or components fall under these definitions, the new classification rule 19 must also be applied:
All products containing or consisting of nanomaterials are classified as follows:
- Class III if they have a high or medium potential for internal exposure;
- Class IIb if they have a low potential for internal exposure, and
- Class IIa if they have an insignificant potential for internal exposure.
And for demonstrating conformity with the basic safety and performance requirements, the following requirement is to be adhered to:
Unless they come into contact only with intact skin, devices shall be designed and manufactured in such a way as to reduce as far as possible the risks associated with the size and properties of the particles which penetrate or may penetrate into the patient's or the user's body. Particular attention should be paid to nanomaterials.
Currently, there is no practice or requirement for a separate declaration on the presence of nanomaterials. However, practical experience will show whether this will become common in the future or will be covered in a joint declaration all around the material properties addressed in this article.
CMR substances in the MDR
CMR substances. The observant reader will now say: We already had this! Well, the term CMR substances was already used and explained at the beginning in the context of SVHC substances. In the context of the MDR there is no separate definition under §2, but in Annex I there is an indirectly linked basic requirement:
The products, or the constituents or materials used in them, [...] may contain the following substances in a concentration higher than 0,1 % by mass only if justified in accordance with section 10.4.2:
- carcinogenic, mutagenic or reprotoxic (CMR) substances of category 1A or 1B as defined in Part 3 of Annex VI to Regulation (EC) No 1272/2008 of the European Parliament and of the Council (1 ), or
At the time, this Regulation had included an amendment to the REACH Regulation. Nevertheless, manufacturers should carefully check whether the sum of CMR substances is congruent in both cases. A holistic view is certainly advisable.
Also the justification according to requirement 10.4.2 wants to be neatly elaborated and available just in case. A mere explanation of the presence is not sufficient, but must be part of the technical documentation according to Annex II 6.2.d). In addition, an appropriate precautionary note according to the essential requirement 23.4.s) must also be indicated on the device to inform the patient and user of the presence.
3. Future inquiries
Just stay up-to-date
You should always stay up-to-date and know whether there were relevant innovations for your products or not, based on the fact that all definitions build the basis for the explanations or application justifications, with the result that previously unaffected materials or components could be affected in the future. These regulations are subject to the constant changes of technical progress and can be revised, supplemented or tightened up. In the case of nanomaterials, for example, the Commission is empowered to adopt delegated acts amending the definitions. And it is also clear from the various regulations referring to CMR substances that changes can be introduced at any time.
Please note that all data and listings do not have the claim of completeness, are without guarantee and serve the pure information.