(10)

In general, a similar risk assessment as presented in Step 3 above has to be performed for the alternative (substances, materials, designs or medical treatment). An inventory should be prepared in order to be able to evaluate possible alternatives. An alternative could be another substance/material or device design modification, or it could be a clinical procedure (e.g., a process, technique, treatment or modification) or a combination of technical and substance alternatives.

Step 4: Inventory of possible alternatives

Prepare a list of possible alternatives (such as substances, materials, designs or medical treatments) (11).

A description of the alternative scenario (CMR/ED phthalate „non-use scenario”) needs to be presented including identification of alternative substances, materials, designs or medical treatment, e.g. by including consideration of all available information, such as alternative medical devices available on the market, information about independent research, published peer-reviewed studies, systematic literature reviews, risk assessment reports or scientific opinions from relevant scientific committees and the results of in-house research and development. The identification of possible alternatives should be properly documented.

Step 5: Identification of the candidates for assessment as most relevant alternatives for phthalates

The MDR indicates that an analysis of all possible alternatives shall be performed. However, when many alternatives are available it would not be feasible to do an extensive evaluation of all alternatives. It is therefore recommended to select a number of most relevant alternatives based on screening against key criteria for function, performance, toxicity, and overall use in the medical device in question (see below). In addition, analysis of availability and technical feasibility might affect choices for alternatives as well. Preferably a number of alternatives should be evaluated, and justification should be provided when fewer than three alternatives are evaluated.

A preliminary analysis of possible alternative substances, materials or designs or medical treatments should be performed. This preliminary analysis should include a description of their possible use as alternative substance, material, designs or medical treatments.

Justification on how and why alternatives are rejected for further assessment by defining inclusion and exclusion criteria should be provided.

Information/data on functionality (e.g., level of flexibility in tubes) as well as performance and/or chemical safety assessment (e.g., hazard profile) may be used for rejection of the less likely alternatives (see below) and no further risk assessment for the alternative is required. The rejection of the less likely alternatives requires justification and documentation. The compliance to chemical requirements, according to the MDR, should be demonstrated after a positive outcome of the assessment of the functionality and performance.

In addition to the comparison in terms of functionality, technical performance and risks to patients and users, which are critical elements for the benefit-risk assessment, Annex I Section 10.4.2 of the MDR states that the justification for the presence of CMR/ED substances should also be based on an analysis of the availability of possible alternatives. Availability has several aspects, including, for example, the availability of necessary quantity (volumes) of the alternative on the market within a required timeframe and the ability to gain access to alternatives that may be proprietary (e.g. via licensing).

If potential alternatives can be identified, a shortlist of the most relevant alternatives can be established for further detailed assessment with regard to technical feasibility, health benefits, comparison of risks, existing legal requirements, availability, and technical performance. In the event that no alternative is identified, information should be presented on the actions undertaken to identify alternatives.

A compilation of resources and elements in support of chemical substitution and an assessment of alternatives can be found on the OECD webpage:
http://www.oecdsaatoolbox.org/

Step 6: Description of identified most relevant alternative(s) and conclusion on their technical feasibility

CMR/ED phthalates are present in medical devices for a specific purpose depending on the intended use of the medical device. For example, phthalates offer the possibility for fine-tuning the flexibility (e.g., providing optimal flexibility of tubes without kinking) of a PVC-based medical device. In addition, DEHP has a stabilising effect on red blood cells in blood bags, reducing haemolysis during storage and improving transfusion efficacy (Klei et al., 2022). Technical feasibility of an alternative is based on the alternative fulfilling the function of the CMR/ED phthalate. Therefore, it is essential to assess the functional properties in relation to the intended use of the medical device. Besides functionality, performance under intended use conditions should also be considered.

Argumentation shall be provided for justifying why possible substances and/or material substitutes, if available, or design or medical treatment changes, if feasible, are inappropriate in relation to maintaining the functionality and/or performance of the medical device. For example, it might be the case that replacement is possible for one specific functional use, whereas for another functionality the use of the CMR/ED phthalate remains necessary. Other aspects related to the performance of the alternatives also need to be considered, like material processing conditions (Crespo et al., 2007), material quality after sterilisation (Burgos and Jiménez 2009), and possible interaction with drugs in therapeutic infusion systems (Treleano et al., 2009, Salloum et al., 2015, Tortolano et al., 2018).

The benefit(s) should also be considered. An inventory of the benefit(s) of the most relevant alternative substances, materials, designs or medical treatments for patient populations (separately for vulnerable patient groups) should be presented (see Section 8).

The evaluation of the most relevant alternatives identified can be done in a tiered way to avoid full assessments for each candidate alternative. For example, based on the outcome of the functionality evaluation, the choice of the most relevant candidates might be reconsidered, and some might be discarded before performing the risk assessment (see Step 7).

The ECHA guidance on the preparation of an application for authorisation and ECHA formats for Analysis of Alternatives provide more detailed information on how to conduct an initial screening of possible alternatives and how to assess the technical feasibility of potential alternatives. Submitted applications for authorisations contain a number of examples (https://echa.europa.eu/applications-for-authorisation-previous-consultations) of technical feasibility assessments for uses of substances of very high concern.

Step 7: Assessment of the risk of the most relevant alternatives

The risk assessment of alternatives is comparative in nature. Its aim is to assist in determining whether the transition to the alternatives would lead to lower/higher benefit and/or risk to human health for patients when compared to the current use of the CMR/ED phthalates in the medical device. The methodology of the assessment in this step is similar to that in Step 3, as performed for the phthalate to be evaluated with reference to the alternative. For the risk assessment, all available information needs to be used including peer-reviewed publications and regulatory studies. The SCHEER recommends using a WoE approach for performing the risk assessment.

If a number of most relevant alternatives were identified under Steps 1-6, a risk assessment of these most relevant alternative substance/material or designs or medical treatments should be performed. The risk assessment should contain a description of the substance/material (alternative design or medical procedure) exposure of various person groups (e.g., including patients, donors, professional users) for which the medical device is intended to be used (considering single or repeated use). The assessment for vulnerable groups should be included as a separate section. For each subgroup, a different level of risk may be accepted based on the potential benefit of the medical device for that particular group. Risk management measures ((EN) ISO 14971, (EN) ISO 10993-1) and their effectiveness to reduce exposure should be described and taken into account in the assessment.

Exposure estimation

Estimate the possible release of the most relevant alternative substance(s) when used in various treatment modalities. The rate of leaching should be considered when estimating the potential exposure to the alternative substance. Multiple use scenarios (including various types of possible contact) should be considered for estimating exposure of the alternative substance also considering repeated use scenarios (e.g. frequent use of dialyzer) and different population groups. This information should preferably be based on data from direct measurement or on an estimation based on worst-case scenario. The leaching tests should be performed using similar conditions as for the original medical device ((EN) ISO 10993-12, (EN) ISO 10993-18). Scientific argumentation should be provided in case of deviation from these conditions. Some information on the exposure to possible alternative substances for DEHP is presented in Annex 8.

Hazard identification

Identify hazards based on literature, supplier documentation and other information (such as risk assessments performed by regulatory bodies). Describe hazards associated with the most relevant alternative substance/material by considering all relevant toxicological endpoints for acute as well as for repeated dose toxicity including human data.
Identify an adequate point of departure (PoD) for risk assessment, meaning that it should be representative of the route and duration of exposure for the specific medical device under evaluation. In case of a threshold Mode of Action, such a PoD could be the most sensitive no-observed-adverse-effect-level (NOAEL) or lowest-observed-adverse-effect-levels (LOAEL), or a dose that causes a predefined response (Benchmark dose – BMD or BMDL, the lower limit of the BMD confidence interval) obtained by benchmark dose modelling. When there are non-threshold effects (e.g. in the case of genotoxic carcinogens), such a dose descriptor could be a T25 value or the benchmark dose associated with a 10% response (BMD10) (EFSA, 2022). Hazards should be evaluated by a relevant exposure route for the intended use of the assessed medical device.

For the hazard identification, special attention should be on the determination of any potential CMR and/or ED property of the alternative substance used. For further information, consider the ECHA Guidance on the application of the CLP criteria
(https://echa.europa.eu/documents/10162/23036412/clp_en.pdf/58b5dc6d-ac2a-4910-9702-e9e1f5051cc5)
or see Annex VI of the CLP Regulation. ED properties of the alternative substance/material can be described according to the recently published EFSA/ECHA guidance document (ECHA 2018) (12).

These effects may include impacts on fertility, birth defects (e.g., cryptorchidism, hypospadias), developmental effects, and other potential toxic effects associated with phthalates with ED properties and reprotoxic effects category 1A/B. It needs also to be considered that the potential alternative (substances, materials, designs or medical treatments) could also have other hazards than those of the CMR/ED activity. These other hazards and their possible associated risks should be discussed for example by using the EN ISO 14971 and the EN ISO 10993 series. See also (EN) ISO 10993-1 Table A.1. Some information on the health hazards of possible alternative substances for DEHP are presented in Annex 9.

Risk characterisation

Evaluate the risk by comparing exposure levels that are considered safe (i.e. health-based reference values), with the expected exposure (realistic worst-case use scenario) to obtain a Risk Characterisation Ratio (RCR). For obtaining a MoS, compare the expected exposure (worst-case scenario) with the relevant PoD in relation to route and duration of exposure. PoD could be the most relevant and lowest NOAEL, LOAEL, BMDL for threshold substances, or T25 or BMD10 for non-threshold substances. Data on the relevant exposure route of the medical device application (e.g. intravenously) should be used (see also (EN) ISO 10993-1 Table A.1).
It has to be noted that patients may be exposed to medical devices only for a limited period of time. (EN) ISO 10993-17 provides information for estimating a toxicological risk based on tolerable intake or tolerable contact level, using a worst-case estimated exposure for each of the constituents. For medical devices, a tolerable contact level (e.g. for irritation) or tolerable intake (e.g. for systemic toxicity) can be determined by (EN) ISO 10993-17.

By dividing the point of departure for risk assessment by appropriate assessment or uncertainty factors, reference values can be derived, such as DNELs, ADI, TDI or TWI for threshold substances, or DMELs for non-threshold substances. Specifically for ED effects, additional assessment factors have been suggested as proposed recently (Hass et al., 2019). Where a reference DNEL and/or a reference DMEL have already been derived in the context of other EU legislations, the assessment could refer to these derived figures without referring to a detailed assessment of how these data have been derived (e.g. under REACH legislation, Food Contact Material legislation).

The risks can be described by calculation of the Margin of Exposure (MoE) or the Margin of Safety (MoS) for the substances present in a medical device, which is the ratio between the lowest relevant PoD and the expected exposure (e.g. realistic worst-case use scenario) and comparison with an adequate MoS, which quantitatively corresponds to the uncertainty factors used to derive the reference values.
Alternatively, it is also possible to compare the reference values (e.g. the TDI) with the expected exposure (worst-case scenario): when the ratio, known as RCR, is <1 there is no concern, whereas values >1 represent a potential concern (and a refinement of the evaluation could be performed, for example not using the worst case scenarios).
If neither of these procedures is followed, a scientifically-based justification should be provided (e.g. new information/studies).

Perform this evaluation for every patient and other groups for which the device is intended to be used.

Determine and describe acceptability of the risk for the use of the most relevant alternatives. Risks may be acceptable when they are outweighed by the benefits for the patient.

Consider any known adverse events associated with the operation of the device using the phthalate, and whether the potential alternatives might affect these adverse events. These considerations can be based upon a systematic literature review (see MEDDEV 2.7/1rev4).

This exercise has to be performed for each of the most relevant alternative substances identified and/or materials.

There are a large number of phthalates, and some, not yet classified/identified as CMR/ED, may be potentially relevant alternatives for the CMR/ED phthalate used in medical devices. However, these phthalates may have CMR or ED hazardous properties and some are already classified/designated for these properties (see above). Such phthalates might be identified as alternatives when their CMR/ED risk is reduced compared to the phthalate intended to be used. In addition, different non-ortho-phthalate substances have also been proposed as alternative plasticisers. The SCENIHR published an updated DEHP Opinion, including some information on potential alternative plasticisers for DEHP (SCENIHR, 2015). Although many alternatives were potentially available, it was also observed that for many of them, the information on potential risks and the necessary risk assessment was rather limited, precluding their use as alternatives. Some information on the exposure and health hazards of possible alternative substances for DEHP are presented in Annex 8 and Annex 9, respectively.

In the event that the risk assessment of a most relevant alternative cannot be performed when PoD or reference values for the alternative are lacking, documentation should be presented on the actions undertaken to obtain information to characterise the risk, including the outcome (for example, QSAR /read-across could be performed).

Note shall be taken that alternative designs or medical treatments might lead to the adaptation of endpoints for the benefit-risk assessment when compared to the toxicological endpoints of CMR/ED phthalates.

The assessment of the risk should be accompanied by an estimation of the uncertainties in the described outcomes, which might be quantitative (e.g., confidence interval, standard deviation) or qualitative (see Section 10).

Conclude the analysis of the most relevant alternative(s) with a summary describing the possible scenario(s) (see Figure 1).