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Guidance on Biological Risk Assessment, CMR Substances, and Phthalates under EU MDR 2017/745

The European Medical Device Regulation (EU MDR 2017/745) establishes rigorous requirements for the safety and performance of medical devices. A critical aspect of this regulation is the assessment of biological risks, particularly focusing on the presence of carcinogenic, mutagenic, or toxic to reproduction (CMR) substances and endocrine disruptors (ED), including phthalates. This article aims to provide a detailed overview of the requirements and standards for biological risk assessment, classification of CMR substances, and the use of phthalates in medical devices, as stipulated by EU MDR 2017/745.

Biological Risk Assessment (BRA) Requirements

The biological risk assessment is an integral part of the conformity assessment process for medical devices under EU MDR 2017/745. Annex I, Chapter II, Section 10.4 of the regulation details the requirements for substances that pose biological risks:

  • Identification of Hazardous Substances: All CMR and ED substances in medical devices must be identified. This includes phthalates that are known to be carcinogenic, mutagenic, or toxic to reproduction.
  • Quantification and Justification: If such substances are present above 0.1% by weight, their presence must be scientifically justified. This includes assessing alternative substances, materials, or designs.
  • Benefit-Risk Analysis: The overall benefit-risk ratio of the device must be favorable. This involves evaluating the risks associated with the hazardous substances and weighing them against the clinical benefits of the device.

As per the General Safety and Performance requirements laid down in Annex I of Medical Device Regulation 2017/745

Design and Manufacture Considerations: Devices must be designed and manufactured to minimize risks posed by substances or particles that may be released from the device. This includes wear debris, degradation products, and processing residues.

Substance Restrictions: Devices that are invasive or come into direct contact with the human body, administer medicines or body fluids, or store such substances must justify the presence of certain hazardous substances if their concentration exceeds 0.1% weight by weight (w/w).

  • CMR Substances: Substances classified as carcinogenic, mutagenic, or toxic to reproduction (CMR) of category 1A or 1B.
  • Endocrine Disruptors: Substances with endocrine-disrupting properties posing probable serious effects to human health.

Justification Requirements: If these substances are present above the specified threshold, a detailed justification must be provided, including an analysis of possible alternatives and their appropriateness

Classification of CMR Substances

CMR substances are classified into different categories based on their level of risk:

  • Category 1A: Known to have CMR properties based on human evidence.
  • Category 1B: Presumed to have CMR properties based on animal studies.
  • Category 2: Suspected to have CMR properties based on limited evidence.

These classifications help in determining the level of scrutiny and regulatory requirements for medical devices containing these substances.

Phthalates in Medical Devices

Phthalates are commonly used as plasticizers in medical devices, particularly in polyvinyl chloride (PVC). However, due to their reproductive toxicity and endocrine-disrupting properties, their use is strictly regulated under EU MDR 2017/745 and other regulations such as REACH (EC) No 1907/2006. However, certain phthalates have been identified as CMR substances, necessitating careful assessment and justification for their use.

  • Ortho-Phthalates: The term "phthalate" in these guidelines generally refers to ortho-phthalates, which are esters of 1,2-benzendicarboxylic acid.
  • Concentration Limits: Devices must justify the use of phthalates if their concentration exceeds 0.1% w/w. The justification must include an analysis of potential patient or user exposure, possible alternatives, and the rationale for their appropriateness or inappropriateness

Types of Phthalates:

  • DEHP (Di-(2-ethylhexyl) phthalate): Widely used in medical devices but known to have CMR properties.
  • DMP (Dimethyl phthalate) and DEP (Diethyl phthalate): Used for other purposes such as additives in cosmetics and household products but also present in some medical devices.

Regulatory Requirements:

  • Justification for Use: Under MDR Annex I, Chapter II, Section 10.4, phthalates above 0.1% w/w can only be used if there are no suitable alternatives, and their use is justified based on a Biological Risk Assessment.
  • Evaluation of Alternatives: Manufacturers must evaluate and document potential alternatives to phthalates, considering their safety, performance, and suitability for the intended medical application.

Update of Guidelines

The guidelines for BRA of CMR/ED phthalates in medical devices have been updated to reflect the latest scientific knowledge and regulatory developments. Key changes include:

Scope and Terminology: Updated to include recent regulatory developments and the latest scientific evidence.

  • Regulatory Developments: Incorporation of the latest EU regulations and directives related to medical device safety.
  • Scientific Evidence: Updates based on recent studies and findings in toxicology and material science, ensuring the guidelines reflect current understanding and practices.

Framework for Evaluation: Improved framework for assessing alternatives to CMR/ED phthalates, emphasizing the evaluation of the most relevant alternatives.

The framework for evaluating alternatives to CMR/ED phthalates has been significantly improved. This updated framework emphasizes a thorough assessment of the most relevant and viable alternatives, ensuring that safer options are considered and implemented wherever possible.

  • Assessment Criteria: Enhanced criteria for evaluating the safety, effectiveness, and feasibility of alternative substances and materials.
  • Comparison of Alternatives: Detailed methodologies for comparing the risks and benefits of potential substitutes for CMR/ED phthalates.
  • Implementation Strategies: Guidance on the practical steps manufacturers can take to transition to safer alternatives.

Exposure and Health Hazards: Additional annexes detailing exposure to alternatives and their health hazards, as well as progress in the development of phthalate alternatives for specific applications like blood bags.

New annexes have been added to the guidelines, providing detailed information on the exposure to and health hazards of alternative substances. These annexes also highlight recent progress in developing alternatives to phthalates for specific applications, such as blood bags.

  • Exposure Assessment: Comprehensive analysis of how alternative substances are likely to interact with patients and healthcare workers.
  • Health Hazard Information: Detailed profiles of the health risks associated with various alternatives, including both short-term and long-term effects.
  • Application-Specific Alternatives: Updates on advancements in alternative materials for specific medical applications, particularly those with high exposure risks, like blood bags.

Methodologies for Benefit-Risk Assessment

The guidelines outline methodologies for conducting a benefit-risk assessment (BRA), ensuring that the use of CMR/ED substances in medical devices is thoroughly justified.

Weight of Evidence (WoE) Approach

The Weight of Evidence (WoE) approach integrates various sources of evidence to assess the safety and effectiveness of substances used in medical devices. This method ensures a balanced and thorough evaluation of all available data.

  • Data Integration: Combining evidence from toxicological studies, clinical data, and material science research.
  • Balanced Evaluation: Weighing the quality and relevance of different evidence sources to arrive at a comprehensive risk assessment.

Uncertainty Analysis

Uncertainty analysis is a crucial component of the BRA, helping to identify and evaluate the uncertainties associated with the assessment. This includes gaps in data and variability in exposure assessments, ensuring that the final risk evaluation is robust and reliable.

  • Data Gaps Identification: Highlighting areas where information is lacking or uncertain.
  • Variability Assessment: Evaluating the variability in exposure scenarios and potential health outcomes.
  • Risk Mitigation Strategies: Developing strategies to address identified uncertainties and mitigate associated risks.

The guidelines for the biological risk assessment (BRA) of CMR/ED phthalates in medical devices under the EU MDR 2017/745 reflect the latest scientific knowledge and regulatory developments. The methodologies for benefit-risk assessment, including the Weight of Evidence approach and uncertainty analysis, ensure a comprehensive and reliable assessment of the safety and effectiveness of medical devices.

SCHEER (Scientific Committee on Health, Environmental and Emerging Risks), Update of the guidelines on the benefit-risk assessment of the presence of phthalates in certain medical devices covering phthalates which are carcinogenic, mutagenic, toxic to reproduction (CMR) or have endocrine-disrupting (ED) properties, preliminary version adopted on 12 March 2024, final version adopted on 14 June 2024.

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