| Dr. Manuela Schwegler
Biological evaluation of medical devices
ISO 10993-1:2018 provides a new intelligent approach to biological safety assessment.
The fifth edition of ISO 10993-1 was already published in August 2018. Even though ISO 10993-1:2018 (Biological evaluation of medical devices - Part 1: Evaluation and testing as part of a risk management system) is not yet harmonised, the consideration of this standard is often already being requested by notified bodies. Especially for medical devices with a high-risk potential, at least a gap analysis is required as part of a conformity assessment procedure. This allows to check whether certain requirements are not fulfilled and whether the biological assessment report should be adapted. The latter depends on whether the non-compliance with the additional requirements can be considered acceptable in the risk management process.
The new standard is to be preferred instead of the harmonized standard (ISO 10993-1:2009) due to the fact that the more recent edition represents the current state of the art. A harmonized standard for the purpose of the Medical Devices Directive (93/42/EEC) is a “technical specification adopted, on a mandate from the Commission, by either or both of these bodies (…)” (referring to the European Committee for Standardization (CEN) or the European Committee for Electrotechnical Standardization (CENELEC)). Conformity with the essential requirements - presumption of conformity – can be assumed when manufacturers use harmonised standards to prevent risks associated with the design, manufacture and packaging of their medical devices. However, harmonisation under the MDR is a long process. According to a list of standards to be harmonised published by the European Commission , the harmonisation of ISO 10993-1:2018 will not be completed until May 2024 at the latest.
Main changes in ISO 10993-1:2018
The additional requirements cover a comprehensive material characterisation, including a detailed description of the manufacturing and cleaning processes and a detailed risk assessment over all materials and processes. The description of the materials involves information on specifications and quality, as well as relevant information on the supplier or contract manufacturer, such as EN ISO 13485 certification. The chemical and physical information is listed in Table A.1 (Endpoints to be addressed in a biological risk assessment) in Annex A of the standard as the only biological endpoint with an X as prerequisite information required for a risk assessment.
This fifth version of the standard makes it clear that biological safety testing should follow a risk-based approach. The first step is to identify biological risks to the patient that may arise from the materials and manufacturing processes used. The risk assessment of the manufacturing process should in particular identify possible contamination and residues. It must be assessed whether these risks are considered acceptable or whether, if necessary, certain particularly critical materials can be replaced by alternatives. Chemical, toxicological, physical, electrical (if applicable), morphological and mechanical properties of the materials should be considered. All risks must be minimised and acceptable when the medical device is used for its intended purpose.
Depending on the conclusions of the material characterisation and on the potential biological risks identified, all other biological endpoints shall be assessed. These are therefore marked with an E for "to be evaluated" in Table A.1 in Annex A of the standard. Obviously, one aim of the new version of the standard is to reduce the number of animal studies. The standard states that animal studies should only be carried out if prior material characterisation (possibly followed by chemical and/or physical analyses) and in vitro studies do not provide sufficient information. As a result, less studies must be conducted as compared to the current harmonised standard of 2009, if adequately justified. However, strategic planning of biological safety testing is necessary to meet the requirements of the standard. A strategic approach, based on scientific justification and following a risk-based approach, is prescribed in the new version of the standard and should be laid down in a biological evaluation plan. In this way, animal studies can be avoided while maintaining or even improving biological compatibility and patient safety.
Biological evaluation plan
Annex B of the standard explicitly requires a plan for the assessment of biological safety. In fact, this requirement is not new: it is already recommended in the harmonised, fourth version of the standard (ISO 10993-1:2009, Annex B): „The evaluation of the biological safety of a medical device should be a strategy planned on a case-by-case basis to identify the hazards and better estimate the risks of known hazards. Testing strategy should include a rationale for the selection and/or the waiving of tests. The rationale should be a clear, concise, logical and scientifically reasoned plan for evaluating biological safety that demonstrates that all biological hazards have been considered and relevant risks assessed and controlled.“
Although the biological evaluation plan is not new, it gains significantly in importance considering the changes in testing strategy with the new standard. It is now already apparent from the summary table (Table A.1-Endpoints to be addressed in a biological risk assessment, Annex A) that each relevant biological endpoint shall be assessed on a risk-based basis. In the plan, a suitable testing strategy for an individual medical device or for a product family should be evaluated and defined. The test strategy shall include a justification for selecting and/or waiving tests.
The best test strategy
For strategic planning, the following questions should be answered in advance:
- How is the medical device classified in terms of type of contact, duration of contact and type of tissue? The categorisation depends on the intended purpose of the product. With regards to the duration of contact, it should be noted that the standard requires consideration of the cumulative duration of contact and, if applicable, the accumulation potential of relevant substances in the body. The categorisation of the medical device determines which biological endpoints shall be considered in the risk assessment.
- Is there an equivalent product with existing biological safety data that can be used for risk assessment? The new version of the standard provides clear specifications for a possible equivalent product: materials, manufacturing and sterilisation processes, geometry and physical properties, type of contact and intended clinical use must be the same. With these strict specifications it can be assumed that only products from the company's own production can be considered as possible equivalent products, since the required information will be difficult to obtain for products from competing manufacturers and, in addition, such similarity between products from different manufacturers can be excluded in most cases.
- Is there a worst case product in a product family in terms of materials, manufacturing processes and/or contact duration with which - representative for the whole product family - all tests should be carried out? When choosing a worst case product, the product with the highest biological risk in clinical use must be identified.
Once these basic strategic questions have been discussed, the conduct of the biological evaluation can be planned.
Assessment of biological endpoints
The biological evaluation plan shall specify the data to be used for the risk assessment of each biological endpoint which is relevant for the medical device concerned. The relevant biological endpoints are taken from Table A.1 of ISO 10993-1:2018 (annex A) and are based on the categorisation of the product in terms of nature and duration of body contact. The risk assessment may be carried out with the use of different sources of information:
Scientific literature, material data sheets and entries in databases such as PubChem or ECHA: information on the materials used, including manufacturing additives, packaging materials and cleaning agents may be sufficient for a written assessment of the safety of the materials. Chemical, toxicological, physical, electrical, morphological and mechanical properties of the materials are relevant for material characterisation. If necessary, a cleaning validation should also be included to show that no residues from the manufacturing process or packaging material are present on the final product. In addition, scientific literature can be used to address biological endpoints. It is a prerequisite that the study used was conducted with a sufficiently similar material or product under comparable conditions of use (intended purpose).
Studies can therefore be waived by referring to the toxicological risk assessment of materials and manufacturing and toxicology data in the literature. In addition, scientific literature can be used to address biological endpoints. It is a prerequisite that the study used was conducted with a sufficiently similar material or product under comparable conditions of use (intended purpose).In addition, scientific literature can be used to address biological endpoints. It is a prerequisite that the study used was conducted with a sufficiently similar material or product under comparable conditions of use (intended purpose).
- Chemical analysis (Extractables & Leachables, E&L studies), physical characterisation: If it is apparent from the preceding material characterisation that a hypothetical worst case release of chemicals for any component would exceed the safety threshold, chemical analyses must be carried out. Here, the duration and type of contact must also be considered. If the result of the previous risk assessment is that relevant threshold values can be exceeded, extraction and migration studies should be planned according to the specifications of ISO 10993-18 ("Chemical characterisation of materials for medical devices within a risk management system") to detect extractable and leachable substances. The results of the chemical analysis shall be toxicologically evaluated according to ISO 10993-17 ("Establishment of allowable limits for leachable substances"). Physical investigations should be planned according to ISO/TS 10993-19 ("Physico-chemical, morphological and topographical characterization of materials") or - in the case of nanomaterials - according to ISO/TR 10993-22. Physical properties are particularly relevant for implants and medical devices that come into contact with circulating blood.
The results of chemical and/or physical analyses - together with the preceding risk assessment of the materials and manufacturing processes - can justify the omission of animal testing. For example, systemic toxicity studies may be considered unnecessary if no critical levels of leachable and potentially toxic substances have been identified.
- Biological tests: If material characterisation, toxicology data in the literature and chemical/physical analysis are not considered sufficiently to adequate assess the biological risk, in vitro tests and, where appropriate, also subsequent in vivo animal studies shall be planned in accordance with the relevant parts of ISO 10993. It is still important to adhere to the 3Rs principle when designing animal studies: Replacement (avoid and replace the animal experiment with another method), Reduction (minimise the number of animals as possible), Refinement (minimise animal suffering and improve welfare).
All tests must be performed “on the final medical device, or representative samples from the final device or materials processed in the same manner as the final medical device (including sterilisation if needed)". The standard also emphasises the order in which the biological tests should be carried out: Animal studies are only to be started once in vitro data were available.
- Clinical experience with the medical device (post-market clinical follow-up, PMCF data): If clinical data are available on the safe use of the device for its intended purpose, they may also be included in the plan. This data includes PMCF studies, analyses of reported incidents and adverse events, customer complaints and registers. However, it is very clear that reliance on the absence of customer complaints is not sufficient to demonstrate good tolerability. An assessment must be made in the biological evaluation plan to determine whether the PMCF data, together with material characterisation and any in vitro tests carried out, are sufficient to assess the biological risk. In this case, animal testing should be avoided.
In accordance with Table A.1 in Annex A and medical device category, the biological evaluation plan should define which information should be used to address each biological endpoint. In addition, other potentially relevant aspects, such as degradation in resorbable implants or the toxicokinetics of leachable substances and degradation products must be considered on a risk-based approach. The results of all analyses and tests performed are collected and evaluated in the biological assessment report.
ISO 10993-1:2018 and MDR
With the new Medical Device Directive (EU) 2017/745 (MDR), the biocompatibility of medical devices is also becoming an even greater focus of notified bodies. Essential requirements regarding biological safety were defined rather concisely in the Medical Device Directive 93/42/EEC (MDD) in Annex I (points 7.1, 7.2 and 7.5). In the MDR, on the other hand, the design and manufacturing requirements relevant to biocompatibility are presented in much more detail (Annex I, Chapter II, 10.1, 10.2, 10.4, 10.6). The general safety and performance requirements describe in detail the requirements for the chemical, biological and physical properties of the product. Further, a percentage value for the presence of CMR substances (carcinogenic, mutagenic or reprotoxic substances) and of substances with endocrine disrupting effects (mentioned here for the first time) is given. The MDR also addresses risks associated with particle size and nanomaterials. All these aspects must be discussed in the biological evaluation. Annex II of the MDR (6.1 b) also stipulates that "(…) the identification of all materials in direct or indirect contact with the patient or user” shall be provided in the Technical Documentation. Physical, chemical and microbiological parameters shall also be described in detail in the Technical Documentation.
Overall, these more detailed requirements for biocompatibility are very much in line with the fifth edition of ISO 10993-1:2018. To demonstrate compliance with the general safety and performance requirements, it is strongly recommended using the new edition when seeking MDR certification. However, since ISO 10993-1:2018 is already state of the art, biological evaluations that are now prepared according to ISO 10993-1:2018 are both MDD and MDR-compliant.
The preparation of an additional document, the biological evaluation plan, may initially appear to be time-consuming. However, an optimal testing strategy - starting with the correct categorisation of the medical device (duration of contact, type of contact), the selection of a worst case product and the risk assessment of each relevant biological endpoint - may be worthwhile if ultimately less or no animal studies have to be performed.
Revisions of other parts of the international ISO 10993 series also clearly show that the reduction and avoidance of animal testing is the desired goal. For the biological end points sensitisation and irritation, the revised standards 10993-10 and 10993-23, which contain alternative in vitro test methods, are expected to be adopted soon. The draft of the revised standard on irritation was already published in May 2019 (ISO/DIS 10993-23:2019-05 - Draft - Biological evaluation of medical devices - Part 23: Tests for irritation). Recently, in April of this year, the draft standard on skin sensitisation was published (DIN EN ISO 10993-10:2020-04 - Draft - Biological evaluation of medical devices - Part 10: Tests for skin sensitization (ISO/DIS 10993-10:2020). This shows that the new approach in biological safety assessment is already on its way.
A risk-based approach and the reduction of animal testing is in line with the current state of the art. We recommend to apply the fifth edition of ISO 10993-1:2018 already today.
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