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Biological evaluation

The purpose of a biological evaluation of a medical 7. m

 inimisation of risks from particles, with special
device is to ensure – from a biological and toxicological attention to nanomaterials (MDR 10.6);
perspective – that the device is safe for both the patient 8. m
 inimisation of risks from aging of the materials
and the user. when used in situations where the device cannot
be maintained or calibrated (such as implants;
The Essential Requirements of the Medical Devices MDD 9.2/MDR 14.2). From a toxicity point of view,
Directive (MDD) and the General Safety and Performance this means that breakdown products of the materials
Requirements of the Medical Device Regulation (MDR) used should be taken into account in the risk
provide some details as to what aspects of biological assessment of long-term devices.
safety of the device should be considered, namely
1. the choice of materials used as regards toxicity EN ISO 10993-1, ‘Biological evaluation of medical devices –
(MDD 7.1/MDR 10.1); part 1: Evaluation and testing within a risk management
2. the compatibility between the materials used and process’, provides guidance on how to perform a
biological tissues, cells and body fluids, taking biological evaluation of a device.
account of the intended purpose of the device
(MDD 7.1/MDR 10.1); However, as biological evaluation is part of the risk
3. minimisation of risks from contaminants and residues, management process of a device, EN ISO 10993-1 should
with particular attention to be paid to the tissues be used in connection with E­ N ISO 14971, ‘Medical
exposed and the duration and frequency of exposure devices – application of risk management to medical
(MDD 7.2/MDR 10.2); the concept minimisation rather devices’.
than acceptable risk is used here as residues, and
contaminants are expected to add risks without any A material for a medical device may appear suitable on
further benefit; the basis of its physical properties, cost and availability,
4. safe use of the device with the substances they but might contain toxic chemical components. Therefore,
will enter into contact with during their normal use strategic thinking manufacturers screen the candidate
(MDD 7.3/MDR 10.3); materials at an early stage to eliminate those that
5. minimisation of risks from substances leaking from the are toxic, and to select those that are sufficiently
device (MDD 7.5/MDR 10.4); biocompatible and nontoxic for their intended use.
6. minimisation of risks from unintentional ingress from Consequently, a precise characterisation of a material
substances into the device (MDD 7.6/MDR 10.5); is an essential step. The final assessment, however,
must be performed on the finished product under actual
conditions of use.

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Sets of tests may be necessary for determining the ƒ List all materials used in the manufacture having direct
potentially adverse or toxic effects of medical devices. or indirect body contact, including auxiliary materials,
The EN ISO 10993-1 test matrix (table A.1) should not additives, process contaminants and residues,
be considered as a checklist for the different tests that leachables, degradation products, other components
have to be performed, but rather as a guide for qualified that interact with the final product, etc., or refer to the
toxicologists who also take into consideration material applicable section of the Technical Documentation
information and historical data from similar devices. Table (4.3 a-f).
A.1 of the EN ISO 10993-1:2018 emphasises that obtaining -W  here appropriate, mention suppliers.
chemical and/or physical information is an important first (Note: Reevaluation is necessary if source or
step in the biological evaluation. Toxicological endpoints specification of the materials used change [ 4.9a].)
are cytotoxicity, sensitisation, irritation or intracutaneous -W  here appropriate, define total surface area
reactivity, systemic toxicity (acute), subchronic toxicity, contacting the body or body fluids.
pyrogenicity (as part of systemic toxicity), genotoxicity, -C  haracterise chemical, toxicological, physical,
implantation and hemocompatibility. Based on a risk electrical, morphological, mechanical properties ­
assessment, further tests need to be considered, e.g. for the materials used (4.2).
tests for chronic toxicity, carcinogenicity, biodegradation, ƒ Describe the manufacturing process or refer to the
toxicokinetics, immunotoxicity, reproductive/developmental applicable section of the Technical Documentation (6.1).
toxicity or other organ-specific toxicities. ƒ If relevant for the biological evaluation, describe the
performance and characteristics of the final product
The manufacturer of a medical device is responsible for as well as physical characteristics (4.3 g, h).
assuring its biological safety and for documenting the ƒ List all known possible biological hazards (4.5).
assessment of toxicological risks.
3. Strategy of the biological evaluation programme
Accepting a certain level of toxicity using a medical The selection and evaluation of any material or device
device implies some level of risk for patients. Therefore, intended for use in humans require a structured programme
the manufacturer has to assess this risk level, and of assessment (4.1), see: EN ISO 10993-1:2018, flowchart (fig. 1).
determine whether or not the benefits of the device
outweigh it. Biological safety cannot be demonstrated adequately
using a ‘checklist’ approach!
Guidance for preparation of
documentation of biological evaluation Toxicological hazard is a property of the chemical
constituents of the materials from which a medical device
according to EN ISO 10993-1:2018
is made, and should be considered in relation to the hazard
identification. Under the risk management framework ­­
1. Purpose/objective
(EN ISO 14971), physical and chemical material
ƒ Purpose of the document
characterisation is crucial for hazard identification
- Mention all relevant standards here.
and risk analysis.

2. Device description
The biological evaluation programme shall address the
ƒ Classification according to MDD/AIMDD/MDR
interaction of:
- Mention the intended use of the medical device.
ƒ the risk management approach with chemical
ƒ Categorisation according to EN ISO 10993-1 based on the:
characterisation (EN ISO 10993-18),
- nature of body contact (Section 5.2 of
ƒ the toxicological hazard identification and risk analysis,
ISO 10993-1:2018. In the following, only standard
ƒ the determination of allowable limits of leachables ­
sections are mentioned in brackets.),
(EN ISO 10993-17) and the overall biological safety
- duration of contact/period of time (5.3).
evaluation.
(The category defines which effects need to be
considered at least [table A.1].)
Furthermore, a thorough evaluation of any existing ƒ Positive results – what to do?
­nonclinical and clinical data or human exposure data, ­ - Verification of results
as well as any experience relevant to the medical device - Chemical characterisation of leachables
shall be made by expert assessors before any further - Overall interpretation of the biological evaluation ­
testing is considered. of the device
- Relevance of clinical use
4. Overview of tests performed in biological
evaluation 6. Justification for tests not performed
ƒ Assign appropriate tests to the biological effects. ­ ƒ The quality and the extent of documentation as well
(Only tests leading to evident results shall be performed.) as the assessment with regard to the intended use
ƒ Chemical analysis for the evaluation of extractables if determine whether or not biological tests shall be
appropriate. (When qualitative analysis alone does not performed with the final product, and to which extent.
provide sufficient data for a toxicological risk analysis to ƒ If the material has a documented safe history of use in
be completed, quantitative chemical analysis is to a specified role that is equivalent to that of the device
be performed and documented [EN ISO 10993-18]. under design, testing might not be needed. Relevant
Measurement of the level of a leachable substance preclinical studies and clinical experience as well as
in a medical device is important in order to allow the actual testing shall be the basis of such a decision (4.1).
assessment of compliance with the allowable limit ƒ Each device should be examined on its own features.
derived for that substance from health-based risk Data may be available from suppliers or in literature. In
assessment [­ EN ISO 10993-17].) this case, full transferability has to be demonstrated. Test
ƒ In vitro and in vivo test methods systems, test sensitivity and concentrations used should
(If the level of a toxic substance is too high, i.e. above the be taken into consideration.
allowable limit, then the device should be evaluated by in ƒ Waiving of tests shall be recorded (7d).
vitro and/or in vivo methods.)
ƒ Testing shall be performed on the sterile final product or 7. Summary/overall evaluation
representative samples taken from the final product, or ƒ Review of available toxicity and prior-use data for each
from materials processed in the same manner as the final material/chemical with body contact (where appropriate,
product (including sterilisation; 6.3.1 a). include data on residual contaminants (e.g. cleaning
ƒ Description of the test samples used aids), additives, catalysts, solvents used in synthesis,
(if known, give LOT/Ref. No., etc.) sterilisation agents and other processing chemicals,
ƒ Statement on the sterile state of the test sample mold release agents, residual monomers, degradation
(If the test sample has not been sterilised, a rationale products, experience from clinical use, etc.)
shall be given that sterilisation has no influence on the ƒ Toxicological risk assessment of leachables
biocompatibility of the final device.) (establishment of allowable limits for leachable
ƒ Give a rationale for the selection of the sample tested. substances [EN ISO 10993-17])
- Worst-case scenario? ƒ Critical evaluation of the literature review (Annex C)
-S  ample size necessary to meet minimum surface area ƒ Compilation of tests performed according to table A.1 –
requirements specified in each test example:
ƒ Assure that no residues coming out of the packaging may
negatively influence the product performance and safety. Test
Protocol No./Project No. Result
Laboratory No./Report date conclusion

5. Test results Cytotoxicity XY/yyyy-mm-dd In this study, under the given

MTT conditions, no substances with
ƒ Copies of test reports need to be submitted. significant cytotoxicity (leading
to a cell growth inhibition of more
ƒ Evidence for test laboratory qualification must be provided than 30 %) were released from the
(e.g. ISO/IEC 17025, accreditation certificate for the test item.

respective method at the time of testing), and methods

must be appropriately validated (4.6, 6.3.2).
ƒ For qualitative results, interpretation and data ­
acceptance criteria shall be given.
ƒ Further relevant information that can be mentioned ƒ Casual problem-solving
in the table: ƒ Dentification of toxicological hazards
- Test sample (part tested), e.g. catheter shaft, balloon ƒ MDR: addressing Requirement 10.4 for CMR and
material, whole device endocrine-disrupting substances
- Specification (polymer type, supplier, trade name, ƒ Early stage identification of irregularities
additives), e.g. PUR, Pellethane® 2363-90A
- Status of test material (final product, sterile) Only performing chemical characterisation of
- Type of body contact, e.g. circulating blood materials is not sufficient
- Contact duration, e.g. limited contact duration ( 24 h)  ith similar processes, historical performance data of the
W
- Standard/norm, e.g. EN ISO 10993-5:2009 device can provide a certain level of assurance. ­However,
- E xtract preparation (medium, surface/mass-to-volume with new products and new processes, there is the need
ratio, temperature, time) for a better understanding not only of the identity of the
- Compilation of tests performed in addition residue, but of the significance of the residue.
ƒ The validity of tests performed according to standards
which have meanwhile been superseded shall be verified One of the greatest challenges in chemical characterisation
by a gap analysis to show whether the product is still in is performing adequate assessment of biological or
compliance with the valid (revised/new) standards. toxicological risks from extractables or chemical residues
ƒ Overall residual risk-benefit evaluation (Annex B.3.3) that can compromise patient safety. EN ISO 10993-17 clearly
ƒ Post-production information (Annex B.3.4) states to the medical device community why and how risk
ƒ Biological evaluation report according to Annex B.4.5.3: assessments are a part of material biocompatibility.
- Summary of the results of the overall evaluation
-C onfirmation that risk analysis and risk control have Why the finished device should be tested
been completed E N ISO 10993-1 specifies testing of finished devices.
ƒ Final assessment of the data reviewed This is important to cover all potential chemical/physical
(The documentation should include an appraisal influences from manufacturing and subsequent processes.
of the toxicological significance of the data. This shall However, it can be helpful to also collect some data
be done by a person experienced in the assessment of on the biocompatibility of the device components.
the biological safety of medical devices. Suitability of the
materials for the intended use should be judged on the Manufacturer‘s experienced the following best practise:
basis that there is sufficient information to provide a 1. to assemble vendor data on candidate materials,
realistic level of assurance that the risk-benefit ratio is 2. to conduct screening of materials,
acceptable or that toxicological risks are not higher than 3. to conduct confirmatory testing on a composite sample
those currently deemed acceptable for existing devices.) from the finished device.

8. Conclusion But there is a risk in testing only a composite sample of

ƒ A final statement of the manufacturer is necessary. ­ the finished device. If an adverse result occurs, it can be
(The manufacturer might conclude that in their opinion, difficult to track down the component causing the problem,
based on the submitted documentation, the product and it may end up by repeating testing on individual
safety is ensured for its intended use.) components. Screening device materials minimises this
risk. Inexpensive nonanimal studies such as cytotoxicity
Some notes for better understanding and hemocompatibility tests can be used to screen device
materials.
Why is a material characterisation important?
2019 © TÜV SÜD Product Service GmbH I PS-MKG/MHS/medinfo/5.3/en/DE

ƒ Part of the assessment of the overall biological safety of Your contact partner at TÜV SÜD Product Service
a medical device (EN ISO 10993-1, ISO 14971) can provide further information.
ƒ First step in the biological evaluation process
ƒ Novel or unknown material Dr. Christina Reufsteck
ƒ Equivalence to known material Phone: +49 89 5008-4196
ƒ Identification of adverse effects Email: christina.reufsteck@tuev-sued.de
ƒ Performance over lifetime (dynamic on-going process)

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