Biological evaluation
ISO 10993-1

Principle of biological evaluation

ISO 10993-1:2018 describes superior steps to be performed sequentially.

1) First, the preparation of the Biological Evaluation Plan (BEP) shall be performed, as the biological evaluation is to be planned as a part of risk management activities. This is in accordance with ISO 14971, which requires planning of such activities. In the BEP, all materials in the product being evaluated are identified and considered in terms of contact type and duration. A detailed physical and chemical characterization is essential to perform a toxicological risk analysis. In addition, a gap analysis is performed to determine which additional tests are necessary.

2) If the gap analysis in the BEP has identified that data on certain aspects of the biological evaluation are missing, appropriate tests should be performed. It should be ensured that qualified laboratories are selected, which are e.g. DAkkS accredited and/or comply with Good Laboratory Practice.

3) The final step is the preparation of the Biological evaluation report (BER), in which, for example, the results from step two are examined to determine whether the previously identified gaps have been sufficiently closed. In addition, the various data are examined to determine whether a data-based statement on the safety of the product is possible. In this way, the necessary conclusions can be made in the BER.

Why do biological evaluations suddenly need to be performed?

The application of any standards in the field of medical devices is and remains voluntary. This is clearly stated in the European standardisation regulation (EU) 1025/2012. The voluntary nature of the application of standards means in practice that the manufacturer always has the possibility to apply the technical solutions included in any standards or even to develop his own technical solutions, provided that it can demonstrate that these different or alternative non-harmonized tools are suitable to meet the legal requirements applicable to the product. The manufacturer can provide such evidence by means of a risk assessment, a gap analysis or similar. Therefore, also in the area of medical devices in the EU, the manufacturer is responsible for whether or not it applies a standard, as part of its overall responsibility for compliance. However, it is generally assumed that the latest versions of standards, with the technical solutions they contain, reflect the "state of the art" [MDCG 2021-5].

In practice, the above paragraph means that the application of standards is indeed voluntary. However, this is rather theoretical, since in most cases the effort to prove at least the equivalent performance level of the other solution and the development of this are more costly than complying with the standard itself.

The requirement to be aligned with the state of the art comes, among other things, from the EU 2017/745 (MDR) in Annex I on the General Safety and Performance Requirements. In addition, requirements for chemical, physical and biological properties (Paragraph 10) are included there. As a manufacturer of medical devices, this path inevitably leads to ISO 10993-1, because even though it is not currently harmonized under the MDR, it still describes in its most current version the path of biological evaluation of medical devices within the framework of risk management. So there is either the option of developing an equivalent solution, proving the equivalence, and then using this solution. Or applying ISO 10993-1 - which requires a great deal of effort in some cases, but is presumably the lesser of two evils.

Nowadays, it is still frequently the case that individual tests on standards from the ISO 10993 series are submitted by manufacturers to the notified body - without considering the link between the results and without fully implementing ISO 10993-1. It is often assumed that ISO 10993-1 is implemented by reading off the tests apparently required for the product from the table in Annex I. However, this alone does not ensure compliance with the standard, and notified bodies verify this more intensely. The result: deviations in audits and reviews of technical documentation.

Biological Evaluation Plan (BEP)

Many factors must be considered to produce a reliable biological evaluation of a medical device. And so, among other things, it is absolutely indispensable that the possible influences of manufacturing and sterilization methods are considered. For example, if excipients are used in manufacturing, they must be identified and included in the considerations.

At the time the BEP will be prepared, the design of the final medical device should be known and should not be changed, so that the biological evaluation can be performed based on it. This also applies if necessary tests are carried out at a later stage. These must be carried out with the final product to ensure transferability to products from series production.

In the context of a new development, however, it is possible that different materials will be tried out on the way to the final product design and replaced by others if they are not suitable. Consideration of biocompatibility aspects should of course be given at an early stage so that a design can be created that can successfully pass the biological evaluation. However, the biological evaluation described here starts at the point where the design is already finalized.

Since ISO 10993-2 contains animal welfare provisions and ISO 10993-1 also follows the principle of identifying existing data instead of constantly generating new ones, a gap analysis and literature search must be carried out. In this way, important information about the materials contained in the product can be identified without conducting tests. The gap analysis then shows which aspects could not or not sufficiently be covered on the basis of the available data, from which necessary tests are derived on a risk basis.

Biological Evaluation Report (BER)

At the time the BER will need to be created, extremely extensive planning has already been carried out as part of the BEP. In addition, the identified gaps were closed and results were collected.

In the Biological Evaluation Report (BER), all data and findings are then brought together and considered with regard to the clinical experience with the product as well as contained materials. From the evaluation of the different endpoints (e.g. cytotoxicity, sensitization, etc.), a conclusion can then be drawn about the biocompatibility of the medical device under evaluation.

The BER is the formal conclusion of the biological evaluation and, with its elaborately derived findings, contains important evidence that is subject to increasingly intensive examination by notified bodies.

Normenreihe der ISO 10993

• ISO 10993-1 Evaluation and testing within a risk management process
• ISO 10993-2 Animal welfare requirement
• ISO 10993-3 Tests for genotoxicity, carcinogenicity and reproductive toxicity
• ISO 10993-4 Selection of tests for interactions with blood
• ISO 10993-5 Tests for in vitro cytotoxicity
• ISO 10993-6 Tests for local effects after implantation
• ISO 10993-7 Ethylene oxide sterilization residuals
• ISO 10993-9 Framework for identification and quantification of potential degradation products
• ISO 10993-10 Tests for irritation and skin sensitization
• ISO 10993-11 Tests for systemic toxicity
• ISO 10993-12 Sample preparation and reference materials
• ISO 10993-13 Identification and quantification of degradation products from polymeric medical devices
• ISO 10993-14 Identification and quantification of degradation products from ceramics
• ISO 10993-15 Identification and quantification of degradation products from metals and alloys
• ISO 10993-16 Toxicokinetic study design for degradation products and leachables
• ISO 10993-17 Establishment of allowable limits for leachable substances
• ISO 10993-18 Chemical characterization of medical device materials within a risk management process
• ISO/TS 10993-19 Chemical, morphological and topographical characterization of materials
• ISO 10993-20 Principles and methods for immunotoxicology testing of medical devices
• ISO/TR 10993-22 Guidance on nanomaterials
• ISO 10993-23 Tests for irritation
• ISO/TR 10993-33 Guidance on tests to evaluate genotoxicity — Supplement to ISO 10993-3