ISO 10993 and biocompatibility – Material certificates are not enough!

Regulations such as the MDR require proof of the biocompatibility of all materials that come, directly or indirectly, into contact with patients or users.

A test-based biocompatibility assessment provides reference data that provides a very good basis in the event of unexpected problems and that helps to quickly and directly identify unknown causes.

However, there has been a trend in the opposite direction in recent years, in other words away from testing and, therefore, away from device safety.

1. Basics

a) Risks resulting from a lack of biocompatibility

Medical device manufacturers must guarantee the safety of their devices and to minimize potential risks. These risks also include biological risks, for example those caused by:

• Chemicals that are leached from the materials in the medical device and absorbed by the body
• Implants that cause a rejection reaction
• Materials that trigger an allergic reaction
• Materials that are broken down or transformed by the body contrary to the intention of the manufacturer
• Implants and materials that do not grow into the body as desired

This article will describe factors that have a negative effect on biocompatibility.

b) Definitions of terms

ISO 10993 defines the term biological risk as follows:

Biological safety is, therefore, the freedom from unacceptable biological risks.

The definition of the term “biocompatibility” is slightly more cryptic:

The term host response here refers to potential undesirable adverse reactions. The standard states that biocompatibility can be demonstrated through biological testing and an evaluation of the leachables.

2. Regulatory requirements for biocompatibility

a) MDR requirements

The Medical Device Regulation (MDR) puts a lot of importance on biocompatibility, as is evident even in the introductory “whereas clauses”. The corresponding requirements are explained in several places:

Annex I: General safety and performance requirements

Annex I does not explicitly mention the term biocompatibility. However, it does say:

Devices shall be designed, manufactured and packaged in such a way as to minimise the risk posed by contaminants and residues to patients, taking account of the intended purpose of the device, and to the persons involved in the transport, storage and use of the devices. Particular attention shall be paid to tissues exposed to those contaminants and residues and to the duration and frequency of exposure.

MDR, Annex I, Section 10.1

In the very first section of Annex I, the MDR demands that the safety and health of patients, users and third parties are not compromised and that manufacturers must eliminate or reduce risks as far as possible through safe design and manufacture”.

Annex II: Technical documentation

In Annex II, the MDR requires manufacturers to document information on all tests, including the

“test design, complete test or study protocols, methods of data analysis […] test conclusions regarding in particular the biocompatibility of the device including the identification of all materials in direct or indirect contact with the patient or user [as well as regarding the…] physical, chemical and microbiological characterisation.”

MDR, Annex II, Section 6.1.b)

The MDR also contains regulations for the event that the manufacturer does not carry out any tests:

Where no new testing has been undertaken, the documentation shall incorporate a rationale for that decision. An example of such a rationale would be that biocompatibility testing on identical materials was conducted when those materials were incorporated in a previous version of the device that has been legally placed on the market or put into service;

MDR, Annex II, Section 6.1.b)

Annex VII: Requirements for notified bodies

This annex affects manufacturers indirectly at least, because in it the MDR requires notified bodies to:

• Guarantee the competence of the notified body staff with regard to biocompatibility
• Up-to-date knowledge of the manufacturer
  Notified bodies must check a manufacturer’s processes designed to ensure that the manufacturer is using the latest scientific knowledge, including with regard to the biocompatibility of materials.

b) ISO 10993-1

The standard ISO 10993-1 was already harmonized under the Medical Device Directive (MDD) and will remain so under the MDR as well (like the entire family of standards).

Therefore, most medical device manufacturers use this standard for guidance, for example when it comes to the endpoints required for the evaluation of biological safety.

The standard describes these endpoints in Table A.1 in Annex A. The following extract from the table shows some examples of the endpoints that have to be evaluated for a medical device that comes into contact with circulating blood.

The standard makes it clear that manufacturers must ensure biological safety over the entire life cycle of a medical device:

“The biological safety of a medical device shall be evaluated by the manufacturer over the whole life cycle of a medical device.”

ISO 10993-1, 4.7

This part also adds to the requirements for “freedom from unacceptable biological risks” as follows:

“The following shall be taken into account for their relevance to overall biological evaluation of the medical device:  …process contaminants and residues… packaging materials… leachable substances… degradation products…”

ISO 10993-1, 4.3

c) FDA requirements

The FDA provides a detailed guidance document on ISO 10993-1 for biocompatibility evaluation, which describes in detail the procedure for evaluating biocompatibility according to ISO 10993-1 and also specifies additional requirements such as further endpoints for certain product categories. The missing endpoints in ISO 10993-1 are one reason why ISO 10993-1:2018 is only partially recognized by the FDA.

Annex G, “Biocompatibility of Certain Devices in Contact with Intact Skin,” was added to the document version published in 2023 to further support the “3R approach” of reducing, refining, and replacing animal testing.

In September 2024, the FDA also published a new draft of a guidance document on biocompatibility that specifically addresses the performance of chemical analyses.

• Objective
  The objective of the document is to standardize the procedure. It thus narrows the leeway that the standard allows.
• Focus
  The focus of the guidance is on extractable studies, i.e., the identification and quantification of substances that are released into solvents after extraction of the medical device.
• Content
  The guidance offers detailed recommendations for performing the extraction, chemical analysis, and the necessity of comprehensive and precise documentation – in addition to ISO 10993-18.
• Target audience
  The document is primarily aimed at toxicologists, biocompatibility evaluators, and experts in toxicological risk evaluations, but above all, at laboratories that carry out chemical analyses.
• Criticism
  It should be noted that the requirements for the scope of chemical analysis, data quality, and, in particular, documentation are very high. This increases product safety but could result in an disproportionate increase in the effort and cost of laboratory testing, even for proven standard materials.

Conclusion: The requirements for biocompatibility are increasing. It is, therefore, important to select and carry out laboratory tests in a very targeted manner.

3. Processing information on biocompatibility

a) Use available information

Manufacturers often gather together all the available information on the materials used to evaluate their biocompatibility, e.g.,

• material data sheets
• certificates
• results of research on known ingredients and additives
• market experience

b) Add missing information

The information mentioned above is a very good starting point. However, often it does not allow for complete statements on biological safety to be made. For example, there is no information that proves that there are no biological risks from

1. Interactions between the various materials
2. Changes in the materials during the device’s life cycle
3. The processing of materials during production
4. The final cleaning of the device
5. etc.

The list of possible influencing factors is very long. They range from hand disinfectants for employees, to impure raw materials, through to unnoticed cable wear on systems. All the factors in the following word cloud have prevented a positive assessment of biocompatibility in the past.

c) Critically evaluate existing information

Manufacturers should also critically question the reliability of the available information and, for example, clarify the following aspects:

• Test methods and parameters
• Raw materials used to obtain these results
• Transferability of the results

It is good that manufacturers rely on information from competitors. However, when arguing that their products are sufficiently similar and have been used on the market for years without problems, they should consider the equivalence of all parameters such as:

• All substance and material types, such as additives and colorings, and not just the main components
• Production process and production tools
• Final cleaning: process, cleaning agent

This information is often missing and leads to gaps in arguments. Substances not listed in the data sheet are not automatically non-critical.

4. Further practical tips

The following graph reflects the Johner Institute’s experience of the typical problems encountered based on our experience with several thousand medical devices.

a) Do not rely on “established opinions”

Some manufacturers argue that cytotoxicity testing alone would be sufficient to guarantee biological safety or that devices with very short skin or mucous membrane contact should be considered non-critical. Neither of these opinions is correct and they do not comply with the MDR requirements described above.

b) Provide the necessary supporting evidence

Unfortunately, both ISO 10993 and MDR confuse us with several statements that could lead us to conclude that, for some devices, no tests are required. And in other places, there are contradictory claims. That’s why we have two concrete practical tips:

1. What notified bodies want to see
   Notified bodies almost always want to see results of tests for the endpoints listed in the table. Or at least a reason why these tests were omitted/replaced.
2. Effects manufacturers must discuss
   It is usually not possible to exclude in advance effects resulting from cleaning agent residues, production residues, sterilization, adhesive hardening, the evaporation of solvents, effects caused by engraving, printing, material impurities from extrusion, inadequate polymerization, packaging components, inadequate material qualities, impermissible plasticizers or other additives, coloring, etc.

c) Do not use inferior materials

A lot of problems can be avoided right from the start by using high quality raw materials. So, for example, there can be way over 200 different extractables if you use poor quality polyurethane (PUR), although not always all at once. In contrast, if you use a very good PUR, there should be no leachables.

d) Tests: make them risk-based

It takes a lot of experience to be able to set a limit above which a material can no longer be considered acceptable. And, of course, extensive knowledge of limits is essential for this.

Most medical devices do not give any abnormal results with regard to biocompatibility testing. The percentage largely depends on the material and type of device. For devices with abnormal results, however, 90% of the deviations can be argued to be acceptable straight away or after subsequent analysis, or can be rectified by simple optimization.

To better assess the risks, use your experience and knowledge of:

• The device and device type (history)
• Similar devices
• Materials
• Preparation and production of the device

5. Conclusion

Demonstrating biocompatibility cannot be done using data sheets alone. Therefore, tests are necessary.

However, these tests should not be seen as a deterrent because the costs are very manageable. That’s the experience of the biocompatibility experts at the Johner Institute who have tested several thousand medical devices.

Keeping the costs of these tests low is possible if you choose the right strategy and

• carefully research the available information,
• list factors that could have an effect on biocompatibility,
• draw conclusions from both of these and create chains of evidence, and
• use a risk-based approach to minimize the cost of the tests, for example, by avoiding unnecessary tests.

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Change history

• 2024-09-27: Chapter 2.c) added
• 2024-05-02: References to further articles added, editorial improvements
• 2019-07-22: First version of the article created