Share |

ISO 10993

Introduction

The Medical Device Industry is one of the fastest growing areas for plastics, with growth rates exceeding GDP growth for several years. This trend is predicted to continue into the future with the ageing population, improvements in plastics technology (both materials and processing), and the development of increasingly innovative medical devices. Despite this significant growth, one thing remains constant. 

The application of any material in a medical device must continue to meet stringent requirements:

  • It must be biocompatible to the levels required for the specific use.
  • It must comply with complex legislative and regulatory requirements.
  • It must comply with environmental regulations.

Biocompatibility

Biocompatibility is a general term used to describe the suitability of a material for exposure to the body or bodily fluids. It is the ability of a material to perform with an appropriate response in a specific application and is very dependent on the particular application or circumstances.  A material will be considered biocompatible (in a specific application) if it allows the body to function without any complications such as allergic reactions or other adverse side effects.  

Biocompatibility is not the same as sterility. Sterility is the treatment of a material to remove or destroy all living organisms (including bacterial or fungal spores), and does not concern itself with the actual biocompatibility of the material. 

If a material is used that is not biocompatible there may be complications such as:

  • Extended chronic inflammation at the contact point or where leachates interact with the body
  • Generation of materials that are toxic to cells (cytotoxicity)
  • Cell disruption
  • Skin irritation
  • Restenosis (narrowing of blood vessels after treatment)
  • Thrombosis (formation of blood clots)
  • Corrosion of an implant (if used)

Lack of biocompatibility can result in disruption of the normal healing processes and additional complications. Biocompatibility is vital for medical devices.

Testing and Assessment

Biocompatibility testing is essential for all materials that will be used in medical devices to minimise any potential hazards to the patient. This should consist of in vitro assessments (studies carried out in an artificial environment) and in vivo assessments (studies carried out in living organisms) that are relevant to the device application. 
Testing should also include a medical device safety evaluation to assess the risks of normal use and any possible misuse of the device.  No single test is sufficient to define biocompatibility and a variety of tests are necessary to determine biocompatibility, depending on the device and application.

ISO 10993/EN 30993: Biological Evaluation of Medical Devices


Medical devices sold in the EU must comply with the EU Medical Devices Directive 93/42/EEC

     This specifies the safety assessment requirements to ensure that patients are not exposed to unnecessary risks. The Directive uses the safety assessments of ISO 10993/EN 30993 (Biological Evaluation of Medical Devices) as a method to define the testing required for devices that are directly or indirectly in contact with the body or bodily fluids. 
Compliance with the Directive is necessary to achieve CE marking of products for sale inside the EU. 

Eighteen parts of ISO 10993 have been issued with more parts under development for future requirements. 

Part 1 of the standard defines how to categorise the safety testing and the other parts define animal welfare requirements, sample preparation and the individual tests. 

The first stage of ISO 10993 is material characterisation. If the material and use are the same as a device that has been historically safe, then biological evaluation may not be required and unnecessary testing can be avoided. For new materials and uses ISO 10993 provides a methodology for choosing a biological evaluation test program.

The test program chosen depends on the ISO 10993 device category. This is based on the material used, the device category and the contact regime. In each category the length of contact is also important in setting the test program. Limited contact is regarded as less than 24 hours, prolonged contact is between 24 hours and 30 days, and permanent contact is greater than 30 days. 

Once the device category, contact regime, and contact timescale have been determined, ISO 10993 suggests the required biological testing for biocompatibility validation. ISO 10993 is not a formal checklist but a guide to the typical information requirements of approval authorities that can be used to design a testing program

United States

There are some significant differences between practice in the USA and the ISO but the test methods used are very similar. Generally ISO test results are acceptable for applications in the USA.

United States Pharmacopoeia (USP)

The USP has largely been superseded by ISO 10993 but some manufacturers have used the USP in the past for testing medical devices. This was primarily the USP 88 Biological Reactivity Tests for in vivo testing to rate plastics in Classes I to VI. These tests measured the biological response of animals to the plastic by direct or indirect contact, or by injection of extracts from the material. 

The tests are:
  • Systemic Injection Test (intravenous and intraperitoneal)
  • Intracutaneous Test
  • Implantation Test
The tests are classification based (Classes I to VI) from the responses to various specified extracts, materials, and routes of administration. The systemic injection test and the intracutaneous test use extracts prepared at one of three standard temperature/time regimes: 50°C for 72 hours, 70°C for 24 hours or 121°C (250°F) for 1hour.

Material Characterisation


Any assessment of biocompatibility requires good material characterisation to ensure that the biocompatibility assessment is dealing with a well-defined material. Without adequate material characterisation, the biocompatibility testing cannot be related to a specific material and is therefore of little use. 

Material characterisation should be used to the extent that it is possible to positively identify the material being used. This is of particular importance with plastics where nominally similar grades may contain varying amounts and types of plasticisers, stabilisers and fillers. These additives are critical in biocompatibility, and not only the material Characterisation

The elements of material characterisation type but the amount of additives must be positively identified. This information is critical in leaching studies where leachates can be toxic or lead to biocompatibility concerns.

One particular aspect of material characterisation is the effect of sterilisation on the plastic. Medical devices may be sterilised once (for single-use products) or subjected to multiple sterilisation's (for multiple use products). Material characterisation should consider sterilisation, and the effect thereof, at an early stage to ensure that the complete product can be sterilised as required with no loss of properties or other deleterious effects.

Chemical testing

Chemical testing for material characterisation can use a variety of techniques such as:

  • Infrared analysis - This can be used to provide detailed qualitative (and semi-quantitative) information on the material present.
  • Extraction analysis - This provides information on potential leachates by a variety of agents.
  • Chromatography - Gas or liquid chromatography can be used to characterise additives, residual monomers and even degradation products from manufacturing.
  • Trace metal analysis - This can be used to identify the presence and amount of trace metals such as lead, tin, barium, etc. which are added as part of the compounding of the plastic.

Mechanical testing

Mechanical testing such as a stress-strain test will identify the basic mechanical properties of the plastic. While not directly concerned with biocompatibility this information enables manufacturers to ensure that the chosen plastic will adequately perform in the application. Mechanical failure in a medical device can be as much of a concern as a biocompatibility failure.

Thermal testing

Thermal techniques such as Differential Scanning Calorimetry (DSC) and Thermal Graphic Analysis (TGA) can also be used as part of material characterisation to identify thermal characteristics such as the melting point (Tm), the glass transition temperature (Tg) and other thermal properties.

Biocompatible Plastics

There is a large range of biocompatible base plastics that can be used for the manufacture of medical devices but this does not mean that all the possible compounds and variants of these plastics are biocompatible. Equally, not all plastics are suitable for the most demanding categories and assessment for each individual application is required. Typical plastics a Fluoropolymers and biocompatibility.

The fluoropolymers, as a group of materials, have excellent biocompatibility and are used in medical applications in a wide variety of ways, such as:

  • Single-lumen Tubing
  • Special profiles
  • Heat shrink tubing
  • Monofilament
  • Multi-lumen tubing
  • Radio-opaque tubing

Biocompatibility with the fluoropolymers is not generally a concern. Many of the materials are approved to USP Class VI, such as PTFE, FEP, PFA, ETFE, and ePTFE.

Summary

Biocompatibility of plastics is a complex area because of the variety of plastics, the additive systems that are available, and the variety of exposure regimes to which they may be subjected.

No possible range of assessment procedures for biocompatibility will ever be able to provide a conclusive judgment of safety - the best that can be achieved is a reasonable assessment based on the current knowledge. The use of plastics in medical device applications, especially the fluoropolymers, will continue to increase, providing more cost-effective solutions to the ever growing demands of modern medical technology.

You must turn on Javascript to use this site