Biological Evaluation of Medical Devices (II) - Update on Standards issues

The first instalment of this review covered the extension of the series of existing ISO 10993 Standards (Parts 1-12), which are primarily biological in nature, to include Parts 13-17 (now 18). This expansion is largely based around the chemical characterisation of materials and represents a subtle movement in the approach to evaluating medical devices. Note that this is contributing to the current strategic discussions about the approach and interpretation of Part 1 of the Standards. This instalment of the Standards Review updates readers on the general issues relating to i) materials characterisation, and ii) characterisation of potential degradation products, i.e. Parts 13-15 and 18. Part 16, relating to toxicokinetic studies, will be discussed in the next instalment.

i) Materials Characterisation (ISO/CD 10993-18)

The first consideration in the selection of materials to be used for the manufacture of any medical device should be ‘fitness for purpose’, especially with regard for the material(s) characteristics and properties (chemical, toxicological, physical, electrical, mechanical and morphological).

Work towards ISO 10993-18 is being considered in terms of chemical and other characterisation (physical, mechanical and morphological). The current draft document specifies a framework for the identification and chemical characterisation of materials used in medical devices so as to provide information relevant to a biological safety assessment.

Its requirements are intended to yield information on the chemical composition of materials used in the manufacturing process and processing additives and residues, device construction materials, and leachable substances from materials used in the device manufacture. It does not cover the identification or quantification of any degradation products. The main clause(s) currently lay out a step-by-step procedure for characterisation testing and reporting; the Annexes summarise the use of chemical characterisation data in risk assessment as a flow diagram and categorise material types.

ii) Framework for Identification and Quantification of Potential Degradation Products (ISO/DIS 10993-9)

This document is currently at final vote stage under parallel procedure in ISO/CEN. It is intended to present the general principles for the design and performance of biodegradation studies and the systematic evaluation of the potential and observed biodegradation products of medical devices, described in 3 ISO draft Standards, ISO 10993-13 (polymers), ISO 10993-14 (ceramics) and ISO 10993-15 (metals and alloys). Note that there is still some underlying disagreement in applicable methodology relating to ISO 10993-15.

ISO 10993-9 is not applicable to viable-tissue engineered products, methods for the generation of degradation products by mechanical processes, or leachable components which are not degradation products. Degradation studies are to be considered if the device is resorbable or is intended to be implanted for >30 days, or an informed consideration of the material(s) system indicates that toxic substances may be released during body contact.

Intended or unintended changes in the bulk material can lead to particulate degradation products and influence surface stability. Such changes can occur during fabrication, sterilisation, implantation (and whilst implanted), intended bioresorption and storage, and due to changes in the physical state (swelling etc). In addition surface release of substances can be induced by various processes, e.g. chemical reaction, migration, de-polymerisation, and peeling etc. Where multi-component systems are being considered, the potential breakdown of structures, de-lamination and migration of substances from one component to another additionally need to be taken into account.

The level of biological tolerability of any degradation products will depend on their nature and concentration, and should primarily be assessed through clinical experience and focused studies. For theoretically-possible, new and/or unknown degradation products, relevant testing will be necessary. In vivo studies are only to be considered in light of the in vitro studies. For well-described and clinically-accepted degradation products, no further investigation may be necessary.