Background

The Scientific Committee on Medicinal Products and Medical Devices has been asked by DGIII to consider the validity of the position taken by DGIII with respect to the assessment of medical devices that incorporate animal tissues.

Specifically SCMPMD was asked the question

In relation to the use of specified risk materials for the manufacture of implantable medical devices or those devices which come into contact with internal tissues during medical treatment, what are the factors to be taken into account when evaluating the risk/benefit analysis?

During the period in which a working Group of SCMPMD has considered this matter, the position of the Commission relating to Specified Risk Materials has evolved and changed. Moreover DGIII has itself revised its own guidelines on the use of animal tissues for medical devices and draft standards on this subject have been published by CEN during the last couple of years.

The SCMPMD has, therefore, in answering the question quoted above, produced an opinion concerning the general approach adopted by the Commission to the procedures for the assessment of medical devices incorporating materials of animal origin, taking into account the various documents and guidelines currently available.

The Documents Available Concerning Medical Devices Incorporating Materials of Animal Origin

1. Directive 93/42/EEC of 14 June 1993. This is the principal Medical Device Directive that sets out the conditions under which any medical device can be sold commercially in member States. Two other medical device directives, Active Implantable Medical Device Directive and the In vitro Diagnostic Device Directive, have also been published.

2. MEDDEV. 2.5/5, revision 2, February 1999 "Guidelines on Assessment of medical Devices Incorporating Materials of Animal Origin with Respect to Viruses and Transmissible Agents". This document provides guidelines, which are not legally binding, that relate to the application of the Medical Device Directives with respect to the minimisation of risks related to viruses and transmissible agents. This is one of a series of MEDDEV documents concerning medical devices that are still undergoing evolutionary change.

3. EN 1441 "Medical Devices: Risk Analysis". CEN October 1997. This is a standard that specifies a procedure for the manufacturer to investigate, using available information, the safety of a medical device, including in vitro diagnostic devices or accessories, by identifying hazards and estimating the risks associated with the device.

4. Draft prEN 12442 "Animal Tissues and Their Derivatives Utilised in the Manufacture of Medical Devices" Part I "Analysis and Management of Risk", Part II "Controls on Sourcing, Collection and Handling", Part III "Validation of the Elimination and/or Inactivation of Viruses and Transmissible Agents". This is a series of standards prepared by CEN under a mandate given to CEN by the Commission, which specify, in conjunction with EN 1441, a procedure to investigate, using available information, the safety of a medical device manufactured using animal tissues or products derived from animal tissues, which are non-viable or rendered non-viable, by identifying hazards and estimating the risks associated with these devices. The three parts of the standard have evolved during the preparation of the present report and the Working Group has had available to it various drafts and associated documents.

The General Approach of the Medical Device Directives

The Directives themselves do not prescribe features of a medical device that guarantee safety, but rather set out a series of Essential Requirements that are designed to eliminate or reduce risk as far as possible in those devices that are deemed to conform to the requirements.

The Essential Requirements of Directive 93/42/EEC that relate to infection and microbial contamination are as follows:

8.1 The devices and manufacturing processes must be designed in such a way as to eliminate or reduce as far as possible the risk of infection to the patient, user and third parties. The design must allow easy handling and, where necessary, minimise contamination of the device by the patient or vice versa during use.

8.2 Tissues of animal origin must originate from animals that have been subjected to veterinary controls and surveillance adapted to the intended use of the tissues.

Notified bodies shall retain information on the geographical origin of animals.

Processing, preservation, testing and handling of tissues, cells and substances of animal origin must be carried out so as to provide optimal security. In particular safety with regard to viruses and other transferable agents must be addressed by implementation of validated methods of elimination or viral inactivation in the course of the manufacturing process.

8.3 Devices delivered in a sterile state must have been manufactured and sterilised by an appropriate, validated process.

These are very general statements. Absolute conformity to these requirements should ensure minimisation of risks associated with the use of animal tissues in medical devices. SCMPMD agrees with the principles set out in these Essential Requirements and confirms that this is a scientifically sound approach. Naturally the implementation of the Essential Requirements is a matter for Notified Bodies during their assessment of information provided by manufacturers, and for the Competent Authorities, for which far greater detail and specification of procedures is required.

The General Approach of CEN to Risk Analysis of Medical Devices

The scope of EN 1441 stipulates that the standard specifically and solely provides a procedure for the manufacturer to investigate the safety of a medical device by identifying hazards and estimating the risks associated with the devices. It does not stipulate levels of acceptability, nor does it give detailed guidance on the management of risks, nor is it intended to cover decision-making procedures regarding the assessment of indications and contra-indications for the use of particular devices.

The risk analysis procedure involves a series of steps, represented in the standard by a flow diagram, which require

a. The identification of the qualitative and quantitative characteristics of the devices,

b. The identification of possible hazards,

c. The estimation of risk for each identifiable hazard,

d. A determination of whether the risk is acceptable or not, and

e. The availability of procedures by which risk is reduced.

Under (a), the procedure requires a listing of all those characteristics that can affect the safety of a device, and, where appropriate, their defined limits. The standard provides a series of sample questions that could be asked in compiling such a list.

Under (b), the standard provides a non-exhaustive list of possible hazards and contributory factors.

Under (c), the standard requires an estimation to be made of risks in both normal and fault condition, and specifies the use of techniques such as FMEA (failure modes and effects analysis), FTA (fault tree analysis), and HAZOP (hazard and operability study).

EN 1441 has to be recognised for what it is. It provides general guidance for manufacturers to consider the broad nature of the risks that may be associated with their devices but cannot by its very nature stipulate what a manufacturer has to do in order to accurately predict adverse clinical outcomes with respect to any device. It is for this reason the EN 1441 cannot by itself satisfactorily address any of the risks associated with the use of animal tissues or their derivatives in medical devices since these risks are highly specific and not necessarily predictable from general considerations of material and device characteristics. The series of CEN standards relating to animal tissues have been produced in order to address the difficulties of relying solely upon EN 1441 with respect to animal issues.

In particular the standard determines that the risk analysis of such devices should take into account the following factors:

- The justification of the use of animal-derived material taking into account the expected clinical benefit and residual risk

- The point at which viable animal tissues or derivatives are utilised in the manufacturing process

- The ability of the medical device manufacturer to demonstrate that the medical device, at the time it is placed on the market, contains no viable animal tissues

- The quantity of material, the contact surface area and the type of tissue coming into contact with body tissues and fluids

- The precise intended use of the animal tissue or derivative

- The origin, species, age and feeding of the animals

- The veterinary control of animals

- The source location within the animal

- The characteristics of production processes that use materials pooled from more than one animal

- Variations in the initial bioburden of sourced tissue

- The possible presence of toxic residues relating to any manufacturing process

In relation to the possible hazards associated with this use of animal tissues or their derivatives the standard indicates that particular attention should be given to the following points:

- Potential contamination by bacteria, moulds, yeasts, parasites, viruses and/or transmissible agents and their susceptibility to elimination and/or inactivation during processing.

- Potential for contaminants on the finished materials which may cause an undesired pyrogenic, immunological or toxicological reaction.

- Potential for the finished material in itself to cause an undesired pyrogenic, immunological or toxicological reaction.

In relation to the requirements for risk management the standard indicates that this should be implemented by taking into account separately the risks related to viruses and transmissible agents, the details of which are provided in parts II and III of the standard. With respect to risks related to bacteria, moulds and yeasts, reference is made to other EN standards which deal with normal procedures for the control of such infections and with respect to undesired responses of the recipient to the materials per se, such as undesired toxicological reactions, reference is made to the series of standards for the biological testing of medical devices (EN 30993).

Part I of this standard prEN 12442, as summarised above, provides effective guidance with respect to the procedures for risk analysis and risk management. SCMPMD considers that this outline procedure is, on the basis of current scientific information, adequate to meet the requirements for minimising risks associated with the use of animal tissues in medical devices.

The details of these procedures are given in Parts II and III. Part II covers in significant detail the requirements for quality systems association with the use of animal tissues and makes a number of important points. First, the standard makes it clear that the risk of transmission of certain diseases is dependent on the source species and possibly strain. It also emphasises that the procedures adopted before, during and after slaughter should not prejudice the risk reduction provided by sourcing, particularly through the avoidance of cross-contamination.

Wherever possible the sourcing of animal material should be subject to control and individual inspection by a veterinarian. If individual animals cannot be inspected justification has to be provided. All animals should be subject to ante-mortem veterinary inspection and certification.

The standard indicates that there should be documented agreement between the manufacturer and supplier of the material of animal origin in relation to their limits of responsibility. The manufacturer also has to give special consideration to the certification and traceability relating to materials of animal origin if pooled at the abattoir or during a subsequent procedure. The limits of pooling permitted have to be justified and documented. More generally the manufacturer is responsible for ensuring that the handling of the material at all times is conducted in accordance with documented procedures that minimise the risk of cross-contamination.

SCMPMD considers that this particular standard provides adequate detailed guidance on the procedures for sourcing, collection and handling of animal tissues that minimise the risks of the transmission of viruses or to other agents from animals to the recipients of medical devices.

Part III of prEN 12442 provides details of the procedures for the validation of processes aimed at the elimination and/or inactivation of viruses and transmissible agents. The standard draws attention to the fact that appropriate quality systems (e.g. EN ISO 9001 and EN ISO 46001) have to be in place to control all stages of manufacture, elements of which are relevant to procedures in this standard. However, this particular part of the standard has been written on the basis that the manufacturing processes for medical devices fabricated from animal tissues have to be considered as "special" processes according to the ISO 9000 and 46000 series of standards for quality systems in view of the fact that the results cannot be fully verified by subsequent inspection and testing of the product. The following factors have therefore to be considered:

- Definition of the process(es) and materials to be used;

- Adequate inactivation validation before routine use

- Performance monitoring of the process during manufacture;

- Appropriate equipment maintenance;

- Staff training, etc.

The standard refers to a series of general requirements concerning documented procedure, personnel, calibration of instrumentation, equipment and ancillaries.

The procedures identified in this standard involve a literature search and an elimination and/or inactivation study should the need for this be identified by the literature search.

The literature search shall identify investigations into the elimination and/or inactivation capacity of the proposed manufacturing process. The manufacturer is required to justify the selection of the studies from the literature with reference to inclusion criteria. The literature search should establish precise definitions or questions to be addressed and should be comprehensive.

Technical information from the literature search shall be used to optimise the decision of an inactivation and/or elimination study. Particular attention is drawn to difficulties of extrapolation, and to the problems posed by the intrinsic variability of materials of animal origin and of the manufacturing processes, which can lead to misinterpretation of the validity of published data.

The manufacturer has to demonstrate whether the literature search provides an indication of which inactivation and/or elimination steps are likely to be effective with respect to viruses or transmissible agents. If the need for an elimination and/or inactivation study is identified, this shall be performed so that it substantiates the effectiveness from the selected steps of manufacture against selected agents. The standard provides detailed guidance on protocols for these studies. These protocols should detail the identified risks associated with the tissue in question, the identification of relevant agents, the rationale for the choice of particular combinations of model agents, the definition of the manufacturing stage chosen to eliminate and/or inactivate the relevant viruses and transmissible agents and details of any scaling down process.

SCMPMD recognises that this standard provides a logical process for the identification of procedures for inactivation and elimination and their validation. It is not believed that superior guidance could be provided on the basis of current knowledge. SCMPMD is concerned, however, that implementation of this standard does require a level of knowledge and skills in sectors of science that have not traditionally been associated with the manufacture of medical devices. All manufacturers of medical devices that utilise animal tissues, however small they may be, should have staff that possess the appropriate skills. Moreover SCMPMD also recognises that application of this standard and consideration of the conclusions drawn place an onerous responsibility on the Notified Bodies, which again may not, by tradition, have extensive experience in these scientific and technological areas.

Detailed Guidance of DGIII in the MEDDEV 2.5/5 Document

As noted earlier this particular MEDDEV document has yet to be finalised. It represents a series of points of guidance concerning the implementation of the various standards and procedures that will permit the Essential Requirements to be met in relation to the use of animal tissues in medical devices. The following are the most important components of this document:

1. The primary principle is to eliminate or reduce risk as far as possible and to provide optimal security, the application of this principle taking into account the concept of benefit/risk ratio and the generally acknowledged state-of-the-art.

2. In particular consideration has to be given to the extent that alternative materials to those of animal origin are available and can be used. At various stages of development of this MEDDEV document the requirement for this consideration to be included in the documentation submitted to a Notified Body has been varied. The current version indicates that the risk analysis report should include a rationale on the use of animal origin material but does not require written justification for the use of animal tissues where adequate alternatives are available. SCMPMD believes that this position should be reversed and that such written justification is essential.

3. When a device contains a substantial component of animal origin or where a component of animal origin is likely to have a significant effect on the properties of the device, the presence of such substance of animal origin shall be stated in the labelling.

4. In order to provide optimal security, minimisation of risks shall address all relevant aspect including the following:

- Animals

- Sourcing

- Nature of starting material used

- Methods used to remove and/or inactivate viruses or transmissible agents

- Quantities of animal starting material required to produce one unit of the medical device

- Quantities of material of animal origin coming into contact with the recipient body

- Route of administration

5. For medical devices which cannot withstand an inactivation process without undergoing unacceptable degradation, taking account of the current state-of-the-art, it is necessary to rely principally on sourcing, collection and handling controls, this approach being justified in the documentation submitted to a Notified Body.

6. Particular attention is drawn to the use of defined materials from animal origin for the manufacture of medical devices in the light of decisions taken at Community level with regard to Transmissible Spongiform Encephalopathies. The document recognises that concepts of levels of infectivity are evolving but stipulates that a manufacturer should not involve the use of 'high infectivity tissues', as defined by the WHO, unless the use of such tissues may exceptionally be justified in view of the benefit to the patient and the absence of adequate therapeutic alternatives. SCMPMD is in agreement with this position.

7. With respect to documentation provided to a Notified body by manufacturers, the principal means for assessment of conformance with the requirements of the Directives in relation to the use of animal derived material is the risk analysis report. SCMPMD supports the use of this report but does believe that greater guidance should be given to the process of justification for the use of such material in comparison to synthetic materials. Additional documentation concerning the following shall be provided:

- Information from the risk analysis report on the origin of animal material used (animal species, animal age, animal feeding, nature of tissue, quantity...)

- Statement on the presence of animal materials in the finished device and/or utilised during manufacture.

- Certificates or other documents establishing the origin of the animals,

- Certificates or documents to demonstrate conformance with veterinary inspection criteria and the nature of this inspection

- Documentation related to the slaughtering of animals, and contractual arrangements with the abattoir.

- Documentation and work instructions relating to the collection, transport and storage of the material.

- Documentation relating to controls performed on raw materials and/or final product.

- Detailed documentation describing the inactivation/elimination process and validation of this inactivation/elimination process.

- Manufacturers audit and review of sub-contractors.

8. The documents sets out the expertise that should be possessed by the Notified Bodies. Bearing in mind that Notified Bodies have not necessarily possessed the relevant scientific expertise related to viruses and transmissible agents in the past, SCMPMD believes that this is a crucial point.

Conclusion



SCMPMD believes that the use of general risk analysis standards, the standards related to the use of animal tissues in medical devices and the MEDDEV documents provides a rational approach to the assessment and management of risk in this situation. In order for this approach to succeed in minimising risk, it is essential that fully and appropriately qualified personnel are involved at all levels, including the Notified bodies, and that the system of monitoring is able to incorporate up-to-date scientific data as it emerges.