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Biological evaluation and regulation of medical devices in the European Union
16 Biological evaluation and regulation of medical devices in the European Union A. T. KEENE, SGS, UK
Abstract: This chapter considers biocompatibility as part of the requirements to comply with the EU Medical Device Directives. It gives an EU perspective as seen from an EU conformity assessment body (‘notified body’). The regulatory framework within which biocompatibility assessment falls is described, and how regulatory requirements can be met. Some of the pitfalls manufacturers may find in the process are considered, and finally it provides a model for presenting biocompatibility data in a manner which should result in a successful assessment by a notified body. Key words: Medical Device Directive, 93/42/EEC, conformity assessment, notified body, biocompatibility.
16.1 Introduction This chapter approaches biocompatibility as part of the requirements to comply with the EU Medical Device Directives (MDDs). Its goal is not to revisit the well articulated use of ISO 10993 presented by other authors in this text, but rather to give an EU perspective as seen from an EU conformity assessment body (‘notified body’). It describes the regulatory framework within which biocompatibility assessment falls, how regulatory requirements can be met, and some of the pitfalls manufacturers fall into. Finally it presents a model for presenting biocompatibility data in a manner that should result in a successful assessment by a notified body.
16.2 The regulatory and legislative framework Prior to 1 January 1993, each member state in the EU controlled the safety and marketing of medical devices in its territory in different ways. The introduction of a number of directives (covering such diverse products as toys, recreational craft and civil explosives, as well as medical devices), removed the barriers presented by divergent national technical standards and regulations, and presented a regulatory framework that allowed manufacturers (both within the EU and beyond) to use a single system to bring their 383 © Woodhead Publishing Limited, 2012
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products to market. This system is the ‘new approach directives’, whose fundamental goal is to allow free movement of goods within the single market. The mechanisms used to achieve that goal are based on prevention of new barriers to trade, mutual recognition and technical harmonisation. (Guide to the implementation of directives based on the new approach and the global approach, 2000.) The medical device regulations are part of this group of new approach directives, and cover all medical devices, divided into three directives. These directives are specific to particular device types as defined within the scope of each directive.
16.2.1
Active implantable medical devices
‘Active implantable medical device’ means any active medical device which is intended to be totally or partially introduced, surgically or medically, into the human body or by medical intervention into a natural orifice, and which is intended to remain after the procedure. These products are governed by the active implantable medical devices directive (AIMDD) 90/385/EEC, which covers all powered implants or partial implants that are left in the human body (e.g. heart pacemakers).
16.2.2
Medical devices
‘Medical device’ means any instrument, apparatus, appliance, software, material or other article, whether used alone or in combination, including the software intended by its manufacturer to be used specifically for diagnostic and/ or therapeutic purposes and necessary for its proper application, intended by the manufacturer to be used for human beings for the purpose of: • diagnosis, prevention, monitoring, treatment or alleviation of disease; • diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap; • investigation, replacement or modification of the anatomy or of a physiological process; • control of conception. and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means. These products are governed by the MDD 93/42/EEC, which encompasses the majority of devices, ranging from ‘simple’ products such as tongue depressors and support bandages, to complex orthopaedic implants, CAT scanners and heart valves. It excludes those products that fall within the scope of either 90/385/EEC or 98/79/EC. © Woodhead Publishing Limited, 2012
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In vitro diagnostic medical devices
‘In vitro diagnostic medical device’ means any medical device which is a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, equipment or system, whether used alone or in combination, intended by the manufacturer to be used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body, solely or principally for purpose of providing information: • • • or •
concerning a physiological or pathological state, or concerning a congenital abnormality, or to determine the safety and compatibility with potential recipients, to monitor therapeutic measures.
These products are governed by the In Vitro Diagnostic Medical Devices Directive (IVDD) 98/79/EC, which addresses medical devices used away from the patient to make a diagnosis of patient medical conditions, such as HIV test kits and pregnancy test kits. All of these directives are CE marking directives, i.e. the manufacturer applies the ‘CE mark’ to indicate the relevant essential requirements (ERs) are met and the product is fit for its intended purpose as specified by the manufacturer. This chapter focuses on requirements for biocompatibility as part of the process of meeting the requirements of the MDD, although the principles applied are similarly applicable to the AIMDD. As biocompatibility is only relevant for medical devices in direct or indirect patient contact, products which fall within the scope of the IVDD directive are not addressed. The MDDs have a number of standard elements, but there are two specific areas relevant to how biocompatibility assessments support the process of CE marking medical devices. These are the essential requirements, and the presumption of conformity route to demonstrating compliance with the requirements of the directive.
16.3 Essential requirements Each directive lays down a set of ‘essential requirements’ that have to be met to allow CE marking. These provide and ensure a high level of protection, and must be applied as a function of the hazard inherent to a given product. Essential requirements define the results to be attained (proportional to the inherent hazards
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of the product), but do not specify or predict the technical solutions for doing so. This flexibility allows the manufacturer to choose the way to meet the requirements; it enables the system to be adaptable to innovation and technical progress, but it can be frustrating for device manufacturers who may say ‘just tell me what I need to do to comply’. The essential requirements articulate the fundamental approach to the whole of the product life cycle, with risk management at its heart, and identify all that is necessary to achieve the objective of the directive. Products may be placed on the market and put into service only if they are in compliance with the essential requirements. The essential requirements most pertinent to biocompatibility from 93/42/ EEC are abstracted below, but for a more complete understanding of the process the reader should refer to the complete directive.
16.3.1
Essential requirements related to biocompatibility from the Medical Device Directive 93/42/EEC
I. GENERAL REQUIREMENTS 1. The devices must be designed and manufactured in such a way that, when used under the conditions and for the purposes intended, they will not compromise the clinical condition or the safety of patients, or the safety and health of users or, where applicable, other persons, provided that any risks which may be associated with their intended use constitute acceptable risks when weighed against the benefits to the patient and are compatible with a high level of protection of health and safety. This shall include: •
•
reducing, as far as possible, the risk of use error due to the ergonomic features of the device and the environment in which the device is intended to be used (design for patient safety), and consideration of the technical knowledge, experience, education and training and where applicable the medical and physical conditions of intended users (design for lay, professional, disabled or other users).
2. The solutions adopted by the manufacturer for the design and construction of the devices must conform to safety principles, taking account of the generally acknowledged state of the art. In selecting the most appropriate solutions, the manufacturer must apply the following principles in the following order:
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eliminate or reduce risks as far as possible (inherently safe design and construction), where appropriate take adequate protection measures including alarms if necessary, in relation to risks that cannot be eliminated, inform users of the residual risks due to any shortcomings of the protection measures adopted.
6. Any undesirable side-effect must constitute an acceptable risk when weighed against the performances intended. II. REQUIREMENTS REGARDING DESIGN AND CONSTRUCTION 7. Chemical, physical and biological properties 7.1 The devices must be designed and manufactured in such a way as to guarantee the characteristics and performances referred to in Section I on the ‘General requirements’. Particular attention must be paid to: • •
•
the choice of materials used, particularly as regards toxicity and, where appropriate, flammability, the compatibility between the materials used and biological tissues, cells and body fluids, taking account of the intended purpose of the device, where appropriate, the results of biophysical or modelling research whose validity has been demonstrated beforehand.
7.2 The devices must be designed, manufactured and packed in such a way as to minimize the risk posed by contaminants and residues to the persons involved in the transport, storage and use of the devices and to the patients, taking account of the intended purpose of the product. Particular attention must be paid to the tissues exposed and to the duration and frequency of exposure. 7.5 The devices must be designed and manufactured in such a way as to reduce to a minimum the risks posed by substances leaking from the device. Special attention shall be given to substances which are carcinogenic, mutagenic or toxic to reproduction, in accordance with Annex I to Council Directive 67/548/EEC of 27 June 1967 on the approximation of laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances. Risk management is fundamental to meeting these essential requirements, and it is noteworthy that the hierarchy of risk control articulated in the
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directive is the same as that detailed with the harmonised standard EN ISO 14971:2009.
16.4
Presumption of conformity
As the new approach directives do not specify the technical solutions to be achieved, but rather give a framework of necessary elements required, the directives allow manufacturers to demonstrate they meet the essential requirements by the route of ‘presumption of conformity’. Article 5 – Reference to standards of 93/42/EEC states 1. Member States shall presume compliance with the essential requirements referred to in Article 3 in respect of devices which are in conformity with the relevant national standards adopted pursuant to the harmonized standards the references of which have been publishes in the Official Journal of the European Communities; Member States shall publish the references of such national standards.
Harmonised standards are European standards, which are adopted by European standards organisations, prepared in accordance with the General Guidelines agreed between the European Commission and the European standards organisations, and follow a mandate issued by the European Commission after consultation with Member States. Harmonised standards are published in the official Journal, and listed on the European Commission website (the harmonised standards applicable to 93/42/EEC are listed at http://ec.europa.eu/enterprise/policies/european-standards/ documents/harmonised-standards-legislation/list-references/medicaldevices/). Thus the broad requirements articulated in the essential requirements of the directive can be practically addressed by using harmonised standards. It is important to note that application of harmonised standards, which give a presumption of conformity, is voluntary, and the legal manufacturer can choose an alternative route to demonstrate the product meets the essential requirements. Furthermore, if harmonised standards are used, if appropriate (and suitably justified) the manufacturer can choose to only apply partially apply the standard. However, in nearly all cases, the application of harmonised standards can help the legal manufacturer to meet the essential requirements, and even in the cases where there may not be product or vertical standards, the existing standards can be used to roadmap requirements. Thus the generic biocompatibility requirements for medical devices as laid out in the essential requirements can be demonstrated specifically by using an appropriate
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harmonised standard. In this way EN ISO 10993 can be used to meet the essential requirements.
16.5
Using the EN ISO 10993 series of standards to meet the essential requirements
At the time of writing, 15 of the 20 published parts of the ISO 10993 series of standards are harmonised, including the most important strategic document EN ISO 10993, part 1. Annex ZA from EN ISO 10993-1:2009 details the relationship between the standard and MDD 93/42/EEC, and similarly Annex ZB shows the relationship with AIMDD 90/385/EEC. The tabulation in Annex ZA presents the relevant clause(s)/subclause(s) of the International Standard, and the corresponding essential requirements as summarised in Table 16.1. Thus Annex ZA indicates that if the biological evaluation is performed according to the clauses listed, the legal manufacturer can state a ‘presumption of conformity’, and use the compliance with ISO 10993 as a route to demonstrate Essential Requirements 7.1, 7.2 and 7.5 have been achieved. The Annex ZA does also carry the caveat that ‘other requirements and other EU Directives may be applicable to the product(s) falling within the scope of this International Standard’, indicating the manufacturer should consider their device within the complete regulatory framework, and ensure all requirements are addressed. The other parts of ISO 10993 that have been harmonised similarly detail the relationship between the essential requirements and the standard, but generally have a qualifying remark indicating the requirements can only be partly addressed by the International Standard, and that presumption of conformity depends on also complying with all the relevant clauses/subclauses of ISO 10993-1. Thus the manufacturer is guided to EN ISO 10993-1, to ensure a complete evaluation is performed.
Table 16.1 Using the EN ISO 10993 series of standards to meet the essential requirements Clause(s)/subclause(s) of EN ISO 109931:2009
Essential requirements of Directive 93/42/EEC on medical devices
Clause 4: General principles applying to biological evaluation of medical devices Clause 5: Categorization of medical devices Clause 6: Biological evaluation process Clause 7: Interpretation of biological evaluation data and overall biological safety assessment
Annex I:7.1, 7.2 and 7.5
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16.5.1
Biocompatibility and performance of medical devices
Practical application of harmonised standards to demonstrate compliance with essential requirements
The previous sections have described the EU regulatory landscape within which biocompatibility assessment operates, and the regulatory compliance rationale for ensuring products are appropriately biocompatible. How then does the implicit requirement to ensure a medical device is biocompatible translate into the practical approach the legal manufacturer undertakes in developing a medical device? When the 4th edition EN ISO 10993-1:2009 superseded the 3rd edition of the standard (EN ISO 10993-1:2003), the new version much more clearly emphasised the biological evaluation as part of the overall risk management process. Thus prior to looking in detail at EN ISO 10993, the manufacturer must turn to the fundamental horizontal standard EN ISO 14971:2009. Horizontal standards (also known as basic standards) cover common requirements for all or a wide range of medical device areas such as risk management, labelling and sterilisation methods. Since risk management is fundamental to the essential requirements, this standard lays out requirements for the risk management process for all medical devices. It articulates the need to consider all hazards appropriate for a medical device, and provides specific details addressing the risk analysis process for biological hazards (Annex I of the standard). Annex I presents a very short guidance, which gives some of the basic principles, but in essence points the manufacturer to the ISO 10993 series of standards. A complete risk management report (the output from the risk management process) will always form part of the technical documentation which demonstrates the essential requirements of MDD 93/42/EEC have been met. This document should present a comprehensive assessment of the hazards identified, the risk control measures taken, and overall acceptability of residual risk. However this risk management report is the final output from the risk management process that should operate throughout the development of the product (and the risk management process will continue for the whole of the product life cycle). Thus biological hazards should be clearly identified within the risk management report, with an appropriate risk evaluation and detailed risk control measures. This process has been covered in detail in other chapters, and the reader is directed to Annex B of EN ISO 10993-1:2009 for guidance on how the biological evaluation fits within the risk management framework.
16.5.2
Conformity assessment process
Annex IX of MDD 93/42/EEC sets out the classification rules which manufacturers should use to determine which class a device falls into, according
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to its properties, function and intended purpose. Devices are assigned to one of four classes: Class I for low-risk devices, Classes IIa and IIb for mediumrisk devices and Class III for high-risk devices. It is important to note that the device classification required by 93/42/EEC is not the same as that utilised within EN ISO 10993-1:2009, and the two classification processes are entirely independent of each other. As previously stated all devices must meet the essential requirements of the MDD, irrespective of device class, however there are different conformity assessment routes to demonstrate compliance. In the case of Class I devices that are non-measuring and non-sterile the manufacturer is responsible for ensuring his product complies with the relevant essential requirements of the directive, and makes a self declaration to that effect. All other devices (i.e. Class I measuring or sterile devices, Class IIa, IIb and III) require conformity assessment by a notified body. The type and depth of assessment varies dependent on the classification of the device, but in all cases the notified body will review the technical file/design dossier for a medical device, and judge whether the product meets the essential requirements. Thus the biocompatibility assessment for the medical device will be reviewed by a notified body.
16.6 The notified body A notified body is a certification organisation that the national authority (the Competent Authority) of an EU Member State designates to carry out one or more of the conformity assessment procedures described in the annexes of the MDD 93/42/EEC. A notified body will be qualified to perform all the functions set out in any annex for which it is designated, and the designation may be restricted to specified types of devices and/or Annexes. At the time of writing there are 76 notified bodies designated to perform conformity assessments according to 93/42/EEC within the EU. Notified bodies can have varying levels of experience and expertise, so it is important that the notified body working with the manufacturer has the appropriate knowledge to assess the biocompatibility of the type of device in question. There are many factors to consider when selecting a notified body, which are outside the scope of discussion related specifically to biocompatibility, so Table 16.2 illustrates some key points to consider as part of the notified body selection process. If the manufacturer has chosen to utilise the presumption of conformity route by using EN ISO 10993 to demonstrate compliance with the relevant essential requirements, the task of the notified body is relatively simple, which is to determine whether the manufacturer has complied with the requirements of the harmonised standard. A later section deals with
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Table 16.2 Key points to consider as part of the notified body (NB) selection process Resource
Working together
• Standing and reputation
• Effective working relationship • Designating competent • Flexibility/ authority responsiveness • Scope of certification • Willingness schemes offered (global to support the access to markets) manufacturer • Size • Willingness to meet • Location • Use of subcontractors • Audit schedule
• Accessibility of personel • Approachability • Pre-audit review
Technical
Commercial
• Expertise in product area
• Costs
• Expertise in biocompatibility • Format/content of NB audit reports • Clinical evaluation expectations • Documentation requirements
• Timelines • Ongoing costs
some of the common pitfalls manufacturers can fall into in submissions, and provides an example of the appropriate content of a biocompatibility assessment. In the rare cases where a manufacturer has not chosen to use the presumption of conformity route to demonstrate the product meets the essential requirements related to biocompatibility, it is likely that the notified body will continue to use the harmonised standards as a framework for the assessment, although they cannot audit precisely against the requirements of the relevant harmonised standard. This can lead to a more protracted review process (with potential time and cost implications). Whilst the presumption of conformity route indicates that compliance with the appropriate harmonised standard is satisfactory to meet the essential requirements identified, it cannot be overstated how important it is to utilise the harmonised standard robustly. This is particularly relevant where no vertical (product) standard exists within the EN ISO 10993 series. The risk analysis of the medical device may identify hazards that should be addressed in addition to those described within EN ISO 10993-1 2009. This issue is addressed in more detail later in the chapter.
16.6.1 Technical file evaluation by the notified body The technical file (or design dossier for Class III devices) holds all the relevant information that demonstrates conformity of the medical device to the
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Table 16.3 An example format for addressing the relevant essential requirements (ER) from Annex I of the directive Essential Applicable Harmonised requirement to the standard(s) device applied
7.1 (text of ER can be included)
Yes
Standards Compliance applied demonstrated partially by/comments or in full
EN ISO Fully - Risk 14971:2009 applied management EN ISO report 10993-1:2009 - Biocompatibility EN ISO assessment 10993-5:2009 - Cytotoxicity EN ISO report 10993-18:2009
Location in technical documentation
Section X Risk Management Section Y Biocompatibility assessment Appendix Z Test reports
requirements of the directive (i.e. that all relevant essential requirements are met). The directive does not give specific guidance on the content of the technical file, so the manufacturer can construct the file as appropriate. However, manufacturers may chose to use a standardised format such as the Summary Technical Documentation as described by Global Harmonisation Task Force (GHTF) document SG1 (PD)/N011R20: STED), which will be helpful for the notified body assessment process. For the purposes of the conformity assessment against the essential requirements of 93/42/EEC related to biocompatibility, there are three documents which the reviewer will focus on. The essential requirements checklist This roadmaps how the manufacturer has addressed the relevant essential requirements from Annex I of the directive. Table 16.3 presents an example format. In this case the manufacturer has clearly indicated the presumption of conformity route has been used to demonstrate how the essential requirement is met, thus the notified body reviewer can easily identify the relevant information to review. The risk management report As biocompatibility forms part of the overarching risk management process the risk management report should clearly identify the biological safety hazards and the risk control measures taken to address the risks identified.
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The biocompatibility assessment The documentation that addresses the biological evaluation according to EN ISO 10993 When the manufacturer is preparing the biological evaluation, the regulatory authority/notified body assessor is one of the important stakeholders, so it is helpful to consider their needs. With all regulatory submissions (whether in the EU or worldwide), the regulatory authority is a key customer, and it remains surprising how many manufacturers do not consider the needs of the reader when preparing their technical documentation. Ideally the notified body will have appropriate expertise specific to your type of device, but that is not always the case. Depending on the product type and classification the whole technical file may be viewed by one expert, but in some cases the relevant sections of the technical file will assessed by an expert in biocompatibility, without sight of the whole technical file. Thus the biocompatibility assessment may need to be auditable in isolation from other technical documentation, such as design verification and validation activities. The points to consider when preparing biological safety documentation for review are listed below: • the assessor may or may not be an expert in biocompatibility; • they will know the technology area; • they may not know your product in detail; • they may not know the history of your product; • they will probably be reviewing against the requirements of the EN ISO 10993 series of standards; • they may be considering biocompatibility as part of overall submission; • they will be looking for a coherent thread between risk management and the biological evaluation; • they will be skilled in identifying data gaps, inconsistencies and insufficient/poor quality data. Use of non-validated/non-standard test methodologies Various parts of the ISO 10993 series of standards describe in some detail validated test methodologies, and these should always be the preferred route for demonstrating compliance with the standard. However, it is not so prescriptive as to limit the biological evaluation to only those test methodologies described within the standard, but it is clear that all testing should be scientifically robust. Thus there may be instances where ‘non-standard’ test methodologies are required, and this is acceptable if duly justified (particularly when novel/innovative products are under assessment). However, it is not appropriate to present a biological evaluation using a non-validated
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methodology (such as a novel cytotoxicity test developed in a university laboratory), when the evaluation could be performed using a recognised validated methodology as described in the EN ISO 10993-5). That does not preclude the use of the data generated in the university methodology as part of the background to the biological evaluation, but it should not be used as the pivotal data set. Use of combined performance and safety tests Whilst the primary aim of the ISO 10993 standards is the protection of humans, it also serves as a framework to minimise the number and exposure of test animals, thus where appropriate the combining of studies to address multiple endpoints is encouraged. However this is subject to the primary endpoints of those tests not being compromised by the secondary endpoint. An example of such a study would be a performance evaluation of an orthopaedic implant in a large animal model. Whilst the primary goal of the study might be to assess mechanical performance of the implant, analysis of serum ion levels could provide supporting evidence for the biocompatibility of the medical device. Similarly for drug device combination products (e.g. drug eluting stents), such combined safety and performance tests can provide valuable information on both the performance of the device component, and also relevant pharmacokinetic data to support drug safety and efficacy parameters.
16.7 Common pitfalls in biological evaluations The most fundamental problem observed in some manufacturer’s submissions is the lack of a coherent risk management process, and the biocompatibility assessment, which should be aligned to it. In these cases it appears the risk management process is not at the heart of the device development, but rather a ‘bolt on’ performed to demonstrate regulatory compliance. Thus the risk analysis does not identify all the relevant hazards, and the risk control measures, whilst being valid activities as part of design and development, do not demonstrate management of the risks identified. In these cases the biological hazards are not clearly identified, and there appears no rationale for the subsequent biological evaluation performed. Figure 16.1 presents an example of the product-development process, with risk management operating as the foundation for the product-development process. Over-layered on the risk management are the interactions with the biocompatibility assessment and the new product-development process. To highlight the interrelationship between risk management and biological safety Table 16.4 presents an example of the hazards identified for a wound dressing to be applied to chronic wounds, identified as part of the EN ISO 14971:2009 risk management process.
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Idea
1
Preliminary investigation
2
Detailed investigation
3
Development (fully functional prototype)
4
Scale up and performance
5
Full production and market launch
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Design and development activities
· Literature activities · Early laboratory work
· Early laboratory work · Exploratory work · Prototyping · Technical feasibility · Market research · Focus panels
· Performance (proof of concept clinical trial) · Stability · Sterilisation · Pilot scale/handmade manufacture · Results in design freeze
· Larger clinical trials · Process scale up · Modifications/tweaks
· Market exposure · Adverse reactions · Broaden indications
Biological safety activities
· ISO 10993-1 · Preliminary biological safety input · Material selection · Safety strategy
· ISO 10993-1 · Confirm strategy · Composition/material review · ISO 10993-17 · ISO 10993-18 · ISO 10993-5 · In vitro assessments · Early assessment of novel components if appropriate · Early pre-clinical efficacy studies including safety endpoints
· ISO 10993-1 · All relevant toxicological endpoints evaluated · ISO 10993-relevant part · Assessment following design freeze · ISO 10993-18 · Fully characterise product · Pre-clinical efficacy · Safety endpoints · Combined safety and efficacy studies
· ISO 10993-1 · ISO 10993-18 · Demonstration of equivalence with pilot scale product
· ISO 10993-1 · ISO 10993-18 · Ongoing product modifications · Changes of raw materials · Process alterations · Adverse reactions from market · IFUs
ISO 14971: Risk management
16.1 An example of some of the relationships between the new-product-development process and biological evaluation. At various stages within the development process there are key inputs where the biological evaluation is critical to the successful development of the product. Underlying all activities, risk management forms the foundation for an effective and efficient new-product-development process (IFUs, instruction for use).
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Table 16.4 An example of the hazards identified for a wound dressing to be applied to chronic wounds, identified as part of the EN ISO 14971:2009 risk management process Hazard
Foreseeable sequence of events
Hazardous situation
Harm
Chemical: Device composition
Polyurethane Leachable materials polymeric present in components device do have an not have adverse appropriate effect either biocompatibility locally or systemically
• Pain • Local irritation • Inflammatory response • Sensitisation • Delayed wound healing • Target organ toxicity • Genetic damage leading to carcinogenicity
Physico-chemical Wound contact characteristics materials of materials not adhere to appropriate for wound bed, contact with causing wound tissue damage on removal
• Pain • Local irritation • Inflammatory response • Delayed wound healing
The hazards described fall under the broad description of ‘biocompatible’. However, a common misconception of manufacturers is that a series of biocompatibility tests, as described by EN ISO 10993-1:2009, demonstrates that a product is suitably biocompatible. Using the guidance presented in Annex A of EN ISO 10993-1:2009, the following evaluation tests would be considered appropriate for breached or compromised surface contact device (contact duration C – permanent), and would form part of the hazard characterisation and risk control activities: • • • • •
cytotoxicity (EN ISO 10993-5), sensitisation (EN ISO 10993-10), irritation or intracutaneous reactivity (EN ISO 10993-10), subchronic toxicity (subacute toxicity) (EN ISO 10993-11), genotoxicity (EN ISO 10993-3).
Whilst these assessments would characterise the risks for those toxicological endpoints, they do not completely address the hazardous situations identified, as delayed wound healing cannot be assessed by the evaluations described. Therefore the manufacturer may need to consider an additional evaluation
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not described within the ISO 10993 series of standards, and in this case a wound healing evaluation in an appropriate model would be required to adequately address the risks identified within the risk management process. This point underlines the need for thorough hazard identification within the risk management process (in this case the fundamental performance requirement of a chronic wound dressing that it does not cause a delay in wound healing or significant damage to the wound bed upon removal was ignored). Once appropriate risks are identified, they may well be addressed by using harmonised standards, but those standards should not be utilised in a ‘blinkered’ manner. It is clear from EN ISO 10993-1 that the standard provides a framework for the biological evaluation, and not a rigid test regime, and it is specifically stated within the standard that it is not intended to provide a rigid set of tests methods, including pass/fail criteria. Within the biological evaluation itself, the most common issue is inadequate/incomplete application of EN ISO 10993-1 2009. The standard presents a process flow for a systematic approach to the biological evaluation, which if followed provides a complete evaluation. Unfortunately some manufacturers may view a biocompatibility assessment purely as ‘the tests’, and whilst this view may not be promulgated by contract research laboratories performing testing, it can be perpetuated by the lack of a complete systematic approach encompassing all aspects of the biological evaluation. This can be particularly prevalent in small and medium enterprises (SMEs), where dedicated expertise in biological safety is not available. Whilst manufacturers may not have the expertise in house to complete the biological evaluation, as the legal manufacturer of the medical device under the requirements of the MDD 93/42/EEC it is their responsibility to ensure the product has a complete biological evaluation and thus meets the essential requirements. The ownership of the biological evaluation process remains with the manufacturer (even if the whole biological evaluation is subcontracted to a contract house or a medical device consultant). Thus the fact the supplier of a component material states it is ‘biocompatible’, and may present test data, does not abrogate the responsibility of the legal manufacturer for the biological safety of the finished product. In this case the validity of that data for the finished product use will be challenged, which brings the challenge for the manufacturer of justifying toxicological equivalence. The 4th edition of EN ISO 10993-1:2009 brought welcome clarification to manufacturers, clearly allowing the use of existing preclinical and clinical data, including history of safe use, to meet the requirements of biological evaluation. Thus the use of existing data is encouraged, to avoid unethical additional animal testing (which also has the benefits of reduced time and cost to manufacturers), however the challenge of justifying the acceptability of existing data for a new medical device can be significant. The use of chemical characterisation (EN ISO 10993-18) facilitates demonstration
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of chemical equivalence, which can then be extrapolated to toxicological equivalence (refer to Annex C of part 18 for further detail). Common examples where such toxicological equivalence can be used are generic components that can be used by many different manufacturers (e.g. adhesives for wound dressings, or polyether ether ketone (PEEK) polymer for implantable devices). In these cases the supplier may state the materials are ‘biocompatible’, and have specific test data relevant to the manufacturer’s end use. However, the processing, sterilisation and finished device use are controlled by the manufacturer, which will directly impact on the overall biocompatibility of the medical device. In these instances the manufacturer must justify why the data presented by the supplier (e.g. a polymer sterilised by ethylene oxide), is acceptable for the end use (where the manufacturer may have chosen to use an alternative method of sterilisation such as gamma irradiation). Particularly in the case of polymeric materials, where molecular weight/monomer content can have a significant impact on the biocompatibility of the material, it is likely that chemical characterisation will form part of the justification for equivalence. Further examples of inadequate biological evaluation submissions include those with simple unsupported statements such as ‘it’s only material x, it’s well known to be safe’, ‘my material is approved by y’, ‘my material complies with an ISO standard’, ‘this material has been used safely for years’. Whilst all of these top level statements may be relevant to the overall biological evaluation, they do not stand as an acceptable evaluation alone (and must be supported by objective evidence, not anecdotal comment). EN ISO 10993-1:2009 encourages the use of existing data, but only within the overall framework of the biological evaluation. Similarly, the observation ‘my competitor’s product contains the same material so it must be biocompatible’ is not an acceptable justification of equivalence without substantial supporting evidence and utilisation of biocompatibility data from another source. All of these shortfalls result from inadequate application of the harmonised standard.
16.8 Managing positive results in the biological safety assessment EN ISO 10993-1:2009 emphasises the biological evaluation within the risk management process, and highlights that the standard presents a framework for the biological evaluation, without pass/fail criteria. Similarly as part of the overall risk management process for a medical device, it is the manufacturer’s responsibility to set acceptable risk levels based on state of the art. Thus, if appropriate, positive or equivocal results from biocompatibility studies may be deemed acceptable within the overall biological evaluation. In these instances it is important the manufacturer clearly presents the
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data, with a rationale or hypothesis for the results obtained, and if possible further analysis (perhaps chemical characterisation) to suggest why such a result has been achieved. Two examples are presented below, but there may often be situations where one test performed presents a problematic result. In these situations it is critical the manufacturer presents a robust justification for the acceptability within the overall biological evaluation, and does not ignore the data. Positive test results can often occur when sensitive in vitro evaluations are performed due to the absence of normal physiological and morphological protective mechanisms (e.g. cytotoxicity in a EN ISO 10993-5:2009 MEM elution assay when evaluating a silver wound dressing), which although providing some hazard identification do not preclude the use of the product if other more relevant in vivo data exists. In the example of the silver dressing the cytotoxicity demonstrated is an inevitable consequence of the silver antimicrobial, but the in vitro cytotoxicity does not translate into adverse wound effects in either preclinical porcine models or clinical use. The acceptability of a positive result must be presented as part of the overall risk management assessment, and in that context the biocompatibility of the device may still be acceptable for the clinical use intended. The use of aggressive solvent extraction methodologies as recommended in the Japanese in vitro cytotoxicity and genotoxicity assays, and the guinea pig sensitisation test, can lead to positive results in these tests, which may not be observed when the physiological solvents described in EN ISO 10993-12 2009 are used. Whilst in some instances the results may be a true representation of the biological hazard presented, in other cases the aggressive solvent extraction can lead to the presence of various moieties that would not be present in normal clinical use, and can be considered ‘false positives’. In this situation it may be appropriate to justify the acceptability of these results when presented in the context of additional testing with physiological media and chemical characterisation demonstrating the discrepancies between aggressive solvent extracts and physiological extracts.
16.9 Presenting the biological evaluation within the technical file As previously discussed, for any regulatory submission it is important to consider the key stakeholders of the information presented. In the case of the biological evaluation the assessor will invariably be assessing the content against EN ISO 10993-1 2009, thus presenting the information in a format consistent with the process flow of the standard will facilitate the process. The Appendix in Section 16.12 illustrates a model presentation of data, and reiterates that the biological evaluation is not just ‘the tests’, but a structured evaluation of the data relevant to biological safety.
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16.10 Conclusion Although the MDD requirements can appear convoluted and confusing, there are clear mechanisms to demonstrate the acceptable biocompatibility of medical devices. The use of the ‘presumption of conformity’ process allows the use of international standards that have been harmonised within the EU, thus enabling manufacturers within the EU and beyond to have a consistent approach to biocompatibility. Robust utilisation of both the risk management standard EN ISO 14971:2009 and EN ISO 10993 series of standards will ensure a thorough biocompatibility assessment is performed, which should lead to a successful assessment of the submission by the notified body.
16.11 Sources of further information and advice • European Commission Guide to the Implementation of Directives Based on New Approach and Global Approach http://ec.europa.eu/enterprise/policies/single-market-goods/documents/ blue-guide/ • European Commission Website for Medical Devices, providing extensive guidance documents, including MEDDEVs, borderline considerations and consensus statements http://ec.europa.eu/health/medical-devices/index_en.htm • European Commission Website of Harmonised Standards for Medical Devices http://ec.europa.eu/enterprise/policies/european-standards/ harmonised-standards/medical-devices/index_en.htm • European Commission Website “NANDO”, detailing designation of notified bodies for MDDs http://ec.europa.eu/enterprise/newapproach/nando/ • Notified Body Operations Group Website, detailing various recommendations for processes and documentation http://www.nbog.eu/
16.12 Appendix: model content of the biological evaluation submission •
Product construction/composition – Intended use – List components/materials with direct/indirect body contact – Diagram of product – Auxiliary materials – additives, processing aids, residues – Sterilisation methodology
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EN ISO 10993:1 Classification of device – Nature of contact – Duration of contact Product characterisation – ISO 10993-18/19 – If appropriate analysis of degradation products (EN ISO 10993-9) – If appropriate establishment of allowable limits of leachable substances ((EN ISO 10993-17) Gap analysis – similarity to other devices (if relevant) – Intended use /device properties – Components – Manufacturing – Sterilisation methodology Historical data review – Literature (from legitimate sources such as the Hazardous Substances Database, Toxline, National Toxicology Program etc. Wikipedia is not considered a robust source) – Relevance of literature – Body contact – Duration Pre-existing internal company information – Robust database – Supporting evidence – Preclinical tests from similar devices – Relevance to the device under assessment Selection of biological evaluation test strategy – Rationale – Justification for tests performed/not performed – Description of tested items – Representative sample – Finished device, part of device, raw material – Sample preparation, solvent – Sterilisation of material Preclinical test results – Summary tabulation – Full test reports supplied in appendices
Test Status Sample/ Test sample of test extract performed/ material preparation test system
Standard/ Test lab/report norm number/report date
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Conclusion – Summary of biological evaluation strategy and results – Clear discussion of all data including equivocal results, justify their acceptability – Statement of meeting requirements of EN ISO 10993 – Evidence of incorporation into risk management documentation
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Abstract: This chapter considers biocompatibility as part of the requirements to comply with the EU Medical Device Directives. It gives an EU perspective as seen from an EU conformity assessment body (‘notified body’). The regulatory framework within which biocompatibility assessment falls is described, and how regulatory requirements can be met. Some of the pitfalls manufacturers may find in the process are considered, and finally it provides a model for presenting biocompatibility data in a manner which should result in a successful assessment by a notified body. Key words: Medical Device Directive, 93/42/EEC, conformity assessment, notified body, biocompatibility.
16.1 Introduction This chapter approaches biocompatibility as part of the requirements to comply with the EU Medical Device Directives (MDDs). Its goal is not to revisit the well articulated use of ISO 10993 presented by other authors in this text, but rather to give an EU perspective as seen from an EU conformity assessment body (‘notified body’). It describes the regulatory framework within which biocompatibility assessment falls, how regulatory requirements can be met, and some of the pitfalls manufacturers fall into. Finally it presents a model for presenting biocompatibility data in a manner that should result in a successful assessment by a notified body.
16.2 The regulatory and legislative framework Prior to 1 January 1993, each member state in the EU controlled the safety and marketing of medical devices in its territory in different ways. The introduction of a number of directives (covering such diverse products as toys, recreational craft and civil explosives, as well as medical devices), removed the barriers presented by divergent national technical standards and regulations, and presented a regulatory framework that allowed manufacturers (both within the EU and beyond) to use a single system to bring their 383 © Woodhead Publishing Limited, 2012
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products to market. This system is the ‘new approach directives’, whose fundamental goal is to allow free movement of goods within the single market. The mechanisms used to achieve that goal are based on prevention of new barriers to trade, mutual recognition and technical harmonisation. (Guide to the implementation of directives based on the new approach and the global approach, 2000.) The medical device regulations are part of this group of new approach directives, and cover all medical devices, divided into three directives. These directives are specific to particular device types as defined within the scope of each directive.
16.2.1
Active implantable medical devices
‘Active implantable medical device’ means any active medical device which is intended to be totally or partially introduced, surgically or medically, into the human body or by medical intervention into a natural orifice, and which is intended to remain after the procedure. These products are governed by the active implantable medical devices directive (AIMDD) 90/385/EEC, which covers all powered implants or partial implants that are left in the human body (e.g. heart pacemakers).
16.2.2
Medical devices
‘Medical device’ means any instrument, apparatus, appliance, software, material or other article, whether used alone or in combination, including the software intended by its manufacturer to be used specifically for diagnostic and/ or therapeutic purposes and necessary for its proper application, intended by the manufacturer to be used for human beings for the purpose of: • diagnosis, prevention, monitoring, treatment or alleviation of disease; • diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap; • investigation, replacement or modification of the anatomy or of a physiological process; • control of conception. and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means. These products are governed by the MDD 93/42/EEC, which encompasses the majority of devices, ranging from ‘simple’ products such as tongue depressors and support bandages, to complex orthopaedic implants, CAT scanners and heart valves. It excludes those products that fall within the scope of either 90/385/EEC or 98/79/EC. © Woodhead Publishing Limited, 2012
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In vitro diagnostic medical devices
‘In vitro diagnostic medical device’ means any medical device which is a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, equipment or system, whether used alone or in combination, intended by the manufacturer to be used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body, solely or principally for purpose of providing information: • • • or •
concerning a physiological or pathological state, or concerning a congenital abnormality, or to determine the safety and compatibility with potential recipients, to monitor therapeutic measures.
These products are governed by the In Vitro Diagnostic Medical Devices Directive (IVDD) 98/79/EC, which addresses medical devices used away from the patient to make a diagnosis of patient medical conditions, such as HIV test kits and pregnancy test kits. All of these directives are CE marking directives, i.e. the manufacturer applies the ‘CE mark’ to indicate the relevant essential requirements (ERs) are met and the product is fit for its intended purpose as specified by the manufacturer. This chapter focuses on requirements for biocompatibility as part of the process of meeting the requirements of the MDD, although the principles applied are similarly applicable to the AIMDD. As biocompatibility is only relevant for medical devices in direct or indirect patient contact, products which fall within the scope of the IVDD directive are not addressed. The MDDs have a number of standard elements, but there are two specific areas relevant to how biocompatibility assessments support the process of CE marking medical devices. These are the essential requirements, and the presumption of conformity route to demonstrating compliance with the requirements of the directive.
16.3 Essential requirements Each directive lays down a set of ‘essential requirements’ that have to be met to allow CE marking. These provide and ensure a high level of protection, and must be applied as a function of the hazard inherent to a given product. Essential requirements define the results to be attained (proportional to the inherent hazards
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of the product), but do not specify or predict the technical solutions for doing so. This flexibility allows the manufacturer to choose the way to meet the requirements; it enables the system to be adaptable to innovation and technical progress, but it can be frustrating for device manufacturers who may say ‘just tell me what I need to do to comply’. The essential requirements articulate the fundamental approach to the whole of the product life cycle, with risk management at its heart, and identify all that is necessary to achieve the objective of the directive. Products may be placed on the market and put into service only if they are in compliance with the essential requirements. The essential requirements most pertinent to biocompatibility from 93/42/ EEC are abstracted below, but for a more complete understanding of the process the reader should refer to the complete directive.
16.3.1
Essential requirements related to biocompatibility from the Medical Device Directive 93/42/EEC
I. GENERAL REQUIREMENTS 1. The devices must be designed and manufactured in such a way that, when used under the conditions and for the purposes intended, they will not compromise the clinical condition or the safety of patients, or the safety and health of users or, where applicable, other persons, provided that any risks which may be associated with their intended use constitute acceptable risks when weighed against the benefits to the patient and are compatible with a high level of protection of health and safety. This shall include: •
•
reducing, as far as possible, the risk of use error due to the ergonomic features of the device and the environment in which the device is intended to be used (design for patient safety), and consideration of the technical knowledge, experience, education and training and where applicable the medical and physical conditions of intended users (design for lay, professional, disabled or other users).
2. The solutions adopted by the manufacturer for the design and construction of the devices must conform to safety principles, taking account of the generally acknowledged state of the art. In selecting the most appropriate solutions, the manufacturer must apply the following principles in the following order:
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eliminate or reduce risks as far as possible (inherently safe design and construction), where appropriate take adequate protection measures including alarms if necessary, in relation to risks that cannot be eliminated, inform users of the residual risks due to any shortcomings of the protection measures adopted.
6. Any undesirable side-effect must constitute an acceptable risk when weighed against the performances intended. II. REQUIREMENTS REGARDING DESIGN AND CONSTRUCTION 7. Chemical, physical and biological properties 7.1 The devices must be designed and manufactured in such a way as to guarantee the characteristics and performances referred to in Section I on the ‘General requirements’. Particular attention must be paid to: • •
•
the choice of materials used, particularly as regards toxicity and, where appropriate, flammability, the compatibility between the materials used and biological tissues, cells and body fluids, taking account of the intended purpose of the device, where appropriate, the results of biophysical or modelling research whose validity has been demonstrated beforehand.
7.2 The devices must be designed, manufactured and packed in such a way as to minimize the risk posed by contaminants and residues to the persons involved in the transport, storage and use of the devices and to the patients, taking account of the intended purpose of the product. Particular attention must be paid to the tissues exposed and to the duration and frequency of exposure. 7.5 The devices must be designed and manufactured in such a way as to reduce to a minimum the risks posed by substances leaking from the device. Special attention shall be given to substances which are carcinogenic, mutagenic or toxic to reproduction, in accordance with Annex I to Council Directive 67/548/EEC of 27 June 1967 on the approximation of laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances. Risk management is fundamental to meeting these essential requirements, and it is noteworthy that the hierarchy of risk control articulated in the
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directive is the same as that detailed with the harmonised standard EN ISO 14971:2009.
16.4
Presumption of conformity
As the new approach directives do not specify the technical solutions to be achieved, but rather give a framework of necessary elements required, the directives allow manufacturers to demonstrate they meet the essential requirements by the route of ‘presumption of conformity’. Article 5 – Reference to standards of 93/42/EEC states 1. Member States shall presume compliance with the essential requirements referred to in Article 3 in respect of devices which are in conformity with the relevant national standards adopted pursuant to the harmonized standards the references of which have been publishes in the Official Journal of the European Communities; Member States shall publish the references of such national standards.
Harmonised standards are European standards, which are adopted by European standards organisations, prepared in accordance with the General Guidelines agreed between the European Commission and the European standards organisations, and follow a mandate issued by the European Commission after consultation with Member States. Harmonised standards are published in the official Journal, and listed on the European Commission website (the harmonised standards applicable to 93/42/EEC are listed at http://ec.europa.eu/enterprise/policies/european-standards/ documents/harmonised-standards-legislation/list-references/medicaldevices/). Thus the broad requirements articulated in the essential requirements of the directive can be practically addressed by using harmonised standards. It is important to note that application of harmonised standards, which give a presumption of conformity, is voluntary, and the legal manufacturer can choose an alternative route to demonstrate the product meets the essential requirements. Furthermore, if harmonised standards are used, if appropriate (and suitably justified) the manufacturer can choose to only apply partially apply the standard. However, in nearly all cases, the application of harmonised standards can help the legal manufacturer to meet the essential requirements, and even in the cases where there may not be product or vertical standards, the existing standards can be used to roadmap requirements. Thus the generic biocompatibility requirements for medical devices as laid out in the essential requirements can be demonstrated specifically by using an appropriate
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harmonised standard. In this way EN ISO 10993 can be used to meet the essential requirements.
16.5
Using the EN ISO 10993 series of standards to meet the essential requirements
At the time of writing, 15 of the 20 published parts of the ISO 10993 series of standards are harmonised, including the most important strategic document EN ISO 10993, part 1. Annex ZA from EN ISO 10993-1:2009 details the relationship between the standard and MDD 93/42/EEC, and similarly Annex ZB shows the relationship with AIMDD 90/385/EEC. The tabulation in Annex ZA presents the relevant clause(s)/subclause(s) of the International Standard, and the corresponding essential requirements as summarised in Table 16.1. Thus Annex ZA indicates that if the biological evaluation is performed according to the clauses listed, the legal manufacturer can state a ‘presumption of conformity’, and use the compliance with ISO 10993 as a route to demonstrate Essential Requirements 7.1, 7.2 and 7.5 have been achieved. The Annex ZA does also carry the caveat that ‘other requirements and other EU Directives may be applicable to the product(s) falling within the scope of this International Standard’, indicating the manufacturer should consider their device within the complete regulatory framework, and ensure all requirements are addressed. The other parts of ISO 10993 that have been harmonised similarly detail the relationship between the essential requirements and the standard, but generally have a qualifying remark indicating the requirements can only be partly addressed by the International Standard, and that presumption of conformity depends on also complying with all the relevant clauses/subclauses of ISO 10993-1. Thus the manufacturer is guided to EN ISO 10993-1, to ensure a complete evaluation is performed.
Table 16.1 Using the EN ISO 10993 series of standards to meet the essential requirements Clause(s)/subclause(s) of EN ISO 109931:2009
Essential requirements of Directive 93/42/EEC on medical devices
Clause 4: General principles applying to biological evaluation of medical devices Clause 5: Categorization of medical devices Clause 6: Biological evaluation process Clause 7: Interpretation of biological evaluation data and overall biological safety assessment
Annex I:7.1, 7.2 and 7.5
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16.5.1
Biocompatibility and performance of medical devices
Practical application of harmonised standards to demonstrate compliance with essential requirements
The previous sections have described the EU regulatory landscape within which biocompatibility assessment operates, and the regulatory compliance rationale for ensuring products are appropriately biocompatible. How then does the implicit requirement to ensure a medical device is biocompatible translate into the practical approach the legal manufacturer undertakes in developing a medical device? When the 4th edition EN ISO 10993-1:2009 superseded the 3rd edition of the standard (EN ISO 10993-1:2003), the new version much more clearly emphasised the biological evaluation as part of the overall risk management process. Thus prior to looking in detail at EN ISO 10993, the manufacturer must turn to the fundamental horizontal standard EN ISO 14971:2009. Horizontal standards (also known as basic standards) cover common requirements for all or a wide range of medical device areas such as risk management, labelling and sterilisation methods. Since risk management is fundamental to the essential requirements, this standard lays out requirements for the risk management process for all medical devices. It articulates the need to consider all hazards appropriate for a medical device, and provides specific details addressing the risk analysis process for biological hazards (Annex I of the standard). Annex I presents a very short guidance, which gives some of the basic principles, but in essence points the manufacturer to the ISO 10993 series of standards. A complete risk management report (the output from the risk management process) will always form part of the technical documentation which demonstrates the essential requirements of MDD 93/42/EEC have been met. This document should present a comprehensive assessment of the hazards identified, the risk control measures taken, and overall acceptability of residual risk. However this risk management report is the final output from the risk management process that should operate throughout the development of the product (and the risk management process will continue for the whole of the product life cycle). Thus biological hazards should be clearly identified within the risk management report, with an appropriate risk evaluation and detailed risk control measures. This process has been covered in detail in other chapters, and the reader is directed to Annex B of EN ISO 10993-1:2009 for guidance on how the biological evaluation fits within the risk management framework.
16.5.2
Conformity assessment process
Annex IX of MDD 93/42/EEC sets out the classification rules which manufacturers should use to determine which class a device falls into, according
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to its properties, function and intended purpose. Devices are assigned to one of four classes: Class I for low-risk devices, Classes IIa and IIb for mediumrisk devices and Class III for high-risk devices. It is important to note that the device classification required by 93/42/EEC is not the same as that utilised within EN ISO 10993-1:2009, and the two classification processes are entirely independent of each other. As previously stated all devices must meet the essential requirements of the MDD, irrespective of device class, however there are different conformity assessment routes to demonstrate compliance. In the case of Class I devices that are non-measuring and non-sterile the manufacturer is responsible for ensuring his product complies with the relevant essential requirements of the directive, and makes a self declaration to that effect. All other devices (i.e. Class I measuring or sterile devices, Class IIa, IIb and III) require conformity assessment by a notified body. The type and depth of assessment varies dependent on the classification of the device, but in all cases the notified body will review the technical file/design dossier for a medical device, and judge whether the product meets the essential requirements. Thus the biocompatibility assessment for the medical device will be reviewed by a notified body.
16.6 The notified body A notified body is a certification organisation that the national authority (the Competent Authority) of an EU Member State designates to carry out one or more of the conformity assessment procedures described in the annexes of the MDD 93/42/EEC. A notified body will be qualified to perform all the functions set out in any annex for which it is designated, and the designation may be restricted to specified types of devices and/or Annexes. At the time of writing there are 76 notified bodies designated to perform conformity assessments according to 93/42/EEC within the EU. Notified bodies can have varying levels of experience and expertise, so it is important that the notified body working with the manufacturer has the appropriate knowledge to assess the biocompatibility of the type of device in question. There are many factors to consider when selecting a notified body, which are outside the scope of discussion related specifically to biocompatibility, so Table 16.2 illustrates some key points to consider as part of the notified body selection process. If the manufacturer has chosen to utilise the presumption of conformity route by using EN ISO 10993 to demonstrate compliance with the relevant essential requirements, the task of the notified body is relatively simple, which is to determine whether the manufacturer has complied with the requirements of the harmonised standard. A later section deals with
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Table 16.2 Key points to consider as part of the notified body (NB) selection process Resource
Working together
• Standing and reputation
• Effective working relationship • Designating competent • Flexibility/ authority responsiveness • Scope of certification • Willingness schemes offered (global to support the access to markets) manufacturer • Size • Willingness to meet • Location • Use of subcontractors • Audit schedule
• Accessibility of personel • Approachability • Pre-audit review
Technical
Commercial
• Expertise in product area
• Costs
• Expertise in biocompatibility • Format/content of NB audit reports • Clinical evaluation expectations • Documentation requirements
• Timelines • Ongoing costs
some of the common pitfalls manufacturers can fall into in submissions, and provides an example of the appropriate content of a biocompatibility assessment. In the rare cases where a manufacturer has not chosen to use the presumption of conformity route to demonstrate the product meets the essential requirements related to biocompatibility, it is likely that the notified body will continue to use the harmonised standards as a framework for the assessment, although they cannot audit precisely against the requirements of the relevant harmonised standard. This can lead to a more protracted review process (with potential time and cost implications). Whilst the presumption of conformity route indicates that compliance with the appropriate harmonised standard is satisfactory to meet the essential requirements identified, it cannot be overstated how important it is to utilise the harmonised standard robustly. This is particularly relevant where no vertical (product) standard exists within the EN ISO 10993 series. The risk analysis of the medical device may identify hazards that should be addressed in addition to those described within EN ISO 10993-1 2009. This issue is addressed in more detail later in the chapter.
16.6.1 Technical file evaluation by the notified body The technical file (or design dossier for Class III devices) holds all the relevant information that demonstrates conformity of the medical device to the
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Table 16.3 An example format for addressing the relevant essential requirements (ER) from Annex I of the directive Essential Applicable Harmonised requirement to the standard(s) device applied
7.1 (text of ER can be included)
Yes
Standards Compliance applied demonstrated partially by/comments or in full
EN ISO Fully - Risk 14971:2009 applied management EN ISO report 10993-1:2009 - Biocompatibility EN ISO assessment 10993-5:2009 - Cytotoxicity EN ISO report 10993-18:2009
Location in technical documentation
Section X Risk Management Section Y Biocompatibility assessment Appendix Z Test reports
requirements of the directive (i.e. that all relevant essential requirements are met). The directive does not give specific guidance on the content of the technical file, so the manufacturer can construct the file as appropriate. However, manufacturers may chose to use a standardised format such as the Summary Technical Documentation as described by Global Harmonisation Task Force (GHTF) document SG1 (PD)/N011R20: STED), which will be helpful for the notified body assessment process. For the purposes of the conformity assessment against the essential requirements of 93/42/EEC related to biocompatibility, there are three documents which the reviewer will focus on. The essential requirements checklist This roadmaps how the manufacturer has addressed the relevant essential requirements from Annex I of the directive. Table 16.3 presents an example format. In this case the manufacturer has clearly indicated the presumption of conformity route has been used to demonstrate how the essential requirement is met, thus the notified body reviewer can easily identify the relevant information to review. The risk management report As biocompatibility forms part of the overarching risk management process the risk management report should clearly identify the biological safety hazards and the risk control measures taken to address the risks identified.
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The biocompatibility assessment The documentation that addresses the biological evaluation according to EN ISO 10993 When the manufacturer is preparing the biological evaluation, the regulatory authority/notified body assessor is one of the important stakeholders, so it is helpful to consider their needs. With all regulatory submissions (whether in the EU or worldwide), the regulatory authority is a key customer, and it remains surprising how many manufacturers do not consider the needs of the reader when preparing their technical documentation. Ideally the notified body will have appropriate expertise specific to your type of device, but that is not always the case. Depending on the product type and classification the whole technical file may be viewed by one expert, but in some cases the relevant sections of the technical file will assessed by an expert in biocompatibility, without sight of the whole technical file. Thus the biocompatibility assessment may need to be auditable in isolation from other technical documentation, such as design verification and validation activities. The points to consider when preparing biological safety documentation for review are listed below: • the assessor may or may not be an expert in biocompatibility; • they will know the technology area; • they may not know your product in detail; • they may not know the history of your product; • they will probably be reviewing against the requirements of the EN ISO 10993 series of standards; • they may be considering biocompatibility as part of overall submission; • they will be looking for a coherent thread between risk management and the biological evaluation; • they will be skilled in identifying data gaps, inconsistencies and insufficient/poor quality data. Use of non-validated/non-standard test methodologies Various parts of the ISO 10993 series of standards describe in some detail validated test methodologies, and these should always be the preferred route for demonstrating compliance with the standard. However, it is not so prescriptive as to limit the biological evaluation to only those test methodologies described within the standard, but it is clear that all testing should be scientifically robust. Thus there may be instances where ‘non-standard’ test methodologies are required, and this is acceptable if duly justified (particularly when novel/innovative products are under assessment). However, it is not appropriate to present a biological evaluation using a non-validated
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methodology (such as a novel cytotoxicity test developed in a university laboratory), when the evaluation could be performed using a recognised validated methodology as described in the EN ISO 10993-5). That does not preclude the use of the data generated in the university methodology as part of the background to the biological evaluation, but it should not be used as the pivotal data set. Use of combined performance and safety tests Whilst the primary aim of the ISO 10993 standards is the protection of humans, it also serves as a framework to minimise the number and exposure of test animals, thus where appropriate the combining of studies to address multiple endpoints is encouraged. However this is subject to the primary endpoints of those tests not being compromised by the secondary endpoint. An example of such a study would be a performance evaluation of an orthopaedic implant in a large animal model. Whilst the primary goal of the study might be to assess mechanical performance of the implant, analysis of serum ion levels could provide supporting evidence for the biocompatibility of the medical device. Similarly for drug device combination products (e.g. drug eluting stents), such combined safety and performance tests can provide valuable information on both the performance of the device component, and also relevant pharmacokinetic data to support drug safety and efficacy parameters.
16.7 Common pitfalls in biological evaluations The most fundamental problem observed in some manufacturer’s submissions is the lack of a coherent risk management process, and the biocompatibility assessment, which should be aligned to it. In these cases it appears the risk management process is not at the heart of the device development, but rather a ‘bolt on’ performed to demonstrate regulatory compliance. Thus the risk analysis does not identify all the relevant hazards, and the risk control measures, whilst being valid activities as part of design and development, do not demonstrate management of the risks identified. In these cases the biological hazards are not clearly identified, and there appears no rationale for the subsequent biological evaluation performed. Figure 16.1 presents an example of the product-development process, with risk management operating as the foundation for the product-development process. Over-layered on the risk management are the interactions with the biocompatibility assessment and the new product-development process. To highlight the interrelationship between risk management and biological safety Table 16.4 presents an example of the hazards identified for a wound dressing to be applied to chronic wounds, identified as part of the EN ISO 14971:2009 risk management process.
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Idea
1
Preliminary investigation
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Detailed investigation
3
Development (fully functional prototype)
4
Scale up and performance
5
Full production and market launch
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Design and development activities
· Literature activities · Early laboratory work
· Early laboratory work · Exploratory work · Prototyping · Technical feasibility · Market research · Focus panels
· Performance (proof of concept clinical trial) · Stability · Sterilisation · Pilot scale/handmade manufacture · Results in design freeze
· Larger clinical trials · Process scale up · Modifications/tweaks
· Market exposure · Adverse reactions · Broaden indications
Biological safety activities
· ISO 10993-1 · Preliminary biological safety input · Material selection · Safety strategy
· ISO 10993-1 · Confirm strategy · Composition/material review · ISO 10993-17 · ISO 10993-18 · ISO 10993-5 · In vitro assessments · Early assessment of novel components if appropriate · Early pre-clinical efficacy studies including safety endpoints
· ISO 10993-1 · All relevant toxicological endpoints evaluated · ISO 10993-relevant part · Assessment following design freeze · ISO 10993-18 · Fully characterise product · Pre-clinical efficacy · Safety endpoints · Combined safety and efficacy studies
· ISO 10993-1 · ISO 10993-18 · Demonstration of equivalence with pilot scale product
· ISO 10993-1 · ISO 10993-18 · Ongoing product modifications · Changes of raw materials · Process alterations · Adverse reactions from market · IFUs
ISO 14971: Risk management
16.1 An example of some of the relationships between the new-product-development process and biological evaluation. At various stages within the development process there are key inputs where the biological evaluation is critical to the successful development of the product. Underlying all activities, risk management forms the foundation for an effective and efficient new-product-development process (IFUs, instruction for use).
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Table 16.4 An example of the hazards identified for a wound dressing to be applied to chronic wounds, identified as part of the EN ISO 14971:2009 risk management process Hazard
Foreseeable sequence of events
Hazardous situation
Harm
Chemical: Device composition
Polyurethane Leachable materials polymeric present in components device do have an not have adverse appropriate effect either biocompatibility locally or systemically
• Pain • Local irritation • Inflammatory response • Sensitisation • Delayed wound healing • Target organ toxicity • Genetic damage leading to carcinogenicity
Physico-chemical Wound contact characteristics materials of materials not adhere to appropriate for wound bed, contact with causing wound tissue damage on removal
• Pain • Local irritation • Inflammatory response • Delayed wound healing
The hazards described fall under the broad description of ‘biocompatible’. However, a common misconception of manufacturers is that a series of biocompatibility tests, as described by EN ISO 10993-1:2009, demonstrates that a product is suitably biocompatible. Using the guidance presented in Annex A of EN ISO 10993-1:2009, the following evaluation tests would be considered appropriate for breached or compromised surface contact device (contact duration C – permanent), and would form part of the hazard characterisation and risk control activities: • • • • •
cytotoxicity (EN ISO 10993-5), sensitisation (EN ISO 10993-10), irritation or intracutaneous reactivity (EN ISO 10993-10), subchronic toxicity (subacute toxicity) (EN ISO 10993-11), genotoxicity (EN ISO 10993-3).
Whilst these assessments would characterise the risks for those toxicological endpoints, they do not completely address the hazardous situations identified, as delayed wound healing cannot be assessed by the evaluations described. Therefore the manufacturer may need to consider an additional evaluation
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not described within the ISO 10993 series of standards, and in this case a wound healing evaluation in an appropriate model would be required to adequately address the risks identified within the risk management process. This point underlines the need for thorough hazard identification within the risk management process (in this case the fundamental performance requirement of a chronic wound dressing that it does not cause a delay in wound healing or significant damage to the wound bed upon removal was ignored). Once appropriate risks are identified, they may well be addressed by using harmonised standards, but those standards should not be utilised in a ‘blinkered’ manner. It is clear from EN ISO 10993-1 that the standard provides a framework for the biological evaluation, and not a rigid test regime, and it is specifically stated within the standard that it is not intended to provide a rigid set of tests methods, including pass/fail criteria. Within the biological evaluation itself, the most common issue is inadequate/incomplete application of EN ISO 10993-1 2009. The standard presents a process flow for a systematic approach to the biological evaluation, which if followed provides a complete evaluation. Unfortunately some manufacturers may view a biocompatibility assessment purely as ‘the tests’, and whilst this view may not be promulgated by contract research laboratories performing testing, it can be perpetuated by the lack of a complete systematic approach encompassing all aspects of the biological evaluation. This can be particularly prevalent in small and medium enterprises (SMEs), where dedicated expertise in biological safety is not available. Whilst manufacturers may not have the expertise in house to complete the biological evaluation, as the legal manufacturer of the medical device under the requirements of the MDD 93/42/EEC it is their responsibility to ensure the product has a complete biological evaluation and thus meets the essential requirements. The ownership of the biological evaluation process remains with the manufacturer (even if the whole biological evaluation is subcontracted to a contract house or a medical device consultant). Thus the fact the supplier of a component material states it is ‘biocompatible’, and may present test data, does not abrogate the responsibility of the legal manufacturer for the biological safety of the finished product. In this case the validity of that data for the finished product use will be challenged, which brings the challenge for the manufacturer of justifying toxicological equivalence. The 4th edition of EN ISO 10993-1:2009 brought welcome clarification to manufacturers, clearly allowing the use of existing preclinical and clinical data, including history of safe use, to meet the requirements of biological evaluation. Thus the use of existing data is encouraged, to avoid unethical additional animal testing (which also has the benefits of reduced time and cost to manufacturers), however the challenge of justifying the acceptability of existing data for a new medical device can be significant. The use of chemical characterisation (EN ISO 10993-18) facilitates demonstration
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of chemical equivalence, which can then be extrapolated to toxicological equivalence (refer to Annex C of part 18 for further detail). Common examples where such toxicological equivalence can be used are generic components that can be used by many different manufacturers (e.g. adhesives for wound dressings, or polyether ether ketone (PEEK) polymer for implantable devices). In these cases the supplier may state the materials are ‘biocompatible’, and have specific test data relevant to the manufacturer’s end use. However, the processing, sterilisation and finished device use are controlled by the manufacturer, which will directly impact on the overall biocompatibility of the medical device. In these instances the manufacturer must justify why the data presented by the supplier (e.g. a polymer sterilised by ethylene oxide), is acceptable for the end use (where the manufacturer may have chosen to use an alternative method of sterilisation such as gamma irradiation). Particularly in the case of polymeric materials, where molecular weight/monomer content can have a significant impact on the biocompatibility of the material, it is likely that chemical characterisation will form part of the justification for equivalence. Further examples of inadequate biological evaluation submissions include those with simple unsupported statements such as ‘it’s only material x, it’s well known to be safe’, ‘my material is approved by y’, ‘my material complies with an ISO standard’, ‘this material has been used safely for years’. Whilst all of these top level statements may be relevant to the overall biological evaluation, they do not stand as an acceptable evaluation alone (and must be supported by objective evidence, not anecdotal comment). EN ISO 10993-1:2009 encourages the use of existing data, but only within the overall framework of the biological evaluation. Similarly, the observation ‘my competitor’s product contains the same material so it must be biocompatible’ is not an acceptable justification of equivalence without substantial supporting evidence and utilisation of biocompatibility data from another source. All of these shortfalls result from inadequate application of the harmonised standard.
16.8 Managing positive results in the biological safety assessment EN ISO 10993-1:2009 emphasises the biological evaluation within the risk management process, and highlights that the standard presents a framework for the biological evaluation, without pass/fail criteria. Similarly as part of the overall risk management process for a medical device, it is the manufacturer’s responsibility to set acceptable risk levels based on state of the art. Thus, if appropriate, positive or equivocal results from biocompatibility studies may be deemed acceptable within the overall biological evaluation. In these instances it is important the manufacturer clearly presents the
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data, with a rationale or hypothesis for the results obtained, and if possible further analysis (perhaps chemical characterisation) to suggest why such a result has been achieved. Two examples are presented below, but there may often be situations where one test performed presents a problematic result. In these situations it is critical the manufacturer presents a robust justification for the acceptability within the overall biological evaluation, and does not ignore the data. Positive test results can often occur when sensitive in vitro evaluations are performed due to the absence of normal physiological and morphological protective mechanisms (e.g. cytotoxicity in a EN ISO 10993-5:2009 MEM elution assay when evaluating a silver wound dressing), which although providing some hazard identification do not preclude the use of the product if other more relevant in vivo data exists. In the example of the silver dressing the cytotoxicity demonstrated is an inevitable consequence of the silver antimicrobial, but the in vitro cytotoxicity does not translate into adverse wound effects in either preclinical porcine models or clinical use. The acceptability of a positive result must be presented as part of the overall risk management assessment, and in that context the biocompatibility of the device may still be acceptable for the clinical use intended. The use of aggressive solvent extraction methodologies as recommended in the Japanese in vitro cytotoxicity and genotoxicity assays, and the guinea pig sensitisation test, can lead to positive results in these tests, which may not be observed when the physiological solvents described in EN ISO 10993-12 2009 are used. Whilst in some instances the results may be a true representation of the biological hazard presented, in other cases the aggressive solvent extraction can lead to the presence of various moieties that would not be present in normal clinical use, and can be considered ‘false positives’. In this situation it may be appropriate to justify the acceptability of these results when presented in the context of additional testing with physiological media and chemical characterisation demonstrating the discrepancies between aggressive solvent extracts and physiological extracts.
16.9 Presenting the biological evaluation within the technical file As previously discussed, for any regulatory submission it is important to consider the key stakeholders of the information presented. In the case of the biological evaluation the assessor will invariably be assessing the content against EN ISO 10993-1 2009, thus presenting the information in a format consistent with the process flow of the standard will facilitate the process. The Appendix in Section 16.12 illustrates a model presentation of data, and reiterates that the biological evaluation is not just ‘the tests’, but a structured evaluation of the data relevant to biological safety.
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16.10 Conclusion Although the MDD requirements can appear convoluted and confusing, there are clear mechanisms to demonstrate the acceptable biocompatibility of medical devices. The use of the ‘presumption of conformity’ process allows the use of international standards that have been harmonised within the EU, thus enabling manufacturers within the EU and beyond to have a consistent approach to biocompatibility. Robust utilisation of both the risk management standard EN ISO 14971:2009 and EN ISO 10993 series of standards will ensure a thorough biocompatibility assessment is performed, which should lead to a successful assessment of the submission by the notified body.
16.11 Sources of further information and advice • European Commission Guide to the Implementation of Directives Based on New Approach and Global Approach http://ec.europa.eu/enterprise/policies/single-market-goods/documents/ blue-guide/ • European Commission Website for Medical Devices, providing extensive guidance documents, including MEDDEVs, borderline considerations and consensus statements http://ec.europa.eu/health/medical-devices/index_en.htm • European Commission Website of Harmonised Standards for Medical Devices http://ec.europa.eu/enterprise/policies/european-standards/ harmonised-standards/medical-devices/index_en.htm • European Commission Website “NANDO”, detailing designation of notified bodies for MDDs http://ec.europa.eu/enterprise/newapproach/nando/ • Notified Body Operations Group Website, detailing various recommendations for processes and documentation http://www.nbog.eu/
16.12 Appendix: model content of the biological evaluation submission •
Product construction/composition – Intended use – List components/materials with direct/indirect body contact – Diagram of product – Auxiliary materials – additives, processing aids, residues – Sterilisation methodology
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EN ISO 10993:1 Classification of device – Nature of contact – Duration of contact Product characterisation – ISO 10993-18/19 – If appropriate analysis of degradation products (EN ISO 10993-9) – If appropriate establishment of allowable limits of leachable substances ((EN ISO 10993-17) Gap analysis – similarity to other devices (if relevant) – Intended use /device properties – Components – Manufacturing – Sterilisation methodology Historical data review – Literature (from legitimate sources such as the Hazardous Substances Database, Toxline, National Toxicology Program etc. Wikipedia is not considered a robust source) – Relevance of literature – Body contact – Duration Pre-existing internal company information – Robust database – Supporting evidence – Preclinical tests from similar devices – Relevance to the device under assessment Selection of biological evaluation test strategy – Rationale – Justification for tests performed/not performed – Description of tested items – Representative sample – Finished device, part of device, raw material – Sample preparation, solvent – Sterilisation of material Preclinical test results – Summary tabulation – Full test reports supplied in appendices
Test Status Sample/ Test sample of test extract performed/ material preparation test system
Standard/ Test lab/report norm number/report date
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Conclusion – Summary of biological evaluation strategy and results – Clear discussion of all data including equivocal results, justify their acceptability – Statement of meeting requirements of EN ISO 10993 – Evidence of incorporation into risk management documentation
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