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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5612_Библиотеки_им_академика_М_И_Перельмана
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Biocompatibility testing
and marketing authorisation
11
of degradable magnesium
implants
Anneke Loos
Hannover Medical School, Hannover, Germany
11.1 Introduction
An implant that disappears after its function has been fulfilled has fascinated
visionary inventors for more than 150 years and will probably lead to revolutionary
changes in the field of surgery once the technical and regulatory hurdles are overcome. Besides polymers, metal alloys based on magnesium, and to a lesser extent
iron, have been the focus of attention of scientists and the medical device industry.
Like with many other innovations on the way from bench to bedside, the properties
of new materials pose a challenge with respect to the current marketing authorisation procedures. The lack of knowledge about the possible (unwanted) negative
consequences that new materials might have on the patient reduces the innovative
potential of new implant materials. In the case of degradable magnesium implants,
their ability to dissolve causes difficulties when standard biological tests are
applied. With regard to safety evaluations, regulatory authorities ask questions concerning the degradation kinetic as well as the frequency of occurrence and the nature of intermediates released by the bulk material or toxic alloy components (e.g.,
aluminium, yttrium, or neodymium) and their localisation in or transport in the
body.
This chapter discusses the biological evaluation of degradable magnesium implants
with respect to the marketing authorisation o f new implants. It starts with the classification of implants, which has become increasingly complicated because manuf acturers have started modifying them with drugs or cells to create additional
properties (Section 2). Since standards are a key aspect of the marketing authorisation
process of implants, Section 3 gives insight into the meaning, development, and application of these documents. Section 4 gives an overview of the different aspects of b iological safety that have to be considered for marketing authorisation. In Section 5,
biocompatibility testing of degradable magnesium implants and the necessary modifications of standard methods for dealing with their intrinsic characteristics are
discussed. Section 6 gives a review of the current approaches and ideas of the scientific
community that are used to gain infor mation about the toxicity of various magnesium
alloys in in vitro and in vivo assays.
Surface Modification of Magnesium and its Alloys for Biomedical Applications. http://dx.doi.org/10.1016/B978-1-78242-077-4.00011-5
Copyright © 2015 Elsevier Ltd. All rights reserved.
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11.2 Classification e which directive applies?
If the aim is to obtain marketing authorisation for a new implant, one of the first
considerations should be the classification of the product. The reason for this is that
the classification can have an impact on many factors, like the requirements concerning
the quality management system of the manufacturer, the marketing authorisation
process, the necessary tests for safety assessment, and the responsible regulatory
authority. This section gives a general overview of the current regulatory situation,
the various ways that an implant can be classified, and the implications of the
classification.
One thing that makes the way from bench to bedside for a new medical product
time-consuming is that the requirements and procedures for marketing authorisation
differ from country to country. The only exemptions are the countries of the European
Union (EU), where a uniform EU legislation applies for all the member countries.
Besides national marketing authorisation, it is also possible for the manufacturer
to request approval for internal European trade, which is then accepted in all of the
28 member countries. Every other country in the world has its own laws, procedures,
and regulatory authorities. Besides Europe, the two biggest markets for implants are
currently Asia and the United States. In the United States, the Food and Drug Administration (FDA) is the competent authority for marketing authorisation of all medical
products. In other countries (e.g., within the European Union), the responsibilities
are divided between different authorities, like the European Medicines Agency
(EMA) and the inspection authorities (“notified bodies” like Technischer
€
Uberwachungsverein (T€UV) or Deutscher Kraftfahrzeug-€Uberwachungs-Verein e.V.
(DEKRA), www.dekra.de). Some effort has been made to harmonise the procedures
in the different countries, e.g., through internationally accepted standards by the International Medical Device Regulators Forum (IMDRF), which carries out the mission of
the Global Harmonization Task Force (GHTF), or by the International Conference on
Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) (www.ich.org).
Medicinal products can be divided into three groups: drugs (or pharm aceuticals),
medical devices, and advanced therapy medicinal products (ATMPs, Figure 11.1).
Drugs can be differentiated from medical devices by their primary mode of action.
Pharmaceuticals act immunologically, pharmacologically, or metabolically, whereas
a medical device does not. Medical devices usually replace or modify the anatomy
or a physiological process. They are used to recognise, prevent, monitor, treat,
compensate, or heal diseases, injuries, and handicaps and for contraception. The group
of ATMPs includes products for cell therapy, gene therapy, and products based on
methods of tissue engineering. Detailed definitions of the product classes can be found
in the legislation of the respective country. Please bear in mind that these definitions
might differ from country to country!
Implants typically belong to the medical devices or ATMP group. However, an
implant can also be classified as a pharmaceutical if it is combined with a drug
and if the only function of the implant is as a carrier for the pharmaceutical (e.g.,
contraceptive hormone implants). Combinations of medical devices and drugs
Biocompatibility testing and marketing authorisation of degradable magnesium implants 333
Figure 11.1 Medicinal products are divided into pharmaceuticals, advanced-therapy medicinal
products (ATMPs), or medical devices.
(e.g., drug-eluting stents) or ATMPs and medical devices (e.g., a collagen matrix
combined with cells) are also possible. Product classification is essential for the
marketing authorisation process, because it indicates which directive applies, the
tests that have to be performed, the quality management system needed for
manufacturing, and the responsible regulatory authority for marketin g authorisation
(Figure 11.2). For example, a typical feature of the marketing authorisation procedure of medical devices is the use of a standard like the International Organization
for Standardization ISO 10993, which does not apply to the preclinical testing of
pharmaceuticals. The classification also has an impact on developmental costs and
time. For example, the marketing authorisation process for a pharmaceutical is 10
times more expensive (US$ 500 million to US$ 2 billion) than and takes twice as
long (approximately 10e12 years) as the marketing authorisation of a medical device
(Adams and Brandnter, 2006; DiMasi, Hansen, and Grabowski, 2003; Kaplan et al.,
2004). In case of doubt, it is highly recommended to seek legal advice for the prod-
uct classification.
In general, the classification of implants made of degradable materials follows the
rules described above. Degradable implants are commonly classified as medical
devices and tested accordingly. Changes in the product classification can occur
when the implant surface is modified (e.g., coated with a drug) or when it is combined
with cells. In these cases, aside from the testing of the final product, the medi cal device
part also has to be tested separately.
To summarise, the proper classification of a new implant should always be one of
the first steps because basics like the required quality management system, test procedures, and regulatory authority might differ depe nding on the classification as medical
device, pharmaceutical, ATMP, or combinations thereof. Implant classification can
differ from country to country because besides the EU, every country has its own
classification rules and marketing authorisation procedures.
334 Surface Modification of Magnesium and its Alloys for Biomedical Applications
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Easy, “cheap” and fast: medical devices
Technical documentation
& risk management ISO 14971
Idea
Choice of notified body
Material of animal origin ISO 22442 (TSE)
Classification / quality management system
REACH Reg. EC 1907 / 2006
Pyrogenic substances?
Sterilisation & packaging
Toxicological testing
ISO 10993
Clinical evaluation
ISO 14155
MEDDEV 2.7.1.
MDD
Product development
Mechanical and chemical testing
ISO 17025, ISO 13485
Slow, expensive, well-established: pharmaceuticals
Toxicological testing
ICH & EMA guidelines
Manufacturing of IMP,
packaging
Approval of
Idea
clinical studies
(national)
Premarket
Application & audit
(notified body)
Declaration of conformity
Approval
Premarket
Postmarket
Approval
(restricted to 5 years)
Submitting of
CTD @ EMA
Postmarket
CE
Average costs:
20–50 Mio. €
5 years
Screening &
preclinical testing
GLP
Clinical studies phase I–III
GMP
Clinical studies phase IV
Average costs:
250 Mio. € / 10–12 years
Figure 11.2 Comparison between the market approval process of pharmaceuticals, medical
devices, and ATMPs in the European Union. CTD ¼ Common Technical Document;
IMP ¼ investigational medicinal product, ICH ¼ International Conference on Harmonization of
Technical Requirements for Registration of Pharmaceuticals, AMNOG ¼
Arzneimittelmarktneuordnungsgesetz (Germany), CAT ¼ Committee for Advanced Therapies,
CHMP ¼ Committee for Medicinal Products for Human Use, EMA ¼ European Medicines
Agency (EMEA), GLP/GMP ¼ Good Laboratory Practice/Good Manufacturing Practice,
TSE ¼ transmissible spongiform encephalopathy. RM ¼ risk management
Biocompatibility testing and marketing authorisation of degradable magnesium implants 335
Challenge: ATMPs
Technical documentation
risk management ISO 13022
Premarket
Postmarket
CAT classification
(60d)
ATMP?
Idea
Product development
TSE?
ISO 22442
CAT certification
(90d, SME only)
Individual
safety
testing
based on
RM
Approval of
clinical study
(national)
GLP GMP
Application of
approval
Clinical study
phase I–III
(EMA)
Evaluation 210d
CAT, CHMP
Approval
Average costs:
? Mio. € / 10–12 years
Figure 11.2 Continued.
11.3 Testing according to international standards
We are surrounded by standardised language, safety requirements, and technical
equipment in our daily lives; we have become so used to this that the only time we
think about standards is when they are missing. One example is the lack of compatibility of power supplies for mobile phones. Every mobile phone needs its own power
supply because an internationally acknowledged uniform, interchangeable connector
plug does not exist at present. The following section covers basic information about
the meaning, classification, development, and use of standards.
11.3.1 What is a standard?
According to ISO (www.iso.org), a standard is defined as a “document approved by a
recognised body, that provides, for common and repeated use, rules, guidelines or characteristics for products or related processes and production methods, with which
compliance is not mandatory. It may also include or deal exclusively with terminology,
symbols, packaging, marking or labelling requirements as they apply to a product , process or production method” (ISO Central Secretariat, 2007). In contrast, the GHTF definition is slightly different and more general: “document, established by consensus and
approved by a recognised body, that provides, for common and repeated use, rules,
guidelines or characteristics for activities or their results, aimed at the achievement of
the optimum degree of order in a given context” (GHTF/SG1/N044:2008). The
GHTF definition additionally refers to the following note to ISO/IEC Guide 2:2004,
definition 3.2: “Standards should be based on the consolidated results of science, technology and experience, and aimed at the promotion of optimum community benefits.”
336 Surface Modification of Magnesium and its Alloys for Biomedical Applications
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Standards make our lives safer by defining minimal safety requirements and
providing a basis for quality assessment (e.g., in the field of construction, food,
traffic, electronics, and medicine). The aim of international standardisation organisations is to publish international agreements in the form of standards to facilitate
the international trade of goods and services and to promote international cooperation in all fields of technical, scientific, economic, and intellectual activity. Standards provide definitions that support communication; they help to eliminate
technical barriers and reduce the overall costs, which results in a positive impact
on the economy (Blind, 2004).
11.3.2 What kinds of standards exist?
Standards can be subdivided into national or international standards according to their
origin and into horizontal or vertical standards according to their scope.
On the international level, all standards are developed at the ISO except for electronics and telecommunications standards, which are provided by the International
Electrotechnical Commission (IEC) and the International Telecommunication Union
(ITU). The European analogues are the European Committee for Standardization
(CEN), the European Committee for Electrotechnical Standardization (CENELEC),
and the European Telecommunications Standards Institute (ETSI). Besides the
international standardisation organisations, almost every country has its own
national organisation: e.g., BNSI (Barbados), SA (Australia), NC (Cuba), EVS
(Estonia), DIN (Germany), COSQC (Iraq), JISC (Japan), ILNAS (Luxembourg),
SNZ (New Zealand), SSMO (Sudan), and ANSI (USA). Scientific or technical
societies also publish guidelines and standards on specific topics. Relevant standardised testing protocols for the toxicological evaluation of implants are also provided
by the Organization for Economic Cooperation and Development (OECD) and the
American Society for Testing and Materials (ASTM International). In general, the
OECD focus is on the assessment of the potential toxicity of environmental substances, whereas ASTM International is more concerned with the safety assessment
of materials for medical applications. Sometimes, the ISO standards refer to OECD
or ASTM methods.
Additionally, a hierarchy of different levels exist for standards (Figure 11.3). Level 1
is the basic or horizontal standard. Documents in this group describe fundamental concepts, principles, or general requirements. They usually cover general safety and performance aspects that are applicable to a wide range of products or processes, e.g.,
risk or quality management, or clinical investigation. With respect to implants, examples of horizontal standards are ISO 14971 “Medical deviceseApplication of risk management to medical devices,” IEC 62366 “Medical deviceseApplication of usability
engineering to medical devices,” ANSI/AAMI HE 74 “Human factors design process
for medical devices,” or ISO 14630 “Non-active surgical implants
ments.” Level 2 is a group standard or a semihorizontal standard that is applicable to
a
eGeneral require-
a
Non-active in this regard means that the implant does not have an externally driven energy source.
Biocompatibility testing and marketing authorisation of degradable magnesium implants 337
Horizontal standards
Basic standard
Group standard
Vertical standards
Product standard
Product standard
Product standard
Product standard
Figure 11.3 According to ISO and GHTF, standards can be classified as basic, group, or
product standard depending on their scope.
Group standard
Product standard
Product standard
Level 1
Basic requirements
Level 2
Requirements for
groups of products
or processes
Level 3
Product or process
specific
Product standard
families of products or processes. Examples of semihorizontal standards are the ISO
11135 series “Sterilization of health care products Ethylene oxide” or the ISO 10993
series “Biological evaluation of medical devices.” Level 3 covers product-specific standards that generally deal with the required safety and performance aspects of a specific
product or process, such as ISO 25539-2 “Cardiovascular implantseEndovascular
devicesePart 2: Vascular stents” for coronary stents.
11.3.3 Development of (international) standards
One important feature of standards mentioned in the GHTF definition is that they are
consensus documents. This means that a more or less randomly mixed (international)
group of approximately 5e20 people, who may have very different opinions and backgrounds, tries to reach a mutual consensus on wording. On an international level, most
of the members of the groups are from industry; however, scientists are rarely part of
this group. Finding a consensus can be very time-consuming and usually takes several
years. As a result, standards are sometimes not very detailed and in general not state of
the art. The procedures of the ISO, which are described in the following section, are an
example of the development of an international standard.
ISO standards are developed by an ISO committee (a technical committee or TC).
The ISO website gives an overview of its committee structure and the standards the
committees are working on. Relevant standards for implants are being developed,
for example, in TC 150 “Implants for surgery,” TC 198 “Sterilization of health care
products,” TC 194 “Biological evaluation of medical devices,” TC 168 “Prosthesis
and orthotics,” TC 106 “Dentistry,” and TC 210 “Quality management and corresponding general aspects for medical devices.” When committees have many members
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and several topics to cover, subcommittees are formed to concentrate on specific
issues.
The experts within the ISO committees are assigned by their corresponding ISO
member bodies, which are usually national standardisation organisations (e.g.,
ANSI, DIN, or BSI; please refer to the ISO website for more information). Only
one national standardisation organisation per country is a member of the ISO. The
ISO member bodies can choose to be participating members or observing members.
This decision depends on the national interests and has implications for the influence
on the development and the contents of a standard. Participating member bodies organise the national committees, which are open to all stakeholders (mirror committees).
If a person wants to contr ibute actively to the development of an ISO standard for a
specific topic, the first step is to identify and contact the national ISO member
body. After admission to the national mirror committee, it is possible to be officially
assigned as an expert to the ISO committee that is responsible for writing the standard.
During development, an ISO standard has to pass through different project stages
(Table 11.1, Figure 11.4). Every stage is connected to a project deliverable. The intervals between the different stages are fixed. Each stage is terminated with a ballot; however, the conditions for further maturing the document might differ at the various
stages. For example, at the preliminary stage, a simple majority vote decides the
fate of a preliminary work item (PWI). In contrast, at the proposal stage, at least
five participating members have to declare their active support of the new work
item proposal (NWIP) and nominate experts. Provided the latter is the case, a simple
majority of the participating members is sufficient for the NWIP to become a working
draft (WD). After publication of a new standard, it will be subjected to periodic review
cycles during which whether the standard is still needed and whether changes are
required or not will be discussed.
Table 11.1 Stages of ISO project deliverables
Stage Name of the document Acronym
Preliminary Preliminary work item PWI
Proposal New work item proposal NWIP
Preparatory Working draft WD
Committee Committee draft CD
Enquiry Draft international standard DIS
Approval Final draft international
standard
Publication International standard IS
Adapted from www.iso.org.
FDIS
Biocompatibility testing and marketing authorisation of degradable magnesium implants 339
Level Stage Name of the document
0
Preliminary stage
Submitting @ ISO requires a project description & project leader
Proposal stage
1
Active support by at least five p-members & nomination of experts
Preparatory stage
2
Comments should be included
Committee stage
3
Approved by a two-thirds majority of p-members
Enquiry stage
4
Proceed dirctly to publication,
If DIS is approved
Publication stage
6
PWI
NWIP
WD / AWD
CD
DIS
5
IS
Optional, can be skipped by
default
Approval stage
Circulation to all
(sub)committee
members for
balloting
Full review by all members
of the parent TC
Circulating for comments
to national mirror committees
ballot by committee members
FDIS
& ballot
Publication at ISO server,
submitting of comments
form all stakeholders &
Figure 11.4 ISO standard development process. Standard development is driven by
consensusethe document matures by including subsequently increasing circles of stakeholders.
For some steps time limits exist. The overall process requires approximately 4e5 years.
PWI ¼ preliminary work item, NWIP ¼ new work item proposal, WD ¼ working draft,
AWD ¼ approved working draft, CD ¼ committee draft, DIS ¼ draft international standard,
FDIS ¼ final draft international standard, TC ¼ technical committee, ISO ¼ International
Organization for Standardization, p-member ¼ participating member.
11.3.4 Using standards
The use of standards is voluntary, and they do not have to be followed exactly. If a
standard is not followed (in whole or in part), a comprehensible explanation/justification in the context of a marketing authorisation application is required. All relevant
ISO standards have to be taken into account for the safety evaluation of an implant
(if it is classified as a medical device). If no ISO standard exists for a certain topic,
any national standard may be used. Manufacturers may use other methods if they
meet the relevant essential principles implemented by law, such as industry agreed
methods, internal standard operating procedures of the manufacturer, or other sources
representing the current state of technology or science. Nevertheless, the acceptability
of these methods has to be revie wed by the regulatory authorities or conformity assessment bodies. However, the advantage of using standards is that a recognised standard
“is deemed to offer the presumption of conformity to specific Essential Principles of
Safety and Performance” (GMHTF/SG1/N044:2008). This means that every time a
standard is applied during the development of a product or process (e.g., biological
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safety testing), the regulatory authorities will not ask further questions regarding the
validity and applicability of the test method covered by the corresponding standard.
Therefore, using stand ards is usually the easiest and quickest way to prove the conformity of the product with the Essential Principals. However, standards are often not
applicable (in whole or in part) to the product in question. In this case, the manufacturer has to explain why the standard was not applicable. This has to be done even if
the reasons are obvious.
Taken together, standards are international agreements to facilitate the international
trade of goods and services and to promote international cooperation in all fields of
technical, scientific, economic, and intellectual activity. Standards can be subdivided
into national or international standards according to their origin and horizontal or vertical standards according to their scope. Standards are consensus documents that make
them sometimes very superficial and the development of which usually takes several
years. Because of this, they are in general technically not state of the art. The use of
standards is voluntary, and they do not have to be followed exactly. Due to a regular
review process, the content can change. Therefore, it is important to work always with
the latest version of a standard.
11.4 Biocompatibility e one aspect of biological safety
In addition to durability and mechanical stability, ensuring biological safety is mandatory for each implant. This does not mean that the implant has to be safe in every regard
(there are no risk-free treatments); it means that the advantages of having the implant
outweigh the possible risks connected with the operation procedure, the implant function, and the implant itself. Of course, this has to be verified for every implant. Risk
management is the method of choice to ensure that the beneficial effects of an implant
will offset the possible risks (“fit for purpose”). Several ISO standards exist that provide guidance in this regard (e.g., ISO 14971 “Application of risk management to medical devices” or the ISO 22442 series regarding the risks connected with materials of
animal origin). All potential dangers should be taken into account; however, they do
not necessarily have to be tested. A convincing argument with references to the literature might also be sufficient in some cases.
The biological safety of implants can be impaired by various biological and chemical
substances (Figure 11.5). For example, it is very important for implants to be free of
microorganisms such as bacteria, fungi, and other parasites to avoid the risk of infection.
This can be achieved with different sterilisation methods such as heat, radiation, or
chemical inactivation. The sterility requirement seems obvious and easy to achieve.
However, the existence of more than 20 ISO standards regarding sterilisation methods
for medical devices and their validation, for sterilisers, and for sterile packaging (please
refer to Table 11.2 for an overview) indicates, that this is a challenge. Sterilisation can
also have an impact on the implant material, e.g., through the creation of free radicals by
disrupting the carbon chains in polymers. Therefore, it is necessary to choose a sterilisation method that is suitable for the implant material (and packaging). For example, a
sterilisation method using water steam would not be suitable for magnesium alloys.
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