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Medical Devices Regulation
CHAPTE R 10
Medical Devices Regulation Teresa Pankiewicz, Marzena Jedrzejczak-Krzepkowska, Marek Kolodziejczyk, Katarzyna Kubiak, Karolina Ludwicka, Stanislaw Bielecki Lodz University of Technology, Institute of Technical Biochemistry, Lodz, Poland
Introduction The information in the previous chapters clearly demonstrates an enormous potential of bacterial nanocellulose (BNC), an entirely natural product. Until now wound dressings, hernia mesh, and tubes (trachea, blood vessels) are the best known medical devices with the use of BNC. Due to its unique properties, it has a clear prospect of medical use. Therefore the intention of this chapter is to present the necessary information which may be helpful for researchers who are involved in the processes of BNC manufacturing, its chemical or physical modifications, creating various types of composites, and consequently for those who appreciate its applicability as a medical device. Such knowledge will, then, be used to a faster and more accurate preparation of data (i.e., research at various stages of a device development, gathering relevant documentation) relating to the certification processes required for commercial use of the products containing BNC. Medical devices are such a kind of commercial products which may become a trade product so they may be put into service or for use if they meet specific requirements. In the European Union (EU) medical devices are regulated by three main Directives [1,2] (there were also some changes to the basic directives); now the fourth Directive is being discussed, such as: • • •
Council Directive 90/385/EEC on Active Implantable Medical Devices (AIMD) (1990) The Council Directive 93/42/EEC on Medical Devices (MDD) (1993) Council Directive 98/79/EC on In Vitro Diagnostic Medical Devices (IVDMD) (1998)
It should be noted that Directive 2007/47/EC amended these two Directives and introduced one change, namely Directive 90/385 (AIMD), 93/42 (MDD), and 98/8 (BPD). The EU states should transpose the requirements of the Directives into national law, because from a formal point of view, the European Directives do not constitute direct legal basis for the citizens of the member states [3–5]. Only the implementation of these requirements in the legislation of individual countries has legal force. Bacterial NanoCellulose http://dx.doi.org/10.1016/B978-0-444-63458-0.00010-X
167
Copyright © 2016 Elsevier B.V. All rights reserved.
168 Chapter 10 Formally, a standard has the status of a harmonized standard since the moment of announcing of the relevant information in the Official Journal of the European Union [6]; there are, however, official databanks that include a list of standards recognized as harmonized [7,8] as well as the official guide for the interpretation of the Directive [2,3]. The majority of harmonized standards are regularly introduced to the normalization of the given state as national standards, for example for Poland it is PN-EN. In the case when translation into the national language is not available, relevant institutions in the given state distribute them as discretionary standards using the content of European standards in the original language by introducing additional symbols (they are marked with an extra “U” symbol in the Polish Committee for Standardization catalogs). In urgent cases, it is possible to adapt the original standard from ISO or a national standard from a different Member State. In the case of many medical devices, especially the simple ones, harmonized standards which define technical requirements are not available. In accordance with the requirements of the Directive, devices must be designed and manufactured according to the current state of knowledge. This knowledge might come from, for example, other European and national standards (as long as they are relatively new), International Organization for Standardization or International Electrotechnical Commission, specialist literature or promotional materials of products with similar characteristics. European Pharmacopeia includes standards which may define the properties of used materials. Regardless of that, horizontal harmonized standards may usually be used in the scope of risk management. Documents which should be taken into account in the design of the product are posted on the website [2].
Obligations of Manufacturers, Authorized Representatives, Importers, Distributors Directive 2007/47/EC requires the registration of medical devices. This responsibility rests on manufacturers and authorized representatives legally established in the community. Prior to placing a product on the market, they are required to submit a device to the relevant institution in individual states in the required time (e.g., in Poland, to the President of the Office at least 14 days before putting it into service for the first time). A manufacturer means a body responsible for the design, manufacture, packaging, and labeling of the device regardless of the fact whether these operations are performed by them or another body on behalf of the manufacturer. An authorized representative is a body that legally represents a manufacturer that is not a natural or legal body established in the Community, but it puts into service and for use a product under its own name. The authorized representative is then responsible for the
Medical Devices Regulation 169 manufacture, thus, inter alia, for the execution of the conformity assessment before putting it into service and for use. A distributor means a natural or legal body established in the Community that provides or makes available a device after putting it into service. An importer means also a natural or legal body established in the Community that puts into service a device from outside the territory of Member States. A health care provider shall be both a distributor and an importer who imports a device intended to provide health care services by this provider on the territory of the given state from another Member State. Both the distributor and importer are responsible for the manufacture and the conformity assessment if they distribute a product that has not been subject to applicable requirements. The obligations of the importers and distributors are clearly determined by the laws in each state. The importer and distributor shall take all necessary steps to ensure that the device, at the time when they are responsible for it, the conditions of its storage, and transport will not affect its compliance with the requirements as defined in the laws in each state. Moreover, they are obliged to submit and identify medical incidents.
Definition of Medical Device and its Classification In accordance with the Directive MDD, a 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: 1. 2. 3. 4.
diagnosis, prevention, monitoring, treatment, or alleviation of disease diagnosis, monitoring, treatment, alleviation, 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.
Principal directives for medical devices, which have been aforementioned, are in a way the pillars of: • • •
MDD—Medical Device Directive-93/42/EEC on Medical Devices AIMD on Active Implantable Medical Devices 90/385/EEC IVD on In Vitro Diagnostics Device Directive—98/79/EC
Thus, briefly, medical devices are such extra pharmacological devices which are intended to be used in diagnosis, treatment, or prevention as well as contraceptives with the emphasis on
170 Chapter 10 the word intended. It is the manufacturer or an authorized representative who decides—based on the existing legislation—whether a given product is a medical device. For instance, a tooth brush, gym equipment, contact lenses, or cosmetics meet all the criteria for medical devices; however, these products are not classified as medical devices although they do meet the relevant requirements. Medical devices are divided into Classes: I, IIa, IIb, III. Classification must be done in accordance with annex IX of the Directive MDD. While classifying medical devices one must use the classification criteria which take into account the time of the uninterrupted contact of the medical device with a patient, a kind of contact with the patient, the degree of invasiveness of the device, local and systemic effect, the function it performs, and technology used. Duration of contact: transient—intended for continuous use for less than 60 min, short-term— intended for continuous use for up to 30 days, and long-term—intended for continuous use for more than 30 days. The degree of invasiveness is determined by the following criteria: transcutaneously or through the natural body foramina applied, surgical invasive, implantation. Initial consideration of these factors gives a basis for further classification which can be made by the manufacturer himself or, in the case of more complicated products, the manufacturer along with the notified body (list of European notified bodies can be found in the Annex). It should be noted again that the rules of classification must be applied while taking into consideration the intention of the product application. The higher the class, the bigger the risk of a given device. After the initial classification of medical devices and determining their degree of invasiveness, one must apply the rules of classification. This problem is regulated in individual states. The problem of classification of the rules is very extensive; however, there are four main rules under which one must assign a given device, and within which there are additional subrules: • • • •
rules applicable to noninvasive medical devices rules applicable to invasive medical devices additional rules applicable to active medical devices special rules
The attribution of a medical device to the given rule is the starting point to the further classification in accordance with the classification pathways, which are different depending on various groups of medical devices. One must bear in mind that the problem of the in vitro diagnostics device as well as AIMD are regulated by separate Directives. If there are discrepancies concerning the classification of the given medical device or the classification of a device to the in vitro diagnostics device that arise between a manufacturer and a notified body, they shall be settled by an administrative
Medical Devices Regulation 171 decision made by relevant instances in the given state and then they must be justified before the European Commission.
Conformity Assessment Procedures Prior to Putting a Medical Device into Service and Use Various conformity assessment procedures are applied depending on the class of the device. Thus, there are various ways of obtaining the CE mark (product certification and registration).
Essential Requirements The conformity assessment is the most important document that should be made in correlation with Annex I of the 93/42/EEC + 2007/47/EC Directive as well as in accordance with the appropriate regulations in the given state. The document concerning the essential requirements must answer the following questions whether a medical device: • • • • • •
is designed, manufactured, and packaged in such a way that it is suitable for one or more of the functions in accordance with the definition of a medical device meets the safety requirements based on the current state of knowledge ensures an appropriate clinical condition and patient safety ensures the safety of health care is protected against infection and microbial contamination and radiation ensures that the declared properties will not be lost during transport and storage
Conformity Assessment Procedures Conformity assessment is carried out depending on product classification. The manufacturer notified body [9] (if the device is subject to the necessary cooperation with the body) chooses the way of conformity assessment as defined in Annexes II-VII of the MDD [6]. It is important to bear in mind that if a device is subject to procedures II-VI, the notified body is indispensable for the assessment. The manufacturer may hire any notified body [9,10], which received relevant permits within the European Union. Such bodies have various scopes of notification and this fact must be taken into consideration while choosing the body. The devices assessed with the participation of the notified body receive a CE symbol with a four-digit number of this body, for instance (ID)0543. Thus, the CE mark placed on the device means that it is safe, the appropriate conformity assessment procedure has been carried out and that it is in compliance with all applicable essential requirements for this device. When the class of a medical device is ultimately determined, it is followed by a procedure that leads to obtaining the CE Declaration of Conformity in accordance with the medical devices MDD 93/42/EEC along with the annexes [1,6].
172 Chapter 10 Documentation of conformity assessment—“EC technical documentation,” including Class III (if applicable) design documentation The main goal of creating a technical documentation of a device in the scope required by MDD is to provide the evidence that demonstrates meeting essential requirements concerning the device in question. The technical documentation basically for all classes of devices should include: • • • • • • • • • • •
• •
information on medical device classification general description of the device including planned variants, its operation as well as its intended use design drawings, diagrams, or description of the methods of production descriptions and explanations necessary to understand drawings and diagrams and operation of a medical device results of physicochemical, microbiological, or other research recommended by the notified body for the given device risk analysis preclinical evaluation clinical evaluation methods of sterilization and validation report labels and instructions for use list of harmonized standards, applied in full or in part as well as descriptions of the solutions adopted in order to meet the essential requirements if harmonized standards have not been fully applied checklist of conformity with essential requirements declaration of conformity
Technical documentation, or in other words materials listed above, are partially nonsecret (the so-called part A) when they do not apply to the manufacturer’s know-how. And the classified part (the so-called part B) is the part that concerns the descriptions relating to the manufacturing technology as well as the details concerning research, tests, and other aspects of validation. These documents do not need to be immediately accessible; they may be stored by the original manufacturer.
Risk Management Risk analysis is a component of risk management and it is mandatory to carry out a risk assessment of the given device. National standards (e.g., PN-EN 14971) specify the procedure according to which Marketing Authorization Holder/Manufacturer carries out the identification of all possible risks. Moreover, it facilitates the estimate of the likelihood of damage, its frequency, and the consequences at all stages of the life cycle of a device from its design, production, installation to the service, or use of the given device for its intended purpose. However, it does not determine the probable and acceptable levels of risk and it
Medical Devices Regulation 173 is not applicable in the case of clinical decision-making. Risk management consists of the following stages: risk assessment, risk acceptability assessment, risk control, risk assessment of the admissibility of the total residual, information from the production and postproduction phase as well as report on risk management.
Clinical Evaluation Clinical evaluation is carried out to determine the level of usefulness and the benefits in relation to the risk on the one hand by the proper impact assessment (i.e., to determine the degree of treatment or the contribution to such), and on the other hand by the estimate of the side effects as well as undesirable situations related to the use of the device. Clinical investigations are designed to determine whether the properties and operation of the device under normal conditions of its use shall comply with the essential requirements. The clinical investigations must be conducted in accordance with the provisions of Annex X (MDD) and procedure ISO EN 14155:2011 [11]. The clinical assessment can be carried out on the basis of: a critical assessment of the currently available scientific literature on the safety, performance and properties, or a critical assessment of the results of clinical investigations and a critical total assessment of the above data. In order to be able to carry out a clinical evaluation for a given product, the manufacturer must obtain the consent of the relevant institution in the given state as well as issue a request for an opinion given by the Bioethics Committee on the study that is being carried out.
Special Processes—Sterilization, Packaging Some medical devices are subject to sterilization processes, they have a specified expiration date, and they must remain sterile. Each of the applied sterilization methods is subject to the process of validation. Similarly, packaging, a kind of used packaging must have appropriate certificates and the system of packaging must be equipped with the documents confirming the validation of the device.
Marking of Medical Devices CE marking can be placed on the device only after the declaration of conformity has been carried out, which should include: • • • • • • •
name and address of the manufacturer name and address of the authorized representative, if applicable data identifying the device declaration of conformity of the device with the requirements of Regulation indication of the harmonized standards applied or technical specifications applied conformity assessment procedure identification number of the notified body, if it took part in the conformity assessment
174 Chapter 10 • •
first and last name, position, and signature of the person authorized by the manufacturer to issue a declaration of conformity place and date of issue
CE mark is placed in a legible and indelible way, primarily in the instructions for use, on the sales packaging, but also on the packaging ensuring the sterility of an AIMD or another sterile medical device and diagnostic medical devices (if possible). Each package must be equipped with instructions for use, which is clearly edited according to the level of training and knowledge of the potential users and the information necessary to identify the manufacturer.
Registrations and Notifications Concerning Devices Before the device is put into service or use, the manufacturer or its authorized representative shall make a submission and registration in the appropriate authority in the given state, within the time specified by the regulations. In contrast, the distributor or importer naturally or legally residing in the given state shall immediately notify the President of the appropriate office, no later than the specified number of days counting from the date of introduction of the first device.
Policies on the Use and Maintaining Devices Medical devices should be used and stored by the user in accordance with the attached instruction. It is recommended to use a language that is spoken in the given state (in Poland, devices provided to the user may also be available in the English language). The manufacturer authorized representative, importer, and distributor shall store medical devices according to recommended procedures for the given device.
Supervision of Products As it has already been mentioned, medical devices must ensure the safety of both patients and caregivers, and therefore they are subject to special security-related activities. All medical devices that are put into service or imported in order to be used on the Polish market must have available information on the product, as well as specific conditions for treatment related to the use and storage of products in accordance with their use determined by their manufacturer. According to the Directive on medical devices, all users are required to comply with the instructions for use provided with the product by the manufacturer. Instructions for use should include numerous details; a few of them are listed below: • •
the information provided on the label with the exception of the serial number (LOT) and expiration date operation parameters and any undesirable effects
Medical Devices Regulation 175 •
•
if the device, in order to work in accordance with its intended purpose, is to work together with other medical devices or equipment, or be connected with them, it should contain sufficient information to its correct connection and operation information needed to check whether the medical device is properly installed and whether it functions correctly and safely, and detailed information on the type and frequency to perform maintenance and calibration needed to ensure that the medical device will always work correctly and safely, along with others.
Electronic instructions for use may also be applied insofar as they concern relevant devices, among others, AIMDs and their accessories, permanently installed medical devices, medical devices with an integrated display system for displaying the instructions for use, independent software. Importer and distributor shall cooperate with the President of the given Office and with the manufacturer or an authorized representative in matters of medical incidents and the safety of products. If they obtain (Zero Conditional) information that the device which was put into service may be dangerous, they are immediately obliged to take action and to instantly notify the President of the Office. They are also, or perhaps above all, obliged to submit any users’ information on the hazards caused by the devices.
Protection of Conformity Assessment Documentation The manufacturer is obliged to keep the record of the conformity assessment of the device for a period of 5 years from the date of completion, and for 15 years for the device to be implanted and AIMD. Medical devices must be designed, manufactured, and packaged in such a way that is appropriate to the functions and parameters of their operation, as specified by the manufacturer. They must comply with all the conditions so that their use—as intended by the manufacturer of the application—directly or indirectly will not threaten the clinical state, the safety of patients, the health and safety of users as well as third parties.
Annex Links [1] http://ec.europa.eu/growth/sectors/medical-devices/, http://ec.europa.eu/growth/sectors/medical-devices/ regulatory-framework/index_en.htm regulatory framework/, legislation, 7.02.2015. [2] http://ec.europa.eu/health/medical-devices/documents/guidelines/index_en.htm, guidance MEDDEVs, 12.02.2015. [3] http://www.cmc-md.eu/decisions.html—decisions made by the Central Management Committee, 12.02.2015. [4] http://ec.europa.eu/growth/sectors/medical-devices/links/contact_points_en.htm, http://ec.europa.eu/health/ medical-devices/files/list-of-contact-points-within-the-national_en.pdf —list of contact points within the national competent authorities, 12.02.2015.
176 Chapter 10 [5] http://www.mdss.com/home/EuropeanAuthorizedReps.htm - MDSS European Authorized Representative Services—the main contact for the European Commission and the National Competent Authorities. [6] http://publications.europa.eu/official/index_en.htm, Official Journal of the European Union, 7.02.2015. [7] http://ec.europa.eu/enterprise/policies/european-standards/harmonised-standards/index_en.htm, harmonized standards, 7.02.2015. [8] http://www.imdrf.org/documents/documents.asp. The International Medical Device Regulators Forum (IMDRF)—discussion forum concerning future directions in medical device regulatory harmonization, 12. 02.2015. [9] http://ec.europa.eu/enterprise/newapproach/nando/index.cfm?fuseaction=directive.pdf&refe_cd=93%2F42% 2FEEC&requesttimeout=900, list of bodies notified, 7.02.2015. [10] http://www.nbog.eu/2.html, the guidelines, which notified bodies, and thus manufacturers should follow, 12.02.2015. [11] http://www.iso.org/iso/catalogue_detail?csnumber=45557 – ISO 14155:2011. Clinical investigation of medical devices for human subjects - Good clinical practice, 24.06.2015
Glossary (given in accordance with directive: MDD, AIMD, 93/42/EEC and directive: 2007/47/EC) •
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•
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•
•
“accessory” means an article which whilst not being a device is intended specifically by its manufacturer to be used together with a device to enable it to be used in accordance with the use of the device intended by the manufacturer of the device; “AIMD” 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 “active medical device” means any medical device relying for its functioning on a source of electrical energy or any source of power other than that directly generated by the human body or gravity “authorized representative” means any natural or legal person established in the community who is explicitly designated by the manufacturer with regard to the latter’s obligations under this directive “clinical data” means the safety and/or performance information that is generated from the use of device. Clinical data are sourced from: • clinical investigation(s) of the device concerned, or • clinical investigation(s) or other studies reported in the scientific literature, of a similar device for which equivalence to the device in question can be demonstrated, or • published and/or unpublished reports on other clinical experience of either the device in question or a similar device for which equivalence to the device in question can be demonstrated “custom-made device” means any device specifically made in accordance with a duly qualified medical practitioner’s written prescription which gives, under his responsibility, specific design characteristics and is intended for the sole use of a particular patient. The above-mentioned prescription may also be made out by any other person authorized by virtue of his qualifications to do so. Mass-produced devices which need to be adapted to
Medical Devices Regulation 177
•
•
•
•
•
•
meet the specific requirements of the medical practitioner or any other professional user are not considered to be custom-made devices; “device intended for clinical investigation” means any device intended for use by a duly qualified medical practitioner when conducting investigations as referred to in Section 2.1 of Annex X in an adequate human clinical environment. For the purpose of conducting clinical investigation, any other person who, by virtue of his professional qualifications, is authorized to carry out such investigation shall be accepted as equivalent to a duly qualified medical practitioner; “device used for in vitro diagnosis” means any device which is a reagent, reagent product, kit, instrument, equipment, or system, whether used alone or in combination, intended by the manufacturer to be used in vitro for the examination of samples derived from the human body with a view to providing information on the physiological state, state of health or disease, or congenital abnormality thereof; “intended purpose” means the use for which the device is intended according to the data supplied by the manufacturer on the labeling, in the instructions, and/or in promotional materials; “manufacturer” means the natural or legal person with responsibility for the design, manufacture, packaging, and labeling of a device before it is placed on the market under his own name, regardless of whether these operations are carried out by that person himself or on his behalf by a third party. The obligations of this Directive to be met by manufacturers also apply to the natural or legal person who assembles, packages, processes, fully refurbishes, and/or labels one or more ready-made products and/or assigns to them their intended purpose as a device with a view to their being placed on the market under his own name. This subparagraph does not apply to the person who, while not a manufacturer within the meaning of the first subparagraph, assembles or adapts devices already on the market to their intended purpose for an individual patient; “medical device” means any instrument, apparatus, appliance, material, or other article, whether used alone or in combination, including the software 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 pharmacologic, immunologic, or metabolic means, but which may be assisted in its function by such means; “medical incident”: malfunction, defect, or deterioration of the device, as well as irregularity in the labeling or the instructions for use, which may or may not lead to
178 Chapter 10
•
•
•
death or serious deterioration in the health of the patient or user of the product, and in the case of a medical device for in vitro diagnostic product or equipment medical diagnostic in vitro—indirectly, another person, or • technical or medical reason connected with the characteristics or performance of a device, which may or could result in death or serious deterioration in the health of the patient or user, in the case of diagnostic medical devices or equipment in vitro diagnostic medical devices • in vitro - indirectly, another person and therefore leading to a decision by the manufacturer of the external safety corrective actions. “notified body” means the bodies designated by the EU Member State to assess whether a product meets required standards. The Commission has assigned identification numbers to the body. “placing on the market” means the first making available in return for payment or free of charge of a device other than a device intended for clinical investigation, with a view to distribution and/or use on the Community market, regardless of whether it is new or fully refurbished; “putting into service” means the stage at which a device is ready for use on the Community market for the first time for its intended purpose.
Medical Devices Regulation Teresa Pankiewicz, Marzena Jedrzejczak-Krzepkowska, Marek Kolodziejczyk, Katarzyna Kubiak, Karolina Ludwicka, Stanislaw Bielecki Lodz University of Technology, Institute of Technical Biochemistry, Lodz, Poland
Introduction The information in the previous chapters clearly demonstrates an enormous potential of bacterial nanocellulose (BNC), an entirely natural product. Until now wound dressings, hernia mesh, and tubes (trachea, blood vessels) are the best known medical devices with the use of BNC. Due to its unique properties, it has a clear prospect of medical use. Therefore the intention of this chapter is to present the necessary information which may be helpful for researchers who are involved in the processes of BNC manufacturing, its chemical or physical modifications, creating various types of composites, and consequently for those who appreciate its applicability as a medical device. Such knowledge will, then, be used to a faster and more accurate preparation of data (i.e., research at various stages of a device development, gathering relevant documentation) relating to the certification processes required for commercial use of the products containing BNC. Medical devices are such a kind of commercial products which may become a trade product so they may be put into service or for use if they meet specific requirements. In the European Union (EU) medical devices are regulated by three main Directives [1,2] (there were also some changes to the basic directives); now the fourth Directive is being discussed, such as: • • •
Council Directive 90/385/EEC on Active Implantable Medical Devices (AIMD) (1990) The Council Directive 93/42/EEC on Medical Devices (MDD) (1993) Council Directive 98/79/EC on In Vitro Diagnostic Medical Devices (IVDMD) (1998)
It should be noted that Directive 2007/47/EC amended these two Directives and introduced one change, namely Directive 90/385 (AIMD), 93/42 (MDD), and 98/8 (BPD). The EU states should transpose the requirements of the Directives into national law, because from a formal point of view, the European Directives do not constitute direct legal basis for the citizens of the member states [3–5]. Only the implementation of these requirements in the legislation of individual countries has legal force. Bacterial NanoCellulose http://dx.doi.org/10.1016/B978-0-444-63458-0.00010-X
167
Copyright © 2016 Elsevier B.V. All rights reserved.
168 Chapter 10 Formally, a standard has the status of a harmonized standard since the moment of announcing of the relevant information in the Official Journal of the European Union [6]; there are, however, official databanks that include a list of standards recognized as harmonized [7,8] as well as the official guide for the interpretation of the Directive [2,3]. The majority of harmonized standards are regularly introduced to the normalization of the given state as national standards, for example for Poland it is PN-EN. In the case when translation into the national language is not available, relevant institutions in the given state distribute them as discretionary standards using the content of European standards in the original language by introducing additional symbols (they are marked with an extra “U” symbol in the Polish Committee for Standardization catalogs). In urgent cases, it is possible to adapt the original standard from ISO or a national standard from a different Member State. In the case of many medical devices, especially the simple ones, harmonized standards which define technical requirements are not available. In accordance with the requirements of the Directive, devices must be designed and manufactured according to the current state of knowledge. This knowledge might come from, for example, other European and national standards (as long as they are relatively new), International Organization for Standardization or International Electrotechnical Commission, specialist literature or promotional materials of products with similar characteristics. European Pharmacopeia includes standards which may define the properties of used materials. Regardless of that, horizontal harmonized standards may usually be used in the scope of risk management. Documents which should be taken into account in the design of the product are posted on the website [2].
Obligations of Manufacturers, Authorized Representatives, Importers, Distributors Directive 2007/47/EC requires the registration of medical devices. This responsibility rests on manufacturers and authorized representatives legally established in the community. Prior to placing a product on the market, they are required to submit a device to the relevant institution in individual states in the required time (e.g., in Poland, to the President of the Office at least 14 days before putting it into service for the first time). A manufacturer means a body responsible for the design, manufacture, packaging, and labeling of the device regardless of the fact whether these operations are performed by them or another body on behalf of the manufacturer. An authorized representative is a body that legally represents a manufacturer that is not a natural or legal body established in the Community, but it puts into service and for use a product under its own name. The authorized representative is then responsible for the
Medical Devices Regulation 169 manufacture, thus, inter alia, for the execution of the conformity assessment before putting it into service and for use. A distributor means a natural or legal body established in the Community that provides or makes available a device after putting it into service. An importer means also a natural or legal body established in the Community that puts into service a device from outside the territory of Member States. A health care provider shall be both a distributor and an importer who imports a device intended to provide health care services by this provider on the territory of the given state from another Member State. Both the distributor and importer are responsible for the manufacture and the conformity assessment if they distribute a product that has not been subject to applicable requirements. The obligations of the importers and distributors are clearly determined by the laws in each state. The importer and distributor shall take all necessary steps to ensure that the device, at the time when they are responsible for it, the conditions of its storage, and transport will not affect its compliance with the requirements as defined in the laws in each state. Moreover, they are obliged to submit and identify medical incidents.
Definition of Medical Device and its Classification In accordance with the Directive MDD, a 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: 1. 2. 3. 4.
diagnosis, prevention, monitoring, treatment, or alleviation of disease diagnosis, monitoring, treatment, alleviation, 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.
Principal directives for medical devices, which have been aforementioned, are in a way the pillars of: • • •
MDD—Medical Device Directive-93/42/EEC on Medical Devices AIMD on Active Implantable Medical Devices 90/385/EEC IVD on In Vitro Diagnostics Device Directive—98/79/EC
Thus, briefly, medical devices are such extra pharmacological devices which are intended to be used in diagnosis, treatment, or prevention as well as contraceptives with the emphasis on
170 Chapter 10 the word intended. It is the manufacturer or an authorized representative who decides—based on the existing legislation—whether a given product is a medical device. For instance, a tooth brush, gym equipment, contact lenses, or cosmetics meet all the criteria for medical devices; however, these products are not classified as medical devices although they do meet the relevant requirements. Medical devices are divided into Classes: I, IIa, IIb, III. Classification must be done in accordance with annex IX of the Directive MDD. While classifying medical devices one must use the classification criteria which take into account the time of the uninterrupted contact of the medical device with a patient, a kind of contact with the patient, the degree of invasiveness of the device, local and systemic effect, the function it performs, and technology used. Duration of contact: transient—intended for continuous use for less than 60 min, short-term— intended for continuous use for up to 30 days, and long-term—intended for continuous use for more than 30 days. The degree of invasiveness is determined by the following criteria: transcutaneously or through the natural body foramina applied, surgical invasive, implantation. Initial consideration of these factors gives a basis for further classification which can be made by the manufacturer himself or, in the case of more complicated products, the manufacturer along with the notified body (list of European notified bodies can be found in the Annex). It should be noted again that the rules of classification must be applied while taking into consideration the intention of the product application. The higher the class, the bigger the risk of a given device. After the initial classification of medical devices and determining their degree of invasiveness, one must apply the rules of classification. This problem is regulated in individual states. The problem of classification of the rules is very extensive; however, there are four main rules under which one must assign a given device, and within which there are additional subrules: • • • •
rules applicable to noninvasive medical devices rules applicable to invasive medical devices additional rules applicable to active medical devices special rules
The attribution of a medical device to the given rule is the starting point to the further classification in accordance with the classification pathways, which are different depending on various groups of medical devices. One must bear in mind that the problem of the in vitro diagnostics device as well as AIMD are regulated by separate Directives. If there are discrepancies concerning the classification of the given medical device or the classification of a device to the in vitro diagnostics device that arise between a manufacturer and a notified body, they shall be settled by an administrative
Medical Devices Regulation 171 decision made by relevant instances in the given state and then they must be justified before the European Commission.
Conformity Assessment Procedures Prior to Putting a Medical Device into Service and Use Various conformity assessment procedures are applied depending on the class of the device. Thus, there are various ways of obtaining the CE mark (product certification and registration).
Essential Requirements The conformity assessment is the most important document that should be made in correlation with Annex I of the 93/42/EEC + 2007/47/EC Directive as well as in accordance with the appropriate regulations in the given state. The document concerning the essential requirements must answer the following questions whether a medical device: • • • • • •
is designed, manufactured, and packaged in such a way that it is suitable for one or more of the functions in accordance with the definition of a medical device meets the safety requirements based on the current state of knowledge ensures an appropriate clinical condition and patient safety ensures the safety of health care is protected against infection and microbial contamination and radiation ensures that the declared properties will not be lost during transport and storage
Conformity Assessment Procedures Conformity assessment is carried out depending on product classification. The manufacturer notified body [9] (if the device is subject to the necessary cooperation with the body) chooses the way of conformity assessment as defined in Annexes II-VII of the MDD [6]. It is important to bear in mind that if a device is subject to procedures II-VI, the notified body is indispensable for the assessment. The manufacturer may hire any notified body [9,10], which received relevant permits within the European Union. Such bodies have various scopes of notification and this fact must be taken into consideration while choosing the body. The devices assessed with the participation of the notified body receive a CE symbol with a four-digit number of this body, for instance (ID)0543. Thus, the CE mark placed on the device means that it is safe, the appropriate conformity assessment procedure has been carried out and that it is in compliance with all applicable essential requirements for this device. When the class of a medical device is ultimately determined, it is followed by a procedure that leads to obtaining the CE Declaration of Conformity in accordance with the medical devices MDD 93/42/EEC along with the annexes [1,6].
172 Chapter 10 Documentation of conformity assessment—“EC technical documentation,” including Class III (if applicable) design documentation The main goal of creating a technical documentation of a device in the scope required by MDD is to provide the evidence that demonstrates meeting essential requirements concerning the device in question. The technical documentation basically for all classes of devices should include: • • • • • • • • • • •
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information on medical device classification general description of the device including planned variants, its operation as well as its intended use design drawings, diagrams, or description of the methods of production descriptions and explanations necessary to understand drawings and diagrams and operation of a medical device results of physicochemical, microbiological, or other research recommended by the notified body for the given device risk analysis preclinical evaluation clinical evaluation methods of sterilization and validation report labels and instructions for use list of harmonized standards, applied in full or in part as well as descriptions of the solutions adopted in order to meet the essential requirements if harmonized standards have not been fully applied checklist of conformity with essential requirements declaration of conformity
Technical documentation, or in other words materials listed above, are partially nonsecret (the so-called part A) when they do not apply to the manufacturer’s know-how. And the classified part (the so-called part B) is the part that concerns the descriptions relating to the manufacturing technology as well as the details concerning research, tests, and other aspects of validation. These documents do not need to be immediately accessible; they may be stored by the original manufacturer.
Risk Management Risk analysis is a component of risk management and it is mandatory to carry out a risk assessment of the given device. National standards (e.g., PN-EN 14971) specify the procedure according to which Marketing Authorization Holder/Manufacturer carries out the identification of all possible risks. Moreover, it facilitates the estimate of the likelihood of damage, its frequency, and the consequences at all stages of the life cycle of a device from its design, production, installation to the service, or use of the given device for its intended purpose. However, it does not determine the probable and acceptable levels of risk and it
Medical Devices Regulation 173 is not applicable in the case of clinical decision-making. Risk management consists of the following stages: risk assessment, risk acceptability assessment, risk control, risk assessment of the admissibility of the total residual, information from the production and postproduction phase as well as report on risk management.
Clinical Evaluation Clinical evaluation is carried out to determine the level of usefulness and the benefits in relation to the risk on the one hand by the proper impact assessment (i.e., to determine the degree of treatment or the contribution to such), and on the other hand by the estimate of the side effects as well as undesirable situations related to the use of the device. Clinical investigations are designed to determine whether the properties and operation of the device under normal conditions of its use shall comply with the essential requirements. The clinical investigations must be conducted in accordance with the provisions of Annex X (MDD) and procedure ISO EN 14155:2011 [11]. The clinical assessment can be carried out on the basis of: a critical assessment of the currently available scientific literature on the safety, performance and properties, or a critical assessment of the results of clinical investigations and a critical total assessment of the above data. In order to be able to carry out a clinical evaluation for a given product, the manufacturer must obtain the consent of the relevant institution in the given state as well as issue a request for an opinion given by the Bioethics Committee on the study that is being carried out.
Special Processes—Sterilization, Packaging Some medical devices are subject to sterilization processes, they have a specified expiration date, and they must remain sterile. Each of the applied sterilization methods is subject to the process of validation. Similarly, packaging, a kind of used packaging must have appropriate certificates and the system of packaging must be equipped with the documents confirming the validation of the device.
Marking of Medical Devices CE marking can be placed on the device only after the declaration of conformity has been carried out, which should include: • • • • • • •
name and address of the manufacturer name and address of the authorized representative, if applicable data identifying the device declaration of conformity of the device with the requirements of Regulation indication of the harmonized standards applied or technical specifications applied conformity assessment procedure identification number of the notified body, if it took part in the conformity assessment
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first and last name, position, and signature of the person authorized by the manufacturer to issue a declaration of conformity place and date of issue
CE mark is placed in a legible and indelible way, primarily in the instructions for use, on the sales packaging, but also on the packaging ensuring the sterility of an AIMD or another sterile medical device and diagnostic medical devices (if possible). Each package must be equipped with instructions for use, which is clearly edited according to the level of training and knowledge of the potential users and the information necessary to identify the manufacturer.
Registrations and Notifications Concerning Devices Before the device is put into service or use, the manufacturer or its authorized representative shall make a submission and registration in the appropriate authority in the given state, within the time specified by the regulations. In contrast, the distributor or importer naturally or legally residing in the given state shall immediately notify the President of the appropriate office, no later than the specified number of days counting from the date of introduction of the first device.
Policies on the Use and Maintaining Devices Medical devices should be used and stored by the user in accordance with the attached instruction. It is recommended to use a language that is spoken in the given state (in Poland, devices provided to the user may also be available in the English language). The manufacturer authorized representative, importer, and distributor shall store medical devices according to recommended procedures for the given device.
Supervision of Products As it has already been mentioned, medical devices must ensure the safety of both patients and caregivers, and therefore they are subject to special security-related activities. All medical devices that are put into service or imported in order to be used on the Polish market must have available information on the product, as well as specific conditions for treatment related to the use and storage of products in accordance with their use determined by their manufacturer. According to the Directive on medical devices, all users are required to comply with the instructions for use provided with the product by the manufacturer. Instructions for use should include numerous details; a few of them are listed below: • •
the information provided on the label with the exception of the serial number (LOT) and expiration date operation parameters and any undesirable effects
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if the device, in order to work in accordance with its intended purpose, is to work together with other medical devices or equipment, or be connected with them, it should contain sufficient information to its correct connection and operation information needed to check whether the medical device is properly installed and whether it functions correctly and safely, and detailed information on the type and frequency to perform maintenance and calibration needed to ensure that the medical device will always work correctly and safely, along with others.
Electronic instructions for use may also be applied insofar as they concern relevant devices, among others, AIMDs and their accessories, permanently installed medical devices, medical devices with an integrated display system for displaying the instructions for use, independent software. Importer and distributor shall cooperate with the President of the given Office and with the manufacturer or an authorized representative in matters of medical incidents and the safety of products. If they obtain (Zero Conditional) information that the device which was put into service may be dangerous, they are immediately obliged to take action and to instantly notify the President of the Office. They are also, or perhaps above all, obliged to submit any users’ information on the hazards caused by the devices.
Protection of Conformity Assessment Documentation The manufacturer is obliged to keep the record of the conformity assessment of the device for a period of 5 years from the date of completion, and for 15 years for the device to be implanted and AIMD. Medical devices must be designed, manufactured, and packaged in such a way that is appropriate to the functions and parameters of their operation, as specified by the manufacturer. They must comply with all the conditions so that their use—as intended by the manufacturer of the application—directly or indirectly will not threaten the clinical state, the safety of patients, the health and safety of users as well as third parties.
Annex Links [1] http://ec.europa.eu/growth/sectors/medical-devices/, http://ec.europa.eu/growth/sectors/medical-devices/ regulatory-framework/index_en.htm regulatory framework/, legislation, 7.02.2015. [2] http://ec.europa.eu/health/medical-devices/documents/guidelines/index_en.htm, guidance MEDDEVs, 12.02.2015. [3] http://www.cmc-md.eu/decisions.html—decisions made by the Central Management Committee, 12.02.2015. [4] http://ec.europa.eu/growth/sectors/medical-devices/links/contact_points_en.htm, http://ec.europa.eu/health/ medical-devices/files/list-of-contact-points-within-the-national_en.pdf —list of contact points within the national competent authorities, 12.02.2015.
176 Chapter 10 [5] http://www.mdss.com/home/EuropeanAuthorizedReps.htm - MDSS European Authorized Representative Services—the main contact for the European Commission and the National Competent Authorities. [6] http://publications.europa.eu/official/index_en.htm, Official Journal of the European Union, 7.02.2015. [7] http://ec.europa.eu/enterprise/policies/european-standards/harmonised-standards/index_en.htm, harmonized standards, 7.02.2015. [8] http://www.imdrf.org/documents/documents.asp. The International Medical Device Regulators Forum (IMDRF)—discussion forum concerning future directions in medical device regulatory harmonization, 12. 02.2015. [9] http://ec.europa.eu/enterprise/newapproach/nando/index.cfm?fuseaction=directive.pdf&refe_cd=93%2F42% 2FEEC&requesttimeout=900, list of bodies notified, 7.02.2015. [10] http://www.nbog.eu/2.html, the guidelines, which notified bodies, and thus manufacturers should follow, 12.02.2015. [11] http://www.iso.org/iso/catalogue_detail?csnumber=45557 – ISO 14155:2011. Clinical investigation of medical devices for human subjects - Good clinical practice, 24.06.2015
Glossary (given in accordance with directive: MDD, AIMD, 93/42/EEC and directive: 2007/47/EC) •
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“accessory” means an article which whilst not being a device is intended specifically by its manufacturer to be used together with a device to enable it to be used in accordance with the use of the device intended by the manufacturer of the device; “AIMD” 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 “active medical device” means any medical device relying for its functioning on a source of electrical energy or any source of power other than that directly generated by the human body or gravity “authorized representative” means any natural or legal person established in the community who is explicitly designated by the manufacturer with regard to the latter’s obligations under this directive “clinical data” means the safety and/or performance information that is generated from the use of device. Clinical data are sourced from: • clinical investigation(s) of the device concerned, or • clinical investigation(s) or other studies reported in the scientific literature, of a similar device for which equivalence to the device in question can be demonstrated, or • published and/or unpublished reports on other clinical experience of either the device in question or a similar device for which equivalence to the device in question can be demonstrated “custom-made device” means any device specifically made in accordance with a duly qualified medical practitioner’s written prescription which gives, under his responsibility, specific design characteristics and is intended for the sole use of a particular patient. The above-mentioned prescription may also be made out by any other person authorized by virtue of his qualifications to do so. Mass-produced devices which need to be adapted to
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meet the specific requirements of the medical practitioner or any other professional user are not considered to be custom-made devices; “device intended for clinical investigation” means any device intended for use by a duly qualified medical practitioner when conducting investigations as referred to in Section 2.1 of Annex X in an adequate human clinical environment. For the purpose of conducting clinical investigation, any other person who, by virtue of his professional qualifications, is authorized to carry out such investigation shall be accepted as equivalent to a duly qualified medical practitioner; “device used for in vitro diagnosis” means any device which is a reagent, reagent product, kit, instrument, equipment, or system, whether used alone or in combination, intended by the manufacturer to be used in vitro for the examination of samples derived from the human body with a view to providing information on the physiological state, state of health or disease, or congenital abnormality thereof; “intended purpose” means the use for which the device is intended according to the data supplied by the manufacturer on the labeling, in the instructions, and/or in promotional materials; “manufacturer” means the natural or legal person with responsibility for the design, manufacture, packaging, and labeling of a device before it is placed on the market under his own name, regardless of whether these operations are carried out by that person himself or on his behalf by a third party. The obligations of this Directive to be met by manufacturers also apply to the natural or legal person who assembles, packages, processes, fully refurbishes, and/or labels one or more ready-made products and/or assigns to them their intended purpose as a device with a view to their being placed on the market under his own name. This subparagraph does not apply to the person who, while not a manufacturer within the meaning of the first subparagraph, assembles or adapts devices already on the market to their intended purpose for an individual patient; “medical device” means any instrument, apparatus, appliance, material, or other article, whether used alone or in combination, including the software 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 pharmacologic, immunologic, or metabolic means, but which may be assisted in its function by such means; “medical incident”: malfunction, defect, or deterioration of the device, as well as irregularity in the labeling or the instructions for use, which may or may not lead to
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death or serious deterioration in the health of the patient or user of the product, and in the case of a medical device for in vitro diagnostic product or equipment medical diagnostic in vitro—indirectly, another person, or • technical or medical reason connected with the characteristics or performance of a device, which may or could result in death or serious deterioration in the health of the patient or user, in the case of diagnostic medical devices or equipment in vitro diagnostic medical devices • in vitro - indirectly, another person and therefore leading to a decision by the manufacturer of the external safety corrective actions. “notified body” means the bodies designated by the EU Member State to assess whether a product meets required standards. The Commission has assigned identification numbers to the body. “placing on the market” means the first making available in return for payment or free of charge of a device other than a device intended for clinical investigation, with a view to distribution and/or use on the Community market, regardless of whether it is new or fully refurbished; “putting into service” means the stage at which a device is ready for use on the Community market for the first time for its intended purpose.