(13).

(13)OJNo. L39, 15.2.1980, p.

1. Directive as last amended by Directive 89/617/EEC (OJ No. L357 7.12.1989, p.28).
2. Protection against radiation. 11.
3. General. 11.1.
4. Devices shall be designed and manufactured in such a way that exposure of patients, users and other persons to radiation shall be reduced as far as possible compatible with the intended purpose, whilst not restricting the application of appropriate specified levels for therapeutic and diagnostic purposes. 11.
5. Intended radiation. 11.2.
6. Where devices are designed to emit hazardous levels of radiation necessary for a specific medical purpose the benefit of which is considered to outweigh the risks inherent in the emission, it must be possible for the user to control the emissions. Such devices shall be designed and manufactured to ensure reproducibility and tolerance of relevant variable parameters. 11.2.
7. Where devices are intended to emit potentially hazardous, visible and/or invisible radiation, they must be fitted, where practicable, with visual displays and/or audible warnings of such emissions. 11.
8. Unintended radiation. 11.3.
9. Devices shall be designed and manufactured in such a way that exposure of patients, users and other persons to the emission of unintended, stray or scattered radiation is reduced as far as possible. 11.
10. Instructions. 11.4.
11. The operating instructions for devices emitting radiation must give detailed information as to the nature of the emitted radiation, means of protecting the patient and the user and on ways of avoiding misuse and of eliminating the risks inherent in installation. 11.
12. Ionizing radiation. 11.5.
13. Devices intended to emit ionizing radiation must be designed and manufactured in such a way as to ensure that, where practicable, the quantity, geometry and quality of radiation emitted can be varied and controlled taking into account the intended use. 11.5.
14. Devices emitting ionizing radiation intended for diagnostic radiology shall be designed and manufactured in such a way as to achieve appropriate image and/or output quality for the intended medical purpose whilst minimizing radiation exposure of the patient and user. 11.5.
15. Devices emitting ionizing radiation, intended for therapeutic radiology shall be designed and manufactured in such a way as to enable reliable monitoring and control of the delivered dose, the beam type and energy and where appropriate the quality of radiation.
16. Requirements for medical devices connected to or equipped with an energy source. 12.
17. Devices incorporating electronic programmable systems must be designed to ensure the repeatability, reliability and performance of these systems according to the intended use. In the event of a single fault condition (in the system) appropriate means should be adopted to eliminate or reduce as far as possible consequent risks. 12.
18. Devices where the safety of the patients depends on an internal power supply must be equipped with a means of determining the state of the power supply. 12.
19. Devices where the safety of the patients depends on an external power supply must include an alarm system to signal any power failure. 12.
20. Devices intended to monitor one or more clinical parameters of a patient must be equipped with appropriate alarm systems to alert the user of situations which could lead to death or severe deterioration of the patient's state of health. 12.
21. Devices must be designed and manufactured in such a way as to minimize the risks of creating electromagnetic fields which could impair the operation of other devices or equipment in the usual environment. 12.
22. Protection against electrical risks devices must be designed and manufactured in such a way as to avoid, as far as possible, the risk of accidental electric shocks during normal use and in single fault condition, provided the devices are installed correctly. 12.
23. Protection against mechanical and thermal risks. 12.7.
24. Devices must be designed and manufactured in such a way as to protect the patient and user against mechanical risks connected with, for example, resistance, stability and moving parts. 12.7.
25. Devices must be designed and manufactured in such a way as to reduce to the lowest possible level the risks arising from vibration generated by the devices, taking account of technical progress and of the means available for limiting vibrations, particularly at source, unless the vibrations are part of the specified performance. 12.7.
26. Devices must be designed and manufactured in such a way as to reduce to the lowest possible level the risks arising from the noise emitted, taking account of technical progress and of the means available to reduce noise, particularly at source, unless the noise emitted is part of the specified performance. 12.7.
27. Terminals and connectors to the electricity, gas or hydraulic and pneumatic energy supplies which the user has to handle must be designed and constructed in such a way as to minimize all possible risks. 12.7.
28. Accessible parts of the devices (excluding the parts or areas intended to supply heat or reach given temperatures) and their surroundings must not attain potentially dangerous temperatures under normal use. 12.
29. Protection against the risks posed to the patient by energy supplies or substances. 12.8.
30. Devices for supplying the patient with energy or substances must be designed and constructed in such a way that the flow-rate can be set and maintained accurately enough to guarantee the safety of the patient and of the user. 12.8.
31. Devices must be fitted with the means of preventing and/or indicating any inadequacies in the flow-rate which could pose a danger. Devices must incorporate suitable means to prevent, as far as possible, the accidental release of dangerous levels of energy from an energy and/or substance source. 12.
32. The function of the controls and indicators must be clearly specified on the devices. Where a device bears instructions required for its operation or indicates operating or adjustment parameters by means of a visual system, such information must be understandable to the user and, as appropriate, the patient.
33. Information supplied by the manufacturer. 13.
34. Each device must be accompanied by the information needed to use it safely and to identify the manufacturer, taking account of the training and knowledge of the potential users. This information comprises the details on the label and the data in the instructions for use. As far as practicable and appropriate, the information needed to use the device safely must be set out on the device itself and/or on the packaging for each unit or, where appropriate, on the sales packaging. If individual packaging of each unit is not practicable, the information must be set out in the leaflet supplied with one or more devices. Instructions for use must be included in the packaging for every device. By way of exception, no such instructions for use are needed for devices in Class I or IIa if they can be used safely without any such instructions. 13.
35. Where appropriate, this information should take the form of symbols. Any symbol or identification colour used must conform to the harmonized standards. In areas for which no standards exist, the symbols and colours must be described in the documentation supplied with the device. 13.
36. The label must bear the following particulars: ( a ) the name or trade name and address of the manufacturer. For devices imported into the Community, in view of their distribution in the Community, the label, or the outer packaging, or instructions for use, shall contain in addition the name and address of either the person responsible referred to in Article 14

(2)of the Directive or of the authorized representative of the manufacturer established within the Community or of the importer established within the Community, as appropriate; ( b ) the details strictly necessary for the user to identify the device and the contents of the packaging; ( c ) where appropriate, the word 'sterile'; ( d ) where appropriate, the batch code, preceded by the word 'lot', or the serial number; ( e ) where appropriate, an indication of the date by which the device should be used, in safety, expressed as the year and month; ( f ) where appropriate, an indication that the device is for single use; ( g ) if the device is custom-made, the words 'custom-made device'; ( h ) if the device is intended for clinical investigations, the words 'exclusively for clinical investigations'; ( i ) any special storage and/or handling conditions; ( j ) any special operating instructions; ( k ) any warnings and/or precautions to take; ( l ) year of manufacture for active devices other than those covered by (e). This indication may be included in the batch or serial number; ( m ) where applicable, method of sterilization. 13.4. If the intended purpose of the device is not obvious to the user, the manufacturer must clearly state it on the label and in the instructions for use. 13.5. Wherever reasonable and practicable, the devices and detachable components must be identified, where appropriate in terms of batches, to allow all appropriate action to detect any potential a risk posed by the devices and detachable components. 13.6. Where appropriate, the instructions for use must contain the following particulars: ( a ) the details referred to in section 13.3, with the exception of (

1. d)and (e); ( b ) the performances referred to in section 3 and any undesirable side effects; ( c ) if the device must be installed with or connected to other medical devices or equipment in order to operate as required for its intended purpose, sufficient details of its characteristics to identify the correct devices or equipment to use in order to obtain a safe combination; ( d ) all the information needed to verify whether the device is properly installed and can operate correctly and safely, plus details of the nature and frequency of the maintenance and calibration needed to ensure that the devices operate properly and safely at all times; ( e ) where appropriate, information to avoid certain risks in connection with implantation of the device; ( f ) information regarding the risks of reciprocal interference posed by the presence of the device during specific investigations or treatment; ( g ) the necessary instructions in the event of damage to the sterile packaging and, where appropriate, details of appropriate methods of resterilization; ( h ) if the device is reussable, information on the appropriate processes to allow reuse, including cleaning, disinfection, packaging and, where appropriate, the method of sterilization of the device to be resterilized, and any restriction on the number of reuses. Where devices are supplied with the intention that they be sterilized before use, the instructions for cleaning and sterilization must be such that, if correctly followed, the device will still comply with the requirements in Section I; ( i ) details of any further treatment or handling needed before the device can be used (for example, sterilization, final assembly, etc.); ( j ) in the case of devices emitting radiation for medical purposes, details of the nature, type, intensity and distribution of this radiation. The instructions for use must also include details allowing the registered medical practitioner to brief the patient on any contra-indications and any precautions to be taken. These details should cover in particular: ( k ) precautions to be taken in the event of changes in the performance of the device; ( l ) precautions to be taken as regards exposure, in reasonably foreseeable environmental conditions, to magnetic fields, external electrical influences, electrostatic discharge, pressure or variations in pressure, acceleration, thermal ignition sources, etc.; ( m ) adequate information regarding the medicinal product or products which the device in question is designed to administer, including any limitations in the choice of substances to be delivered; (
2. n)precautions to be taken against any special, unusual risks related to the disposal of the device; (
3. o)medicinal substances incorporated into the device as an integral part in accordance with Section 7,4; (
4. p)degree of accuracy claimed for devices with a measuring function. 14. Where conformity with the essential requirements must be based on clinical data, as in Section I

(6), such data must be established in accordance with Schedule 10. SCHEDULE II. (Corresponding to Annex 2 of the Directive). EC DECLARATION OF CONFORMITY. (Full quality assurance system). 1. The manufacturer must ensure application of the quality system apparoved for the design, manufacture and final inspection of the products concerned, as specified in Section 3 and is subject to audit as laid down in Sections 3.3 and 4 and to Community surveillance as specified in Section 5. 2. The declaration of conformity is the procedure whereby the manufacturer who fulfils the obligations imposed by Section 1 ensures and declares that the products concerned meet the provisions of the Directive which apply to them. The manufacturer must affix the CE marking in accordance with Article 17 of the Directive and draw up a written declaration of conformity. This declaration must cover a given number of the products manufactured and be kept by the manufacturer. 3. Quality system. 3.1. The manufacturer must lodge an application for assessment of his quality system with a notified body. The application must include: — the name and address of the manufacturer and any additional manufacturing site covered by the quality system, — all the relevant information on the product or product category covered by the procedure, — a written declaration that no application has been lodged with any other notified body for the same product-related quality system, — the documentation on the quality system, — an undertaking by the manufacturer to fulfil the obligations imposed by the quality system approved, — an undertaking by the manufacturer to keep the approved quality system adequate and efficacious, — an undertaking by the manufacturer to institute and keep up to date a systematic procedure to review experience gained from devices in the post-production phase and to implement appropriate means to apply any necessary corrective action. This undertaking must include an obligation for the manufacturer to notify the competent authorities of the following incidennts immediately on learning of them: (

1. i)any malfunction or deterioration in the characteristics and/or performance of a device, as well as any inadequacy in the instructions for use which might lead to or might have led to the death of a patient or user or to a serious deterioration in his state of health; (
2. ii)any technical or medical reason connected with the characteristics or performance of a device leading for the reasons referred to in subparagraph (
3. i)to systematic recall of devices of the same type by the manufacturer. 3.2. Application of the quality system must ensure that the products conform to the provisions of the Directive which apply to them at every stage, from design to final inspection. All the elements, requirements and provisions adopted by the manufacturer for his quality system must be documented in a systematic and orderly manner in the form of written policies and procedures such as quality programmes, quality plans, quality manuals and quality records. It shall include in particular an adequate description of: (
4. a)the manufacturer's quality objectives; (
5. b)the organisation of the business and in particular: — the organizational structures, the responsibilities of the managerial staff and their organizational authority where quality of design and manufacture of the products is concerned, — the methods of monitoring the efficient operation of the quality system and in particular its ability to achieve the desired quality of design and of product, including control of products which fail to conform; (
6. c)the procedures for monitoring and verifying the design of the products and in particular: — a general description of the product, including any variants planned, — the design specifications, including the standards which will be applied and the results of the risk analysis, and also a description of the solutions adopted to fulfil the essential requirements which apply to the products if the standards referred to in Article 5 of the Directive are not applied in full, — the techniques used to control and verify the design and the processes and systematic measures which will be used when the products are being designed, — if the device is to be connected to other device(
7. s)in order to operate as intended, proof must be provided that it conforms to the essential requirements when connected to any such device(
8. s)having the characteristics specified by the manufacturer, — a statement indicating whether or not the device incorporates, as an integral part, a substance as referred to in Section 7.4 of Schedule 1 and data on the tests conducted in this connection, — the clinical data referred to in Schedule 10, — the draft label and, where appropriate, instructions for use; (
9. d)the inspection and quality assurance techniques at the manufacturing stage and in particular: — the processes and procedures which will be used, particularly as regards sterilization, purchasing and the relevant documents, — the product identification procedures drawn up and kept up to date from drawings, specifications or other relevant documents at every stage of manufacture; (
10. e)the appropriate tests and trials which will be carried out before, during and after manufacture, the frequency with which they will take place, and the test equipment used; it must be possible to trace back the calibration of the test equipment adequately. 3.3. The notified body must audit the quality system to determine whether it meets the requirements referred to in Section 3.2. It must presume that quality systems which implement the relevant harmonized standards conform to these requirements. The assessment team must include at least one number with past experience of assessments of the technology concerned. The assessment procedure must include an inspection on the manufacturer's premises and, in duly substantiated cases, on the premises of the manufacturer's suppliers and/or subcontractors to inspect the manufacturing processes. The decision is notified to the manufacturer. It must contain the conclusions of the inspection and a reasoned assessment. 3.4. The manufacturer must inform the notified body which approved the quality system of any plan for substantial changes to the quality system or the product-range covered. The notified body must assess the changes proposed and verify whether after these changes the quality system still meets the requirements referred to in Section 3.2. It must notify the manufacturer of its decision. This decision must contain the conclusions of the inspection and a reasoned assessment. 4. Examination of the design of the product. 4.1. In addition to the obligations imposed by Section 3, the manufacturer must lodge with the notified body an application for examination of the design dossier relating to the product which he plans to manufacture and which falls into the category referred to in Section 3.1. 4.2. The application must describe the design, manufacture and performances of the product in question. It must include the documents needed to assess whether the product conforms to the requirements of the Directive, as referred to in Section 3.2 (c). 4.3. The notified body must examine the application and, if the product conforms to the relevant provisions of the Directive, issue the application with an EC design-examination certificate. The notified body may require the application to be completed by further tests or proof to allow assessment of conformity with the requirements of the Directive. The certificate must contain the conclusions of the examination, the conditions of validity, the data needed for identification of the approved design, where appropriate, a description of the intended purpose of the product. In the case of devices referred to in Schedule 1, Section 7.4, the notified body shall, in view of the aspects addressed in that paragraph, consult one of the competent bodies established by the Member States in accordance with Directive 65/65/EEC before taking a decision. The notified body will give due consideration to the views expressed in this consultation when making its decision. It will convey its final decision to the competent body concerned. 4.4. Changes to the approved design must receive further approval from the notified body which issued the EC design-examination certificate wherever the changes could affect conformity with the essential requirements of the Directive or with the conditions prescribed for use of the product. The applicant shall inform the notified body which issued the EC design-examination certificate of any such changes made to the approved design. This additional approval must take the form of a supplement to the EC design-examination certificate. 5. Surveillance. 5.1. The aim of surveillance is to ensure that the manufacturer duly fulfils the obligations imposed by the approved quality system. 5.2. The manufacturer must authorize the notified body to carry out all the necessary inspections and supply it with all relevant information, in particular: — the documentation on the quality system, — the data stipulated in the part of the quality system relating to design, such as the results of analyses, calculation tests, etc., — the data stipulated in the part of the quality system relating to manufacture, such as inspection reports and test data, calibration data, qualification reports of the personnel concerned, etc. 5.3. The notified body must periodically carry out appropriate inspections and assessments to make sure that the manufacturer applies the approved quality system and must supply the manufacturer with an assessment report. 5.4. In addition, the notified body may pay unannounced visits to the manufacturer. At the time of such visits, the notified body may, where necessary, carry out or ask for tests in order to check that the quality system is working properly. It must provide the manufacturer with an inspection report and, if a test has been carried out, with a test report. 6. Administrative provisions. 6.1. The manufacturer must, for a period ending at least five years after the last product has been manufactured, keep at the disposal of the national authorities: — the declaration of conformity, — the documentation referred to in the fourth indent of Section 3.1, — the changes referred to in Section 3.4, — the documentation referred to in Section 4.2, and — the decisions and reports from the notified body as referred to in Sections 3.3, 4.3, 4.4, 5.3 and 5.4. 6.2. The notified body must make available to the other notified bodies and the competent authority, on request, all relevant information concerning quality system approvals issued, refused or withdrawn. 6.3. In respect of devices subject to the procedure in Section 4, when neither the manufacturer nor his authorized representative is established in the Community, the obligation to keep available the technical documentation shall fall to the person responsible for placing the device on the Community market or the importer referred to in Schedule 1, Section 13.3 (a). 7. Application to devices in classes IIa and IIb.

(2)and

(3)of the Directive, this Schedule may apply to products in Classes IIa and IIb. Section 4, however, does not apply. SCHEDULE III. (Corresponding to Annex 3 of the Directive). EC TYPE-EXAMINATION. 1. EC type-examination is the procedure whereby a notified body ascertains and certifies that a representative sample of the production covered fulfils the relevant provisions of the Directive. 2. The application includes: — the name and address of the manufacturer and the name and address of the authorized representative if the application is lodged by the representative, — the documentation described in Section 3 needed to assess the conformity of the representative sample of the production in question, hereinafter referred to as the 'type', with the requirements of the Directive. The applicant must make a 'type' available to the notified body. The notified body may request other samples as necessary, — a written declaration that no application has been lodged with any other notified body for the same type, 3. The documentation must allow an understanding of the design, the manufacture and the performances of the product and must contain the following items in particular: — a general description of the type, including any variants planned, — design drawings, methods of manufacture envisaged, in particular as regards sterilization, and diagrams of components, sub-assemblies, circuits, etc., — the descriptions and explanations necessary to understand the above-mentioned drawings and diagrams and the operation of the product, — a list of the standards referred to in Article 5 of the Directive, applied in full or in part, and descriptions of the solutions adopted to meet the essential requirements if the standards referred to in that Article have not been applied in full, — the results of the design calculations, risk analysis, investigations, technical tests, etc. carried out, — a statement indicating whether or not the device incorporates, as an integral part, a substance as referred to in Section 7.4 of Schedule 1 and data on the tests conducted in this connection, — the clinical data referred to in Schedule 10, — the draft label and, where appropriate, instructions for use. 4. The notified body must: 4.1 Examine and assess the documentation and verify that the type has been manufactured in conformity with that documentation; it must also record the items designed in conformity with the applicable provisions of the standards referred to in Article 5 of the Directive, as well as the items not designed on the basis of the relevant provisions of the above mentioned standards; 4.2. Carry out or arrange for the appropriate inspections and the tests necessary to verify whether the solutions adopted by the manufacturer meet the essential requirements of the Directive if the standards referred to in Article 5 of the Directive have not been applied; if the device is to be connected to other device(

1. s)in order to operate as intended, proof must be provided that it conforms to the essential requirements when connected to any such device(
2. s)having the characteristics specified by the manufacturer; 4.3. Carry out or arrange for the appropriate inspections and the tests necessary to verify whether, if the manufacturer has chosen to apply the relevant standards, these have actually been applied. 4.4. Agree with the applicant on the place where the necessary inspections and tests will be carried out. 5. If the type conforms to the provisions of the Directive, the notified body issues the applicant with an EC type-examination certificate. The certificate must contain the name and address of the manufacturer, the conclusions of the inspection, the conditions of validity and the data needed for identification of the type approved. The relevant parts of the documentation must be annexed to the certificate and a copy kept by the notified body. In the case of devices referred to in Schedule I, Section 7.4, the notified body shall, in view of the aspects addressed in that paragraph, consult one of the competent bodies established by the Member States in accordance with Directive 65/65/EEC before taking a decision. The notified body will give due consideration to the views expressed in this consultation when making its decision. It will convey its final decision to the competent body concerned. 6. The applicant must inform the notified body which issued the EC type-examination certificate of any significant change made to the approved product. Changes to the approved product must receive further approval from the notified body which issued the EC type-examination certificate wherever the changes may affect conformity with the essential requirements or with the conditions prescribed for use of the product. This new approval must, where appropriate, take the form of a supplement to the initial EC type-examination certificate. 7. Administrative provisions, 7.1. The notified body must make available to the other notified bodies on request, all relevant information on EC type-examination certificates and supplements issued, refused or withdrawn. 7.2. Other notified bodies may obtain a copy of the EC type-examination certificates and/or the supplements thereto. The annexes to the certificates must be made available to other notified bodies on reasoned application, after the manufacturer has been informed. 7.3. The manufacturer or his authorized representative must keep with the technical documentation copies of EC type-examination certificates and their additions for a period ending at least five years after the last device has been manufactured. 7.4. When neither the manufacturer nor his authorized representative is established in the Community, the obligation to keep available the technical documentation shall fall to the person responsible for placing the device on the Community market or the importer referred to in Schedule 1, Section 13.3 (a). SCHEDULE VI. (Corresponding to Annex 4 of the Directive). EC VERIFICATION. 1. EC verification is the procedure whereby the manufacturer or his authorized representative established in the Community ensures and declares that the products which have been subject to the procedure set out in Section 4 conform to the type described in the EC type-examination certificate and meet the requirements of the Directive which apply to them. 2. The manufacturer must take all the measures necessary to ensure that the manufacturing process produces products which conform to the type described in the EC type-examination certificate and to the requirements of the directive which apply to them. Before the start of manufacture, the manufacturer must prepare documents defining the manufacturing process, in particular as regards sterilization where necessary, together with all the routine, pre-established provisions to be implemented to ensure homogeneous production and, where appropriate, conformity of the products with the type described in the EC type-examination certificate and with the requirements of the Directive which apply to them. The manufacturer must affix the CE marking in accordance with Article 17 of the Directive and draw up a declaration of conformity. In addition, for products placed on the market in sterile condition, and only for those aspects of the manufacturing process designed to secure and maintain sterility, the manufacturer must apply the provisions of Schedule 5, Sections 3 and 4. 3. The manufacturer must undertake to institute and keep up to date a systematic procedure to review experience gained from devices in the post-production phase and to implement appropriate means to apply any necessary corrective action. This undertaking must include an obligation for the manufacturer to notify the competent authorities of the following incidents immediately on learning of them: (
3. i)any malfunction or deterioration in the characteristics and/or performance of a device, as well as any inadequacy in the labelling or the instructions for use which might lead to or might have led to the death of a patient or user or to a serious deterioration in his state of health; (
4. ii)any technical or medical reason connected with the characteristics or performance of a device for the reasons referred to in subparagraph (
5. i)leading to systematic recall of devices of the same type by the manufacturer. 4. The notified body must carry out the appropriate examinations and tests in order to verify the conformity of the product with the requiremennts of the Directive either by examining and testing every product as specified in Section 5 or by examining and testing products on a statistical basis as specified in Section 6, as the manufacturer decides. The aforementioned checks do not apply to those aspects of the manufacturing process designed to secure sterility. 5. Verification by examination and testing of every product. 5.1. Every product is examined individually and the appropriate tests defined in the relevant standard(
6. s)referred to in Article 5 of the Directive or equivalent tests must be carried out in order to verify, where appropriate, the conformity of the products with the EC type described in the type-examination certificate and with the requirements of the Directive which apply to them. 5.2. The notified body must affix, or have affixed its identification number to each approved product and must draw up a written certificate of conformity relating to the tests carried out. 6. Statistical verification. 6.1. The manufacturer must present the manufactured products in the form of homogeneous batches. 6.2. A random sample is taken from each batch. The products which make up the sample are examined individually and the appropriate tests defined in the relevant standard(
7. s)referred to in Article 5 of the Directive or equivalent tests must be carried out to verify, where appropriate, the conformity of the products with the type described in the EC type-examination certificate and with the requirements of the Directive which apply to them in order to determine whether to accept or reject the batch. 6.3. Statistical control of products will be based on attributes, entailing a sampling system ensuring a limit quality corresponding to a probability of acceptance of 5 per cent, with a non-conformity percentage of between 3 per cent and 7 per cent. The sampling method will be established by the harmonized standards referred to in Article 5 of the Directive, taking account of the specific nature of the product categories in question. 6.4. If the batch is accepted, the notified body affixes or has affixed its identification number to each product and draws up a written certificate of conformity relating to the tests carried out. All products in the batch may be put on the market except any in the sample which failed to conform. If a batch is rejected, the competent notified body must take appropriate measures to prevent the batch from being placed on the market. In the event of frequent rejection of batches, the notified body may suspend the statistical verification. The manufacturer may, on the responsibility of the notified body, affix the notified body's identification number during the manufacturing process. 7. Administrative provisions. The manufacturer or his authorized representative must, for a period ending at least five years after the last product has been manufactured, make available to the national authorities: — the declaration of conformity, — the documentation referred to in Section 2, — the certificates referred to in Sections 5.2 and 6.4, — where appropriate, the type-examination certificate referred to in Schedule 3. 8. Application to devices in Class IIa.

(2)of the Directive, this Schedule may apply to products in Class IIa, subject to the following exemptions: 8.1. In derogation from Sections 1 and 2, by virtue of the declaration of conformity the manufacturer ensures and declares that the products in Class IIa are manufactured in conformity with the technical documentation referred to in Section 3 of Schedule 7 and meet the requirements of the Directive which apply to them; 8.2. In derogation from Sections 1, 2, 5 and 6, the verifications conducted by the notified body are intended to confirm the conformity of the products in Class IIa with the technical documentation referred to in Section 3 of Schedule 7. SCHEDULE V. (Corresponding to Annex 5 of the Directive). EC DECLARATION OF CONFORMITY. (Production Quality Assurance). 1. The manufacturer must ensure application of the quality system approved for the manufacture of the products concerned and carry out the final inspection, as specified in Section 3, and is subject to the Community surveillance referred to in Section 4. 2. The declaration of conformity is the part of the procedure whereby the manufacturer who fulfils the obligations imposed by Section 1 ensures and declares that the products concerned conform to the type described in the EC type-examination certificate and meets the provisions of the Directive which apply to them. The manufacturer must affix the CE marking in accordance with Article 17 of the Directive and draw up a written declaration of conformity. This declaration must cover a given number of identified specimens of the products manufactured and must be kept by the manufacturer. 3. Quality system. 3.1. The manufacturer must lodge an application for assessment of his quality system with a notified body. The application must include: — the name and address of the manufacturer, — all the relevant information on the product or product category covered by the procedure, — a written declaration that no application has been lodged with any other notified body for the same products, — the documentation on the quality system, — an undertaking to fulfil the obligations imposed by the quality system is approved, — an undertaking to maintain the practicability and effectiveness of the approved quality system, — where appropriate, the technical documentation on the types approved and a copy of the EC type-examination certificates, — an undertaking by the manufacturer to institute and keep up to date a systematic procedure to review experience gained from devices in the post-production phase and to implement appropriate means to apply any necessary corrective action. This undertaking must include an obligation for the manufacturer to notify the competent authorities of the following incidents immediately on learning of them: (

1. i)any malfunction or deterioration in the characteristics and/or performance of a device, as well as any inadequacy in the labelling or the instructions for use which might lead to or might have led to the death of a patient or user or to a serious deterioration in his state of health; (
2. ii)any technical or medical reason connected with the characteristics or performance of a device for the reasons referred to in subparagraph (
3. i)above leading to a systematic recall of devices of the same type by the manufacturer. 3.2. Application of the quality system must ensure that the products conform to the type described in the EC type-examination certificate. All the elements, requirements and provisions adopted by the manufacturer for his quality system must be documented in a systematic and orderly manner in the form of written policy statements and procedures. This quality system documentation must permit uniform interpretation of the quality policy and procedures such as quality programmes, plans, manuals and records. It must include in particular an adequate description of: (
4. a)the manufacturer's quality objectives; (
5. b)the organization of the business and in particular: — the organisational structures, the responsibilities of the managerial staff and their organizational authority where manufacture of the products is concerned, — the methods of monitoring the efficient operation of the quality system and in particular its ability to achieve the desired quality of product, including control of products which fail to conform; (
6. c)the inspection and quality assurance techniques at the manufacturing stage and in particular: — the processes and procedures which will be used, particularly as regards sterilization, purchasing and the relevant documents, — the product identification procedures drawn up and kept up to date from drawings, specifications or other relevant documents at every stage of manufacture; (
7. d)the appropriate tests and trials to be carried out before, during and after manufacture, the frequency with which they will take place, and the test equipment used; it must be possible adequately to trace back the calibration of the test equipment. 3.3. The notified body must audit the quality system to determine whether it meets the requirements referred to in Section 3.2. It must presume that quality systems which implement the relevant harmonized standards conform to these requirements. The assessment team must include at least one member with past experience of assessments of the technology concerned. The assessment procedure must include an inspection on the manufacturer's premises and, in duly substantiated cases, on the premises of the manufacturer's suppliers to inspect the manufacturing processes. The decision must be notified to the manufacturer after the final inspection and contain the conclusions of the inspection and a reasoned assessment. 3.4. The manufacturer must inform the notified body which approved the quality system of any plan for substantial changes to the quality system. The notified body must assess the changes proposed and verify whether after these changes the quality system still meets the requirements referred to in Section 3.2. After the abovementioned information has been received the decision is notified to the manufacturer. It must contain the conclusions of the inspection and a reasoned assessment. 4. Surveillance. 4.1. The aim of surveillance is to ensure that the manufacturer duly fulfils the obligations imposed by the approved quality system. 4.2. The manufacturer authorizes the notified body to carry out all the necessary inspections and must supply it with all relevant information, in particular: — the documentation on the quality system, — the date stipulated in the part of the quality system relating to manufacture, such as inspection reports and test data, calibration data, qualification reports of the personnel concerned, etc. 4.3. The notified body must periodically carry out appropriate inspections and assessments to make sure that the manufacturer applies the approved quality system and supply the manufacturer with an assessment report. 4.4. In addition, the notified body may pay unannounced visits to the manufacturer. At the time of such visits, the notified body may, where necessary, carry out or ask for tests in order to check that the quality system is working properly. It must provide the manufacturer with an inspection report and, if a test has been carried out, with a test report. 5. Administrative provisions. 5.1. The manufacturer must, for a period ending at least five years after the last product has been manufactured, make available to the national authorities: — the declaration of conformity, — the documentation referred to in the fourth indent of Section 3.1, — the changes referred to in Section 3.4, — the documentation referred to in the seventh indent of Section 3.1, — the decisions and reports from the notified body as referred to in Sections 4.3 and 4.4, — where appropriate, the type-examination certificate referred to in Schedule 3. 5.2. The notified body must make available to the other notified bodies, on request, all relevant information concerning the quality system approvals issued, refused or withdrawn. 6. Application to devices in Class IIa.

(2)of the Directive, this Schedule may apply to products in Class IIa, subject to the following exemption: 6.1. In derogation from Sections 2,3.1 and 3.2, by virtue of the declaration of conformity the manufacturer ensures and declares that the products in Class IIa are manufactured in conformity with the technical documentation referred to in Section 3 of Schedule 7 and meet the requirements of the Directive which apply to them. SCHEDULE 6. (Corresponding to Annex 6 of the Directive). EC DECLARATION OF CONFORMITY. (product Quality Assurance). 1. The manufacturer must ensure application of the quality system approved for the final inspection and testing of the product, as specified in Section 3 and must be subject to the surveillance referred to in Section 4. In addition, for products placed on the market in sterile condition, and only for those aspects of the manufacturing process designed to secure and maintain sterility, the manufacturer must apply the provisions of Schedule 5, Sections 3 and 4. 2. The declaration of conformity is the part of the procedure whereby the manufacturer who fulfils the obligations imposed by Section 1 ensures and declares that the products concerned conform to the type described in the EC type-examination certificate and meet the provisions of the Directive which apply to them. The manufacturer affixes the CE marking in accordance with Article 17 of the Directive and draws up a written declaration of conformity. This declaration must cover a given number of identified specimens of the products manufactured and be kept by the manufacturer. The CE marking must be accompanied by the identification number of the notified body which performs the tasks referred to in this Schedule. 3. Quality system. 3.1. The manufacturer lodges an application for assessment of his quality system with a notified body. The application must include: — the name and address of the manufacturer, — all the relevant information on the product or product category covered by the procedure, — a written declaration specifying that no application has been lodged with any other notified body for the same products, — the documentation on the quality system, — an undertaking by the manufacturer to fulfil the obligations imposed by the quality system approved, — an undertaking by the manufacturer to keep the approved quality system adequate and efficacious, — where appropriate, the technical documentation on the types approved and a copy of the EC type-examination certificates, — an undertaking by the manufacturer to institute and keep up to date a systematic procedure to review experience gained from devices in the post-production phase and to implement appropriate means to apply any necessary corrective action. This undertaking must include an obligation for the manufacturer to notify the competent authorities of the following incidents immediately on learning of them: (

1. i)any malfunction or deterioration in the characteristics and/or performance of a device, as well as any inadequacy in the labelling or the instructions for use which might lead to or might have led to the death of a patient or user or to a serious deterioration in his state of health; (
2. ii)any technical or medical reason connected with the characteristics or the performance of a device for the reasons referred to in subparagraph (
3. i)leading to a systematic recall of devices of the same type by the manufacturer. 3.2. Under the quality system, each product or a representative sample of each batch is examined and the appropriate tests defined in the relevant standard(
4. s)referred to in Article 5 of the Directive or equivalent tests are carried out to ensure that the products conform to the type described in the EC type-examination certificate and fulfil the provisions of the Directive which apply to them. All the elements, requirements and provisions adopted by the manufacturer must be documented in a systematic and orderly manner in the form of written measures, procedures and instructions. This quality system documentation must permit uniform interpretation of the quality programmes, quality plans, quality manuals and quality records. It must include in particular an adequate description of: — the quality objectives and the organizational structure, responsibilities and powers of the managerial staff with regard to product quality, — the examinations and tests that will be carried out after manufacture; it must be possible to trace back the calibration of the test equipment adequately, — the methods of monitoring the efficient operation of the quality system, — the quality records, such as reports concerning inspections, tests, calibration and the qualifications of the staff concerned, etc. The aforementioned checks do not apply to those aspects of the manufacturing process designed to secure sterility. 3.3. The notified body audits the quality system to determine whether it meets the requirements referred to in Section 3.2. It must presume that quality systems which implement the relevant harmonized standards conform to these requirements. The assessment team must include at least one member with past experience of assessments of the technology concerned. The assessment procedure must include an inspection on the manufacturer's premises and, in duly substantiated cases, on the premises of the manufacturer's suppliers to inspect the manufacturing processes. The decision must be notified to the manufacturer. It must contain the conclusions of the inspection and a reasoned assessment. 3.4. The manufacturer must inform the notified body which approved the quality system of any plan for substantial changes to the quality system. The notified body must assess the changes proposed and verify whether after these changes the quality system will still meet the requirements referred to in Section 3.2. After receiving the above mentioned information it must notify the manufacturer of its decision. This decision must contain the conclusions of the inspection and a reasoned assessment. 4. Surveillance. 4.1. The aim of surveillance is to ensure that the manufacturer duly fulfils the obligations imposed by the approved quality system. 4.2. The manufacturer must allow the notified body access for inspection purposes to the inspection, testing and storage locations and supply it with all relevant information, in particular: — the documentation on the quality system, — the technical documentation, — the quality records, such as inspection reports, test data, calibration data, qualification reports of the staff concerned, etc. 4.3. The notified body must periodically carry out appropriate inspections and assessments to make sure that the manufacturer applies the quality system and must supply the manufacturer with an assessment report. 4.4. In addition, the notified body may pay unannounced visits to the manufacturer. At the time of such visits, the notified body may, where necessary, carry out or ask for tests in order to check that the quality system is working properly and that the production conforms to the requirements of the Directive which apply to it. To this end, an adequate sample of the final products, taken on site by the notified body, must be examined and the appropriate tests defined in the relevant standard(
5. s)referred to in Article 5 of the Directive or equivalent tests must be carried out. Where one or more of the samples fails to conform, the notified body must take the appropriate measures. It must provide the manufacturer with an inspection report and, if a test has been carried out, with a test report. 5. Administrative provisions. 5.1. The manufacturer must, for a period ending at least five years after the last product has been manufactured, make available to the national authorities: — the declaration of conformity, — the documentation referred to in the seventh indent of Section 3.1, — the changes referred to in section 3.4, — the decisions and reports from the notified body as referred to in the final indent of Section 3.4 and in Sections 4.3 and 4.4, — where appropriate, the certificate of conformity referred to in Schedule 3. 5.2. The notified body must make available to the other notified bodies, on request, all relevant information concerning the quality system approvals issued, refused or withdrawn. 6. Application to devices in Class IIa.

(2)of the Directive, this Schedule may apply to products in Class IIa, subject to this derogation: 6.1. By derogation from Sections 2,3.1 and 3.2 by virtue of the declaration of conformity the manufacturer ensures and declares that the products in class IIa are manufactured in conformity with the technical documentation referred to in Section 3 of Schedule 7 and meet the requirements of the Directive which apply to them. SCHEDULE 7. (Corresponding to Annex 7 of the Directive). EC DECLARATION OF CONFORMITY. 1. The EC Declaration of conformity is the procedure whereby the manufacturer or his authorized representative established in the Community who fulfils the obligations imposed by Section 2 and, in the case of products placed on the market in a sterile condition and devices with a measuring function, the obligations imposed by section 5 ensures and declares that the products concerned meet the provisions of the Directive which apply to them. 2. The manufacturer must prepare the technical documentation described in Section 3. The manufacturer or his authorized representative established in the Community must make this documentation, including the declaration of conformity, available to the national authorities for inspection purposes for a period ending at least five years after the last product has been manufactured. Where neither the manufacturer nor his authorized representative are established in the Community, this obligation to keep the technical documentation available must fall to the person(

1. s)who place(
2. s)the product on the Community market. 3. The technical documentation must allow assessment of the conformity of the product with the requirements of the Directive. It must include in particular: — a general description of the product, including any variants planned, — design drawings, methods of manufacture envisaged and diagrams of components, sub-assemblies, circuits, etc., — the descriptions and explanations necessary to understand the abovementioned drawings and diagrams and the operations of the product, — the results of the risk analysis and a list of the standards referred to in Article 5 of the Directive, applied in full or in part, and descriptions of the solutions adopted to meet the essential requirements of the Directive if the standards referred to in that Article have not been applied in full, — in the case of products placed on the market in a sterile condition, description of the methods used, — the results of the design calculations and of the inspections carried out, etc.; if the device is to be connected to other device(
3. s)in order to operate as intended, proof must be provided that it conforms to the essential requirements when connected to any such device(
4. s)having the characteristics specified by the manufacturer, — the test reports and, where appropriate, clinical data in accordance with Schedule 10, — the label and instructions for use. 4. The manufacturer shall institute and keep up to date a systematic procedure to review experience gained from devices in the post-production phase and to implement appropriate means to apply any necessary corrective actions, taking account of the nature and risks in relation to the product. He shall notify the competent authorities of the following incidents immediately on learning of them: (
5. i)any malfunction or deterioration in the characteristics and/or performance of a device, as well as any inadequacy in the labelling or the instructions for use which might lead to or might have led to the death of a patient or user or to a serious deterioration in his state of health; (
6. ii)any technical or medical reason connected with the characteristics on the performance of a device for the reasons referred to in subparagraph (
7. i)leading to systematic recall of devices of the same type by the manufacturer. 5. With products placed on the market in sterile condition and Class I devices with a measuring function, the manufacturer must observe not only the provisions laid down in this Schedule but also one of the procedures referred to in Schedule 4, 5 or 6. Application of the above mentioned Schedules and the intervention by the notified body is limited to: — in the case of products placed on the market in sterile condition, only the aspects of manufacture concerned with securing and maintaining sterile conditions, — in the case of devices with a measuring function, only the aspects of manufacture concerned with the conformity of the products with the metrological requirements. Section 6.1. of this Schedule is applicable. 6. Application to devices in Class IIa.

(2)of the Directive, this Schedule may apply to products in Class IIa, subject to the following derogation: 6.

1. Where this Schedule is applied in conjunction with the procedure referred to in Schedule 4, 5 or 6, the declaration of conformity referred to in the above mentioned Schedules forms a single declaration. As regards the declaration based on this Schedule, the manufacturer must ensure and declare that the product design meets the provisions of the Directive which apply to it. SCHEDULE
2. (Corresponding to Annex 8 of the Directive). STATEMENT CONCERNING DEVICES FOR SPECIAL PURPOSES.
3. For custom-made devices or for devices intended for clinical investigations the manufacturer or his authorized representative established in the Community must draw up the statement containing the information stipulated in Section
5. The statement must contain the following information: 2.
6. For custom-made devices: — data allowing identification of the device in question, — a statement that the device is intended for exclusive use by a particular patient, together with the name of the patient, — the name of the registered medical practitioner or other authorised person who made out the prescription and, where applicable, the name of the clinic concerned, — the particular features of the device as specified in the relevant medical prescription, — a statement that the device in question conforms to the essential requirements set out in Schedule 1 and, where applicable, indicating which essential requirements have not been fully met, together with the grounds; 2.
7. For devices intended for the clinical investigations covered by Schedule 10: — data allowing identification of the device in question, — an investigation plan stating in particular the purpose, scientific, technical or medical grounds, scope and number of devices concerned, — the opinion of the ethics committee concerned and details of the aspects covered by its opinion, — the name of the registered medical practitioner or other authorized person and of the institution responsible for the investigations, — the place, starting date and scheduled duration for the investigations, — a statement that the device in question conforms to the essential requirements apart from the aspects covered by the investigations and that, with regard to these aspects, every precaution has been taken to protect the health and safety of the patient.
8. The manufacturer must also undertake to keep available for the competent national authorities: 3.
9. For custom-made devices, documentation allowing an understanding of the design, manufacture and performances of the product, including the expected performances, so as to allow assessment of conformity with the requirements of the Directive. The manufacturer must take all the measures necessary to ensure that the manufacturing process produces products which are manufactured in accordance with the documentation mentioned in the first paragraph; 3.
10. For devices intended for clinical investigations, the documentation must contain: — a general description of the product, — design drawings, methods of manufacture envisaged, in particular as regards sterilization, and diagrams of components, sub-assemblies, circuits, etc., — the descriptions and explanations necessary to understand the abovementioned drawings and diagrams and the operation of the product, — the results of the risk analysis and a list of the standards referred to in Article 5 of the Directive, applied in full or in part, and descriptions of the solutions adopted to meet the essential requirements of the Directive if the standards referred to in that Article have not been applied, — the results of the design calculations, and of the inspections and technical tests carried out, etc. The manufacturer must take all the measures necessary to ensure that the manufacturing process produces products which are manufactured in accordance with the documentation referred to in the first paragraph of this section. The manufacturer must authorize the assessment, or audit where necessary, of the effectiveness of these measures.
11. The information contained in the declarations concerned by this Schedule should be kept for a period of time of at least five years. SCHEDULE
12. (Corresponding to Annex 9 of the Directive). CLASSIFICATION CRITERIA. I. Definitions.
13. Definitions for the classification rules. 1.
14. Duration. Transient. Normally intended for continuous use for less than 60 minutes. Short term. Normally intended for continuous use for not more than 30 days. Long term. Normally intended for continuous use for more than 30 days. 1.
15. Invasive devices. Invasive device. A device which, in whole or in part, penetrates inside the body, either through a body orifice or through the surface of the body. Body orifice. Any natural opening in the body; as well as the external surface of the eyeball, or any permanent artificial opening, such as a stoma. Surgically invasive device. An invasive device which penetrates inside the body through the surface of the body, with the aid or in the context of a surgical operation. For the purposes of the Directive devices other than those referred to in the previous subparagraph and which produce penetration other than through an established body orifice, shall be treated as surgically invasive devices. Implantable device. Any device which is intended: — to be totally introduced into the human body or, — to replace an epithelial surface or the surface of the eye, by surgical intervention which is intended to remain in place after the procedure, Any device intended to be partially introduced into the human body through surgical intervention and intended to remain in place after the procedure for at least 30 days is also considered an implantable device. 1.
16. Reusable surgical instrument. Instrument intended for surgical use by cutting, drilling, sawing, scratching, scraping, clamping, retracting, clipping or similar procedures, without connection to any active medical device and which can be reused after appropriate procedures have been carried out. 1.
17. Active medical device. Any medical device operation of which depends on a source of electrical energy or any source of power other than that directly generated by the human body or gravity and which acts by converting this energy. Medical devices intended to transmit energy, substances or other elements between an active medical device and the patient, without any significant change, are not considered to be active medical devices. 1.
18. Active therapeutical device. Any active medical device, whether used alone or in combination with other medical devices, to support, modify, replace or restore biological functions or structures with a view to treatment or alleviation of an illness, injury or handicap. 1.
19. Active device for diagnosis. Any active medical device, whether used alone or in combination with other medical devices, to supply information for detecting, diagnosing, monitoring or treating physiological conditions, states of health, illnesses or congenital deformities. 1.
20. Central circulatory system. For the purposes of the Directive, 'central circulatory system' means the following vessels: arteriae pulmonales, aorta ascendens, arteriae coronariae, arteria carotis communis, arteria carotis externa, arteria carotis interna, arteriae cerebrales, truncus brachicephalicus, venae cordis, venae pulmonales, vena cava superior, vena cava inferior. 1.
21. Central nervous system. For the purposes of the Directive, 'central nervous system' means brain, meninges and spinal cord. II. Implementing Rules.
22. Implementing rules. 2.
23. Application of the classification rules shall be governed by the intended purpose of the devices. 2.
24. If the device is intended to be used in combination with another device, the classification rules shall apply separately to each of the devices. Accessories are classified in their own right separately from the device with which they are used. 2.
25. Software, which drives a device or influences the use of a device, falls automatically in the same class. 2.
26. If the device is not intended to be used solely or principally in a specific part of the body, it must be considered and classified on the basis of the most critical specified use. 2.
27. If several rules apply to the same device, based on the performance specified for the device by the manufacturer, the strictest rules resulting in the higher classification shall apply. III. Classification.
28. Non-invasive devices. 1.
29. Rule
30. All non-invasive devices are in Class I, unless one of the rules set out hereinafter applies. 1.
31. Rule
32. All non-invasive devices intended for channelling or storing blood, body liquids or tissues, liquids or gases for the purpose of eventual infusion, administration or introduction into the body are in Class IIa: — if they may be connected to an active medical device in Class IIa or a higher class, — if they are intended for use for storing or channelling blood or other body liquids or for storing organs, parts of organs or body tissues, in all other cases they are in Class I. 1.
33. Rule
34. All non-invasive devices intended for modifying the biological or chemical composition of blood, other body liquids or other liquids intended for infusion into the body are in Class IIb, unless the treatment consists of filtration, centrifugation or exchanges of gas, heat, in which case they are in Class IIa. 1.
35. Rule
36. All non-invasive devices which come into contact with injured skin: — are in Class I if they are intended to be used as a mechanical barrier, for compression or for absorption of exudates, — are in Class IIb if they are intended to be used principally with wounds which have breached the dermis and can only heal by secondary intent, — are in Class IIa in all other cases, including devices principally intended to manage the micro-environment of a wound.
37. Invasive devices. 2.
38. Rule
39. All invasive devices with respect to body orifices, other than surgically invasive devices and which are not intended for connection to an active medical device: — are in Class I if they are intended for transient use, — are in Class IIa if they are intended for short-term use, except if they are used in the oral cavity as far as the pharynx, in an ear canal up to the ear drum or in a nasal cavity, in which case they are in Class I, — are in Class IIb if they are intended for long-term use, except if they are used in the oral cavity as far as the pharynx, in an ear canal up to the ear drum or in a nasal cavity and are not liable to be absorbed by the mucous membrane, in which case they are in Class IIa. All invasive devices with respect to body orifices, other than surgically invasive devices, intended for connection to an active medical device in Class IIa or a higher class, are in Class IIa. 2.
40. Rule
41. All surgically invasive devices intended for transient use are in Class IIa unless they are: — intended specifically to diagnose, monitor or correct a defect of the heart or of the central circulatory system through direct contact with these parts of the body, in which case they are in Class III, — reusable surgical instruments, in which case they are in Class I, — intended to supply energy in the form of ionizing radiation in which cases they are in Class IIb, — intended to have a biological effect or to be wholly or mainly absorbed in which case they are in Class IIb, — intended to administer medicines by means of a delivery system, if this is done in a manner that is potentially hazardous taking account of the mode of application, in which they are in Class IIb. 2.
42. Rule
43. All surgically invasive devices intended for short-term use are in Class IIa unless they are intended: — either specifically to diagnose, monitor or correct a defect of the heart or of the central circulatory system through direct contact with these parts of the body, in which case they are in Class III, — or specifically for use in direct contact with the central nervous system, in which case they are in Class III, — or to supply energy in the form of ionizing radiation in which case they are in Class IIb, — or to have a biological effect or to be wholly or mainly absorbed in which case they are in Class III, — or to undergo chemical change in the body, except if the devices are placed in the teeth, or to administer medicines, in which case they are in Class IIb. 2.
44. Rule
45. All implantable devices and long-term surgically invasive devices are in Class IIb unless they are intended: — to be placed in the teeth, in which case they are in Class IIa, — to be used in direct contact with the heart, the central circulatory system or the central nervous system, in which case they are in Class III, — to have a biological effect or