Translational Pathway for Catheter Ablation
Preclinical Evaluation for Catheter Ablation
Author
Tim Laske, PhD
This section will focus on the totality of development activities, including design verification and preliminary validation activities that must take place prior to performing human clinical trials. Note that this section focuses on the catheter and not on the details of the electrical safety testing of the energy source or any associated accessories, including the often necessary mapping and navigation systems.
Quality Management System
Any organization that undertakes to manufacture and distribute a medical device must first develop a quality management system (QMS). Although a QMS can be structured in many forms to meet the needs of the organization, International Organization for Standardization (ISO) 13485 offers wide-ranging guidelines encompassing topics as broad as documentation practices and management responsibilities through product realization and measurement/analysis requirements. (ISO standards can be found at https://www.iso.org/standards.html.) Design and development activities such as planning, understanding inputs, and the processes that relate inputs to outputs as well as design verification and validation are all key elements of a QMS. Process monitoring and measurement is critical to provide consistent product from day to day but also to identify bounds on what constitutes acceptable product. These limits must be identified and controlled through manufacturing process validation(s) and subsequent monitoring. A corrective and preventative action (or CAPA) process is then implemented to deal with situations outside of process limits.
Design verification testing and validation activities such as preclinical studies are targeted at rigorous evaluation of product representative of an acceptable range of process results, such as dimensional requirements. One example of this rigorous evaluation is fatigue characterization of catheter structures. This design verification test is conducted on both product and test conditions representing extremes in the expected construction and clinical usage, respectively. Such considerations are basic requirements of a QMS and ISO 5840. Additional examples of these requirements are elaborated on in the following.
Design Requirements
As with the design and development of any medical device, the engineer must first understand the design requirements based on the use conditions. This includes a system-level risk assessment that should be initiated early in the design development phase. Design verification testing, and preclinical (in vivo) testing are both conducted to demonstrate that the design outputs ― the list of specification blueprints describing how each device is manufactured ― meet these design inputs providing some measure of safety for further clinical evaluation. The importance of the characterization of use conditions cannot be overemphasized since this knowledge serves as the fundamental basis for establishing design/performance requirements. These use conditions may be consistent with historical use, or may have important differences that are associated with changes in clinical practice, subtle changes in device design, or other factors that are unique to the product under development.
Selecting the right tests based on the design and use conditions is critical to ensure that the testing performed addresses all of the pertinent questions to mitigate risk. Three basic steps can help develop an appropriate test strategy:
- Asking the right questions.
- Developing the right test methods.
- Verifying test methods to appropriately challenge the design.
For each of these requirements, individual test reports are provided for each bench and laboratory test, computer modeling analysis (e.g., finite element analysis of heat transfer), and in vivo animal study. Each test report should include the purpose, test method, sample selection, results, discussion of the acceptability of the results, and when appropriate, justification and clinical applicability of the acceptance criteria.
Physical and Chemical Characteristics of Ablation Catheters
ISO 10555-1: Intravascular catheters – Sterile and single-use catheters – Part 1: General requirements (ISO 10555-1:2013; corrected version 2013-07-01) 2013 provides general requirement for intravascular catheters, including ablation catheters:
Requirements
- General
- The catheter shall have been sterilized by an appropriate validated method and shall comply with 2 to 4.8 in the sterile condition.
- Radio-detectability
- Parts of the catheter shall be radio-detectable if required as determined by the risk assessment. Compliance should be demonstrated by an appropriate test method, such as ASTM F640-12 or DIN 13273-7.
- Biocompatibility
- The catheter shall be free from biological hazard. (NOTE: See ISO 10993-1 for the selection of appropriate test methods.)
- Surface
- When examined by normal or corrected-to-normal vision with a minimum x 2.5 magnification, the external surface of the effective length of the catheter shall appear free from extraneous matter.
- The external surface of the effective length of the catheter, including the distal end, shall be free from process and surface defects that could cause trauma to vessels during use.
- If the catheter is lubricated, the lubricant shall not be visible as drops of fluid on the external surface when the catheter is examined under normal or corrected-to-normal vision.
- Corrosion resistance
- When tested in accordance with the method given in Annex A, metallic components of the catheter intended for fluid path contact shall show no signs of corrosion. (Note: Annex A and subsequent Annexes mentioned herein are part of ISO 10555-1:2013.)
- Peak tensile force
- When tested in accordance with the method given in Annex B, the peak tensile force of each test piece shall be as given in Table 1.
- Freedom from leakage
- The hub or connection fitting assembly or any other part of the catheter shall not leak liquid when tested in accordance with the method given in Annex C. For hydratable intravascular catheters, this requirement shall be met in both the pre- and post-hydration states.
- Air shall not leak into the hub assembly during aspiration when tested in accordance with the method given in Annex D. For hydratable intravascular catheters, this requirement shall be met in both the pre- and post-hydration states.
Table 1. Peak Tensile Force of Catheter Test Pieces
| Smallest Outside Diameter of Tubular Portion of Test Piece
(mm) |
Minimum Peak Tensile Force
(N) |
| ≥0.55 to <0.75
≥0.75 to <1.15 ≥1.15 to <1.85 ≥1.85 |
3
5 10 15 |
| NOTE: This part of ISO 10555 does not specify requirements for peak tensile force for tubing of <0.55 mm outside diameter (prehydration outside diameter for hydratable intravascular catheters) or for a distal tip and its junction to the shaft tube. These values should be determined by the manufacturer based on risk assessment. | |
- Freedom from leakage
- The hub or connection fitting assembly or any other part of the catheter shall not leak liquid when tested in accordance with the method given in Annex C. For hydratable intravascular catheters, this requirement shall be met in both the pre- and post-hydration states.
- Air shall not leak into the hub assembly during aspiration when tested in accordance with the method given in Annex D. For hydratable intravascular catheters, this requirement shall be met in both the pre- and post-hydration states.
- Hubs
- If the catheter is supplied with either an integral or a separate hub, it shall be a female hub that shall comply with ISO 594-1 and ISO 594-2.
- Flow rate
- For devices for which flow rate is defined, when tested in accordance with Annex E, the flow rate for each lumen shall be a minimum of 80% of that stated by the manufacturer for catheters of nominal outside diameter less than 1.0 mm or a minimum of 90% of that stated by the manufacturer for catheters of nominal outside diameter equal to 1.0 mm or greater.
- If the flow rate through hydratable catheters is determined, it shall be determined in post-hydration states.
- Power injection
- If the catheter is indicated for power injection, the catheter burst pressure shall exceed the peak pressure present in the catheter at maximum flow conditions as determined by Annexes F and G.
- Side holes
- The design, number, and positioning of side holes shall be such as to minimize adverse effects on the catheter and trauma to the tissues.
- Distal tip
- The distal tip shall be smooth, rounded, tapered, or similarly finished in order to minimize trauma to vessels during use.
- Designation of nominal size
- Outside diameter
- Unless otherwise specified in one other part of this International Standard for a particular type of catheter, the outside diameter shall be expressed as the nominal dimension in millimeters, rounded upwards to the nearest 0.01 mm or 0.1 mm.
- For devices that are not round by design, the size shall be designated by the dimension of the largest axis. Where relevant, manufacturers may choose to report additional information regarding the device profile, such as the dimension of the second axis for an oval shape.
- Nominal effective length
- The nominal effective length shall be expressed in millimeters for effective lengths of <100 mm.
- The nominal effective length shall be expressed in millimeters or centimeters for effective lengths of ≥100 mm.
- Note: Tolerances to the effective length are not specified.
Information to be supplied by the manufacturer is also included in the document, such as marking on the device and/or primary packaging, instructions for use, and marking on the secondary packaging.
Manufacturing
Upon successful completion of the design process, and validation of the design via clinical study, the manufacturer must demonstrate the capability of producing the device repeatedly within the required specifications, to ensure that the mass-produced devices deliver the results observed during design validation. This can be a significant undertaking. Validation of the individual manufacturing processes requires an evaluation of those critical processes which drive the functional performance of the devices and demonstration, objectively, that those processes are stable and show repeated conformance to specifications. In general, the activities are divided as follows:
- Installation Qualification – Performed to document objective evidence that all equipment used within a process has been installed correctly, and all functions are operating as intended.
- Operational Qualification – Performed to document evidence that a process, when performed at its extreme high/low parameters, produces a product that meets the required process outputs. This evaluates the robustness of the process.
- Performance Qualification – Performed to document evidence that a process can repeatedly produce a product that meets required outputs consistently over multiple lots/batches.
Manufacturing validations are performed as above as a requirement for commercial distribution of the device upon regulatory approval. These activities can often be equal in duration as the design process and require a great deal of planning and resources for execution. Additionally, these activities may not be completed when a device is being studied in human clinical trials, and a manufacturer may rely on verification of the outputs of each lot/batch produced, rather than investing time in the validation of a process that could change in response to validation data or further design changes. Some processes within the manufacturing overall process are identified as highly critical (e.g., sterilization) and may require continuous monitoring even after the process has been validated. Further, all manufacturing validation activities are also subject to the manufacturer’s QMS and must maintain an updated level of documentation.
Essential Requirements Matrix
An example of a review of the Essential Requirements is provided in the following matrix for an ablation catheter in order to determine compliance with the Essential Requirements of the Medical Device Directive (MDD) 93/42/EEC. (Note: The designer should always confirm that she/he is using the most current and relevant requirements for their device type, geography, clinical indications, etc.)
| CLAUSES: ANNEX-1 of DIRECTIVE 93/42/EEC | Technical Standards Complied with | MANUFACTURER COMPLIANCE DOCUMENTS | |||
| No. | Directive Requirement | ||||
| 1. | The devices must be designed and manufactured in such a way that, when used under the conditions and for the purposes intended, they will not compromise the clinical condition or the safety of patients, or the safety and health of users or, where applicable, other persons, provided that any risks which may be associated with their use constitute acceptable risks when weighed against the benefits to the patient and are compatible with a high level of protection of health and safety.
This shall include: |
EN ISO 14971
EN 60601-1 EN 556-1 EN 62366-1
|
Risk Management
Product Specification(s) Sterilization Validation Ergonomics Animal Testing Verification Report(s): Bench Verification Report(s): Electrical Safety Biocompatibility Clinical Evaluation Report Usability |
||
| · Reducing, as far as possible, the risk of use error due to the ergonomic features of the device and the environment in which the device is intended to be used (design for patient safety), and | EN ISO 14971
EN 62366-1
|
Risk Management
Verification Report(s): Bench Ergonomics Usability |
|||
| · Consideration of the technical knowledge, experience, education and training and where applicable the medical and physical conditions of intended users (design for lay, professional, disabled, or other users). | EN ISO 14971
EN 60601-1 EN 62366-1
|
Risk Management
Verification Report(s): Bench Clinical Evaluation Report Product Specification(s) Biocompatibility Instructions for Use Product Label(S) Usability |
|||
| 2. | The solutions adopted by the manufacturer for the design and construction of the devices must conform to safety principles, taking account of the generally acknowledged state-of-the-art. In selecting the most appropriate solutions, the manufacturer must apply the following principles in the following order: | EN 60601-1
EN ISO 14971 EN 62366-1 |
Risk Management
Product Specification(s) Verification Report(s): Bench Verification Report(s): Electrical Safety Usability |
||
| · Eliminate or reduce risks as far as possible (inherently safe design and construction); | EN ISO 14971
EN 62366-1
|
Risk Management
Product Specification(s) Verification Report(s): Bench Biocompatibility Usability |
|||
| · Where appropriate take adequate protection measures including alarms if necessary, in relation to risks that cannot be eliminated; | EN ISO 14971
|
Risk Management
Product Specification(s) Verification Report(s): Bench Biocompatibility Usability |
|||
| · Inform users of the residual risks due to any shortcomings of the protection methods adopted. | EN ISO 14971
EN 62366-1
|
Risk Management
Product Specification(s) Verification Report(s): Bench Biocompatibility Instructions for Use Usability |
|||
| 3. | The devices must achieve the performance intended by the manufacturer and be designed, manufactured, and packaged in such a way that they are suitable for one or more of the functions referred to in Article 1(2) (a) as specified by the manufacturer. | None | Product Specification(s)
Verification Report(s): Bench Packaging – Sterile Barrier, Shipping & Shelf-Life Risk Management Instructions for Use |
||
| 4. | The characteristics and performance referred to in sections 1, 2, and 3 must not be adversely affected to such a degree that the clinical condition and safety of the patients and, where applicable, of other persons are compromised during the lifetime of the device as indicated by the manufacturer, when the device is subjected to the stresses that can occur during normal conditions of use. | EN ISO 14971
EN 62366-1
|
Packaging – Sterile Barrier, Shipping & Shelf-Life
Verification Report(s): Bench Risk Management Clinical Evaluation Report Biocompatibility Usability |
||
| 5. | The devices must be designed, manufactured, and packed in such a way that their characteristics and performances during their intended use will not be adversely affected during transport and storage taking account of the instructions and information provided by the manufacturer. | EN ISO 14971
EN 60601-1
|
Packaging – Sterile Barrier, Shipping & Shelf-Life
Packaging Validation Risk Management Product Labels Instructions for Use Biocompatibility Verification Report(s): Bench Product Specification(s) |
||
| 6. | Any undesirable side effects must constitute an acceptable risk when weighed against the performances intended. | EN ISO 14971
EN 60601-1 |
Risk Management
Clinical Evaluation Report Biocompatibility |
||
| 6a | Demonstration of conformity with the essential requirements must include a clinical evaluation in accordance with Annex X. | MEDDEV 2.7.1 Rev. 3:2009, Guidelines On Medical Devices – Clinical evaluation: A guide for manufacturers and Notified Bodies | Clinical Evaluation Report
|
||
| 7. | |||||
| 7.1 | The devices must be designed and manufactured in such a way as to guarantee the characteristics and performances referred to in Section I on the “General Requirements”. Particular attention must be paid to:
– the choice of materials used, particularly as regards toxicity and, where appropriate, flammability; |
EN 60601-1
EN ISO 14971 EN ISO 10993-1 EN ISO 10993-4 EN ISO 10993-5 ISO 10993-10 EN ISO 10993-11 EN ISO 10993-18 |
Biocompatibility
Product Specification(s) Risk Management
|
||
| – The compatibility between the materials used and biological tissues, cells, and body fluids, taking account of the intended purpose of the device. | EN ISO 14971
EN ISO 10993-1 EN ISO 10993-4 EN ISO 10993-5 ISO 10993-10 EN ISO 10993-11 EN ISO 10993-18 |
Biocompatibility
Product Specification(s) Risk Management |
|||
| 7.2 | The devices must be designed, manufactured, and packed in such a way as to minimize the risk posed by contaminants and residues to the persons involved in the transport, storage and use of the devices and to the patients, taking account of the intended purpose of the product. Particular attention must be paid to the tissues exposed and the duration and frequency of the exposure. | EN ISO 10993-1
EN ISO 10993-4 EN ISO 10993-5 EN ISO 11607-1 EN ISO 10993-7 ISO 10993-10 EN ISO 10993-11 EN ISO 10993-18 |
Product Specification(s)
Controlled Environment Packaging – Sterile Barrier, Shipping & Shelf-Life Risk Management Biocompatibility Verification Report(s): Bench Sterilization Validation |
||
| 7.3 | The devices must be designed and manufactured in such a way that they can be used safely with the materials, substances, and gases with which they enter into contact during normal use or during routine procedures. | EN ISO 11607-1
EN ISO 10555-1
|
Verification Report(s): Bench
Biocompatibility Risk Management Packaging – Sterile Barrier, Shipping & Shelf-Life Product Specification(s) |
||
| 7.5 | The devices must be designed and manufactured in such a way as to reduce to a minimum the risks posed by substances leaking from the device.
|
EN ISO 10993-1
EN ISO 10993-4 EN ISO 10993-5 EN ISO 10993-7 ISO 10993-10 EN ISO 10993-11 EN ISO 10993-18 EN ISO 11607-1 EN ISO 10555-1 EN 60601-1
|
Packaging – Sterile Barrier, Shipping & Shelf-Life (Label Legibility)
Verification Report(s): Bench Risk Management Sterilization Validation Biocompatibility Product Specification(s)
|
||
| 7.6 | The devices must be designed and manufactured in such a way as to reduce, as much as possible, risks posed by the unintentional ingress of substances into the device taking into account the device and the nature of the environment in which it is intended to be used. | EN ISO 11607-1
EN ISO 11607-2 ISO 14644-1 EN 60601-1
|
Product Specification
Risk Management Packaging – Sterile Barrier, Shipping & Shelf-Life Verification Report(s): Bench Controlled Environment Packaging Validation Plan |
||
| 8. | |||||
| 8.1 | The devices and manufacturing processes must be designed in such a way as to eliminate or reduce as far as possible the risk of infection to the patient, user, and third parties. The design must allow easy handling and, where necessary, minimize contamination of the device by the patient, or vice versa, during use. | EN ISO 10555-1
EN ISO 14644-1 EN 556-1 EN ISO 11607-1 EN ISO 11607-2 ISO 11135 |
Product Specification(s)
Controlled Environment Sterilization Validation Packaging Validation Packaging – Sterile Barrier, Shipping & Shelf-Life Packaging Validation Plan Usability |
||
| 8.3 | Devices delivered in a sterile state must be designed, manufactured, and packed in a non-reusable pack and/or according to appropriate procedures to ensure they are sterile when placed on the market and remain sterile, under the storage and transport conditions laid down, until the protective packaging is damaged or opened. | EN ISO 11607-1
EN ISO 11607-2 ISO 14644-1 EN ISO 11135-1 EN ISO 10555-1 |
Packaging Validation
Packaging – Sterile Barrier, Shipping & Shelf-Life Product Specification(s) Packaging Validation Plan Controlled Environment |
||
| 8.4 | Devices delivered in a sterile state must have been manufactured and sterilized by an appropriate, validated method. | EN ISO 11135
EN ISO 10993-7 EN ISO 11607-2 EN 556-1 EN ISO 10555-1 |
Sterilization Validation
Package Validation Packaging Validation Plan |
||
| 8.5 | Devices intended to be sterilized must be manufactured in appropriately controlled (e.g., environmental) conditions. | ISO 14644-1
EN ISO 11607-1 EN ISO 11607-2 |
Controlled Environment
Packaging – Sterile Barrier, Shipping & Shelf-Life |
||
| 9. | |||||
| 9.1 | If the device is intended for use in combination with other devices or equipment, the whole combination, including the connection system, must be safe and must not impair the specified performance of the devices. Any restrictions on use must be indicated on the label or in the instructions for use. | EN 1041
EN ISO 11607-1 EN ISO 10555-1 EN 60601-1 EN 62366-1 |
Animal Testing
Verification: Electrical Safety Verification Report(s): Bench Risk Management Instructions for Use Packaging Validation Usability |
||
| 9.2 | Devices must be designed and manufactured in such a way as to remove or minimize as far as is possible:
— the risk of injury, in connection with their physical features, including the volume/pressure ratio, dimensional, and, where appropriate ergonomic features. |
EN ISO 10555-1
EN ISO 11607-1 EN 60601-1
|
Ergonomics
Animal Testing Verification Report(s): Electrical Safety Verification Report(s): EMI/EMC Verification Report(s): Bench Product Requirements Specification Product Label(s) Usability |
||
| 13. | |||||
| 13.1 | Each device must be accompanied by the information needed to use it safely and properly, taking into account the training and knowledge of the potential users, and to identify the manufacturer.
· 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, when 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 instruction for use is needed for devices in Class I or Class IIa if they can be used safely without any such instructions. |
EN 1041
EN ISO 11607-1 EN ISO 10555-1 EN 60601-1 |
Instructions for Use
Product Label(s)
|
||
| 13.2 | Where appropriate this information should take the form of symbols. Any symbol or identification color used must conform to the harmonized standards. In areas for which no standards exist, the symbols and colors must be described in the documentation supplied with the device. | EN 980
EN 1041 EN 60601-1 EN ISO 10555-1 |
Instructions for Use
Product Label(s) |
||
| 13.3 | |||||
| (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 the instructions for use, shall contain in addition the name and address of the authorized representative in situations where the manufacturer does not have a registered place of business in the community: | EN 980
EN 1041 EN ISO 10555-1 EN ISO 11607-1 EN 60601-1 |
Product Label(s)
|
||
| (b) | The details strictly necessary for the user to identify the device and the contents of the packaging; | EN 980
EN 1041 EN ISO 10555-1 EN ISO 11607-1 EN 60601-1 |
Product Label(s) | ||
| (c) | Where appropriate, the word ‘STERILE’; | EN 556-1
EN 980 EN 1041 EN ISO 10555-1 EN 60601-1 |
Product Label(s)
Sterilization Validation |
||
| (d) | Where appropriate, the batch code, preceded by the word ‘LOT’, or the serial numbers; | EN 980
EN 1041 EN ISO 10555-1 EN ISO 11607-1 EN 60601-1 |
Product Label(s) | ||
| (e) | Where appropriate, an indication of the date by which the device should be used safely, expressed as the year and month; | EN 980
EN 1041 EN ISO 10555-1 EN ISO 11607-1 EN 60601-1 |
Product Label(s) | ||
| (f) | Where appropriate, an indication that the device is for single use. A manufacturer’s indication of single use must be consistent across the community; | EN 980
EN 1041 EN ISO 10555-1 EN ISO 11607-1 EN 60601-1 |
Product Label(s) | ||
| (i) | Any special storage and/or handling conditions; | EN 980
EN 1041 EN ISO 10555-1 EN ISO 11607-1 EN 60601-1 |
Product Label(s) | ||
| (j) | Any special operating instructions; | EN 980
EN 1041 EN ISO 10555-1 EN ISO 11607-1 EN 60601-1 |
Product Label(s) | ||
| (k) | Any warnings and/or precautions to take; | EN 980
EN 1041 EN ISO 10555-1 EN 60601-1 |
Product Label(s) | ||
| (l) | Year of manufacture for active devices other than those covered by (c). This indication may be included in the batch or serial number. | Not applicable
|
Not applicable | ||
| (m) | Where applicable, method of sterilization. | EN 980
EN 1041 EN ISO 10555-1 EN ISO 11607-1 EN 60601-1 |
Product Label(s) | ||
| 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 instruction for use. | EN 1041
EN ISO 10555-1 |
Instructions for Use
Product Label(s) |
||
| 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 risk posed by the devices and detachable components. | EN 1041
EN 60601-1 |
Instructions for Use
Product Label(s) |
||
| 13.6 | Where appropriate, the instructions for use must contain the following particulars: | ||||
| (a) | The details referred to in 13.3 with the exception of d) and e); | EN 1041
EN ISO 10555-1 EN 60601-1 |
Instructions for Use | ||
| (b) | The performances referred to in Section 3 and any undesirable side effects; | EN 1041
EN ISO 10555-1 |
Instructions for Use | ||
| (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; | EN 1041
EN 60601-1 EN ISO 10555-1
|
Instructions for Use | ||
| (g) | The necessary instructions in the event of damage to the sterile packaging and, where appropriate, details of appropriate methods of re-sterilization; | EN 1041
EN ISO 10555-1 EN 60601-1 |
Instructions for Use | ||
| If the device bears an indication that the device is for single use, information on known characteristics and technical factors known to the manufacturer that could pose a risk if the device were to be re-used. If in accordance with Section 13.1 no instructions for use are needed, the information must be made available to the user upon request. | EN 1041
EN ISO 11607-1 EN 60601-1 |
Instructions for Use
|
|||
| (q) | Date of issue or the latest revision of the instructions for use. | EN 1041
EN ISO 10555-1 |
Instructions for Use | ||
The following standards are provided as examples of the requirements for the development of an ablation catheter and the associated system. (Note: Designers should always confirm that they are using the most current and relevant requirements for their device type, geography, clinical indications, etc.)
| MMD 93/42/EEC CONFORMITY ASSESSMENT REFERENCED STANDARDS | |
| REFERENCED STANDARDS & REVISIONS | TITLE |
| EN 556-1:2001 /AC:2006 | Sterilization of medical devices – Requirements for medical devices to be designated “STERILE” – Part 1: Requirements for terminally sterilized medical devices |
| EN 980:2008 | Symbols for use in the labelling of medical devices |
| EN 1041:2008 | Information supplied by the manufacturer of medical devices |
| FDA Guidelines – Use of International Standard ISO 10993 | Biological Evaluation of Medical Devices Part 1: Evaluation and Testing |
| EN ISO 10993-1:2009/ AC:2010 | Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process |
| EN ISO 10993-4: 2009 | Biological evaluation of medical devices – Part 4: Selection of tests for interactions with blood (ISO 10993-4:2002, including Amd. 1:2006) |
| EN ISO 10993-5: 2009 | Biological evaluation of medical devices – Part 5: Tests for in vitro cytotoxicity (ISO 10993-5:2009) |
| EN ISO 10993-7: 2008 | Biological evaluation of medical devices – Part 7: Ethylene oxide sterilization residuals |
| ISO 10993-10: 2010* | Biological evaluation of medical devices — Part 10: Tests for irritation and skin sensitization |
| EN ISO 10993-11: 2009 | EN ISO 10993-11:2009 Biological evaluation of medical devices – Part 11: Tests for systemic toxicity (ISO 10993-11:2006) |
| EN ISO 10993-18: 2009 | Biological evaluation of medical devices – Part 18: Chemical characterization of materials |
| ISO 11135-1: 2014† | Sterilization of health care products – Ethylene oxide – Part 1: Requirements for the development, validation, and routine control of a sterilization process for medical devices. |
| EN ISO 11607-2: 2006 + A1:2014 | Packaging for terminally sterilized medical devices – Part 2: Validation requirements for forming, sealing and assembly processes |
| EN ISO 14971: 2007 and 2012 | Medical devices – Application of risk management to medical devices |
| EN ISO 13485: 2012/ AC:2012 | Medical devices — Quality management systems — Requirements for regulatory purposes |
| ISO 14644-1: 2015* | Cleanrooms and associated controlled environments – Part 1: Classification of air cleanliness by particle concentration – Second Edition |
| EN 60601-1: 2006/ A1:2013 | Medical electrical equipment — Part 1: General requirements for basic safety and essential performance |
| EN ISO 10555-1: 2013 | Sterile, single-use intravascular catheters — Part 1: General requirements |
| EN 62366-1:2015 | Medical Devices – Part 1: Application of usability engineering to medical devices |
| EN 60601-1-2: 2007 + AC:2010 | Medical electrical equipment – Part 1-2: General requirements for basic safety and essential performance – Collateral Standard: Electromagnetic disturbances – Requirements and tests |
*ISO 14644-1 and ISO 10993-10 are not harmonized within the European Union, are considered state of the art, and no harmonized equivalents are available. Given this, they will be used to support compliance to the essential requirements of the Medical Device Directives (MDD).
†ISO 11135-1:2014 is the current state of art version of the standard and this version has not yet been harmonized. Thus, it is being used in support of the MDD.