ISO – International Organization for Standardization, is the international, non-governmental body for drafting and establishing technical and non-technical standards. These standards are developed by different committees within the ISO. Having around 165 member states, with one representative from each, ISO is a global entity catering to the needs of industry requirements.
Are ISO standards important?
The ISO medical device standards are the Bible for many countries, especially ones which do not have predefined regulations or processes. For regulated countries, in addition to their respective regulations and guidance, ISO standards are also preferred. The most popularly referred ISO standard is the ISO 13485:2016 Medical devices — Quality management systems — Requirements for regulatory purposes. In addition to general standards, ISO also publishes product-specific guidance such as for Implants, Orthopedic, Medical Electric Equipment, and many more.
Global ISO Requirements
In Europe, the European Commission has the Medical Device Regulation MDR 2017/745 and In-vitro Diagnostic Device Regulation IVDR 2017/746. These regulations provide a detailed framework for introducing a medical device in the European market. However, in addition to that, certain ISO standards may also be referred to for ensuring a better-quality product. Some of the many popularly used standards include:
ISO 14971:2019 Medical Devices – Application of Risk Management to medical devices
ISO 15223-1:2021 Medical devices – Symbols to be used with information to be supplied by the manufacturer – Part 1: General requirements
IEC 60601-2-83 Medical electrical equipment – Part 2-83: Particular requirements for the basic safety and essential performance of home light therapy equipment
IEC 60601-1 Medical electrical equipment – Part 1: General requirements for basic safety and essential performance
The European Commission also has Harmonized Standards, developed by European Standards Organization CEN, CENELEC, or ETSI, per the international standards. It provides a list of the applicable harmonized standards for enhanced product safety and quality.
In the USA, the US Food and Drug Administration (FDA) has a Code of Federal Regulations (CFR) and Guidance.
CFRs are legally binding. Manufacturers must comply with the requirements of CFR
The guidance provides Agency’s thinking on regulatory issues. They are NOT legally binding
In addition to these, the FDA also accepts certain recognized consensus standards from different organizations such as ISO, CLSI, ANSI, IEC, CEN, etc. These standards may be used to justify a Declaration of Conformity for a product. The widely accepted medical device ISO standards are, but are not limited to:
ISO 10993 – Biological Evaluation for Medical Devices
ISO 14160 – Sterilization of Healthcare Products
ISO 11737 – Sterilization of Medical Devices
In Canada, the Standards Council of Canada (SCC) is the ISO member body. Similar to the US FDA, the Therapeutic Products Directorate (TPD) of Health Canada periodically releases a list of acceptable international or national standards for medical devices. Manufacturers can use these recognized standards in conjunction with the Health Canada’s Medical Devices Regulations (SOR-98/282) and the Guidance Documents, to prove product conformity and safe use in the market.
China‘s National Medical Products Administration (NMPA) is developing indigenous standards that more closely align with those of ISO. Biocompatibility testing is one avenue where the scope and requirements for China are more than that of the US/EU. Hence, NMPA has developed various biocompatibility testing standards which are to be used in addition to the ISO standard.
For the rest of the world’s medical device industry,
India encourages ISO certification for all its industries. The medical sector must be ISO 13485 compliant while the pharmaceutical sector must be ISO 9001 compliant for Quality Management Systems, in addition to other relevant and applicable ISO standards.
Japan’s The Japanese Industrial Standards Committee (JISC) is an ISO member body. The regulatory authority, Pharmaceutical and Medical Device Agency (PMDA) revised its Ordinance No. 169 in 2021 to closely align with the ISO 13485:2016 standard. The transition period is 3 years and must comply by March 25, 2024
For the Korean regulatory authority, aligning the requirements of Korean Good Manufacturing Practice (GMP) to that of ISO 13485:2016 is believed to be a step closer to entering the Medical Device Single Audit Program (MDSAP)
Russia’s Federal Service for Surveillance in Healthcare (Roszdravnadzor) is known to accept ISO 13485:2016 certification. Information on acceptance of other ISO standards cannot be confirmed. It does not accept market approvals in the US, EU, or other countries as a reference for market authorization in Russia
Australia’s Standard Australia is a member of the ISO, IEC, and ICSID. It strongly encourages the use of international standards, except where their use is ineffective or inappropriate and does not develop any national Australian standard for which there is already an international standard in existence. In 2019, TGA published Therapeutic Goods (Conformity Assessment Standard for Quality Management Systems) Order 2019which provides a list of applicable conformity assessment standards.
Brazil’s ANVISA accepts Good Manufacturing Practices (GMP) along with the ISO 13485
Can QMS be established solely based on ISO standards?
For countries that do not have their own QMS regulations, the ISO standard can be used as a reference. For countries with established local regulations, and that accepts ISO, both ISO standard and local/national regulations must be considered.
Are ISO standards freely available?
No. ISO standards are available for purchase from the ISO official website. However, they do have FREE read-only formats available.
Comparing ISO standards to local regulations, which one takes precedence?
The local or national regulation always takes precedence over the ISO standard.
Can the manufacturer use an older version of an ISO standard for compliance?
No. Manufacturers must make sure they comply with the active or most recent version of the ISO standard. This is not restricted just to ISO standards but applies to National regulations too. Manufacturers must keep their QMS up to date with the latest requirements of the industry. The ideal way to be updated is to refer to the latest version of any Standard or Regulation.
Disclaimer: Regulations/legislations are subjected to changes from time to time and the author claims no responsibility for the accuracy of information.
MDGC Guidance on significant changes regarding the transitional provision under Article 110(3) of the IVDR aims to provide clarification on the concept of ‘significant changes in the design and intended purpose’. This article applies to manufacturers of devices that comply with Directive 98/79/EC and is placed on the market or put into operation after the transition period ends on May 26, 2022, irrespective of the involvement of notified body under the IVDD. It is important to note that IVDR Article 110(3) prohibits the issuance of new IVDD certificates.
Devices that are eligible to be on the market after 26 May 2022
Article 110(3) of Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR), as amended by Regulation (EU) 2022/1121, states that the following devices may be placed on the market or put into service under certain conditions after the IVDR’s effective date, i.e. 26 May 2022, until the end of the various transition periods specified in Article 110(3) IVDR:
Devices which have a valid certificate issued by a notified body under the Directive 98/79/EC on in vitro diagnostic medical devices (IVDD), and
Devices for which a declaration of conformity was drawn up prior to 26 May 2022. In accordance with the IVDD and for which the conformity assessment procedure pursuant to the IVDR (contrary to the IVDD) requires the involvement of a notified body
Conditions mentioned in Article 110(3)
The transitional provisions in Article 110(3) IVDR must be applied only if the devices continue to comply with the IVDD and there are no major changes in the design or intended purpose of the device after the IVDR takes effect. However, requirements of EU 2017/746 relating to post-market surveillance, market surveillance, vigilance, economic operator registration, and device registration will apply and replace the provisions of that Directive.
What are the certificates that remain valid?
Considerations for Assessment
Manufacturers generally will try to avoid any significant changes in the design or intended purpose of the medical device after the date of application of IVDR to benefit from the transition period mentioned in Article 110(3), IVDR. The two types of changes under which the manufacturers can reap the benefits of the transition period mentioned in Article 110(3), IVDR are the following:
Changes that do not concern the design or intended purpose
Change made is not a significant one
In case of the changes mentioned above, the manufacturer can implement the change during the transition period without the need for certification under IVDR but is expected to comply with the documentation requirements of the IVDD. Additionally, in the case of devices covered by a certificate from the notified body, manufacturers must check with their notified body if the changes belong to the types mentioned above. If so, the notified body will issue a written statement for the same. The written statement will expire on the date of expiry of the IVDD certificate or 26 May 2025, whichever comes first. The manufacturer is expected to present this written statement and other documentation on request from the market surveillance authorities. If the conformity assessment procedure under the IVDD requires the QMS to be approved by the notified body, then the manufacturer must ensure that the conditions under which the certificate was granted are maintained. The point to be noted here is that the existing IVDD certification will not be amended at any time.
Changes not concerning the design or intended purpose
Changes in manufacturer organisation (administrative change) or changes in the manufacturing process must not be considered a change in design or intended purpose even if they are to be mentioned in the information supplied with the device (e.g., Label or instructions for use). Examples are mentioned in the MDCG guidance documents.
Changes in the design or intended purpose
The flowcharts are given in the annex section of the MDCG guidance document to help manufacturers, notified bodies, and market surveillance authorities decide whether or not a change of the design or intended purpose of the device is considered significant under IVDR Article 110(3).
The following changes are NOT to be considered significant changes:
Changes related to corrective actions assessed and accepted by the competent authority
Correction of spelling mistakes or merely editorial changes of the information to be supplied with the device (e.g., label or instructions for use)
Updates of the information to be supplied with the device if they are required by law other than the IVDR (e.g., CLP Regulation (EC) 1272/2008 read in conjunction with Annex I, section 8.3. IVDD) are mere clarifications and do not adversely affect the devices’ safety and performance in relation to existing or new risks.
The MDCG guidance document on Article 110(3) provides the main flowchart followed by sub flowcharts which are to be used on specific conditions as listed below:
Chart A– Changes in the intended purpose
Charts B to E – Changes in the design
Chart C – Software changes
Chart D – Changes related to an ingredient or material
For a device consisting of Software, what is considered significant and non-significant changes?
Non-significant change: · Bug fixes, updates of standard third-party OS, security updates, the appearance of the user interface, operating efficiencies and Changes in UI which do not affect performance. Significant change: · New or major change of OS, any component, modification of architecture, database structure. Change of algorithm, the addition of a new database, required user input replaced by a closed-loop algorithm, presentation of medical data in a new format or by a new dimension or measuring unit.
Does change in Sterilisation impact or be called a significant change?
Non-significant change: · Change of the sterilisation cycle parameters under the approved QMS, shelf life validated by protocols approved by the notified body
Significant change: · Change of sterilisation method, including changing a device from ‘non-sterile’ to ‘sterile’, design or packaging changes that adversely affect the sterility assurance or the effectiveness of the sterilisation
Is there an MDCG guidance document that states the Significant changes for devices certified under MDD or AIMDD?
Information for use (IFU) and labels must be provided with every In-Vitro diagnostic medical device, containing information to identify the device, its manufacturer and any relevant safety and performance information for the user or any other person. Such information may be found on the device itself, in the packaging, or in the user instructions (IFU), and if the manufacturer has a website, it must be made available and maintained up to date on the website.
Updates in Labelling Requirements (CHAPTER III, EU IVDR)
The name or trade name of the device
The UDI carrier as referred to in Article 24 and Part C of Annex VI
Where there is no indication of the date until when it may be used safely, the date of manufacture. This date of manufacture may be included as part of the lot number or serial number, provided the date is clearly identifiable
Where relevant, an indication of the net quantity of contents, expressed in terms of weight or volume, numerical count, or any combination of thereof, or other terms which accurately reflect the contents of the package
Where appropriate, an indication of the sterile state of the device and the sterilisation method, or a statement indicating any special microbial state or state of cleanliness
Warnings or precautions to be taken that need to be brought to the immediate attention of the user of the device or to any other person. This information may be kept to a minimum in which case more detailed information shall appear in the instructions for use, taking into account the intended users
If the instructions for use are not provided in paper form in accordance with point (f) of Section 20.1, a reference to their accessibility (or availability), and where applicable the website address where they can be consulted
If the device is intended for single use, an indication of that fact. A manufacturer’s indication of single use shall be consistent across the Union
If the device is intended for self-testing or near-patient testing, an indication of that fact
Where rapid assays are not intended for self-testing or near-patient testing, the explicit exclusion hereof
Where device kits include individual reagents and articles that are made available as separate devices, each of those devices shall comply with the labelling requirements and with the requirements of this Regulation
The label for devices for self-testing shall bear the following particulars: (i) The type of specimen(s) required to perform the test (e.g. blood, urine or saliva) (ii) The need for additional materials for the test to function properly (iii) Contact details for further advice and assistance The name of devices for self-testing shall not reflect an intended purpose other than that specified by the manufacturer
Information on the packaging which maintains the sterile condition of a device (‘sterile packaging’): The following particulars shall appear on the sterile packaging: (a) an indication permitting the sterile packaging to be recognised as such, (b) a declaration that the device is in a sterile condition, (c) the method of sterilisation, (d) the name and address of the manufacturer, (e) a description of the device, (f) the month and year of manufacture, (g) an unambiguous indication of the time limit for using the device safely, expressed at least in terms of year and month and, where relevant, the day, in that order, (h) an instruction to check the instructions for use for what to do if the sterile packaging is damaged or unintentionally opened before use
Updates in Information for use Requirements(CHAPTER III, EU IVDR)
The device’s intended purpose:
what is detected and/or measured
its function (e.g. screening, monitoring, diagnosis or aid to diagnosis, prognosis, prediction, companion diagnostic)
the specific information that is intended to be provided in the context of: —a physiological or pathological state; — congenital physical or mental impairments; — the predisposition to a medical condition or a disease; — the determination of the safety and compatibility with potential recipients; — the prediction of treatment response or reactions; — the definition or monitoring of therapeutic measures
whether it is automated or not
whether it is qualitative, semi-quantitative or quantitative
the type of specimen(s) required
where applicable, the testing population; and
for companion diagnostics, the International Non-proprietary Name (INN) of the associated medicinal product for which it is a companion test
The intended user, as appropriate (e.g., self-testing, near patient and laboratory professional use, healthcare professionals
For devices intended for use in combination with or installed with or connected to other devices and/or general-purpose equipment:
— information to identify such devices or equipment, in order to obtain a validated and safe combination, including key performance characteristics, and/or
— information on any known restrictions to combinations of devices and equipment.
In-use stability which may include the storage conditions, and shelf life following the first opening of the primary container, together with the storage conditions and stability of working solutions, where this is relevant
If the device is supplied as sterile, an indication of its sterile state, the sterilisation method and instructions in the event of the sterile packaging being damaged before use
Information that allows the user to be informed of any warnings, precautions, measures to be taken and limitations of use regarding the device. That information shall cover, where appropriate:
warnings, precautions and/or measures to be taken in the event of malfunction of the device or its degradation as suggested by changes in its appearance that may affect performance,
warnings, precautions and/or measures to be taken as regards the exposure to reasonably foreseeable external influences or environmental conditions, such as magnetic fields, external electrical and electromagnetic effects, electrostatic discharge, radiation associated with diagnostic or therapeutic procedures, pressure, humidity, or temperature,
warnings, precautions and/or measures to be taken as regards the risks of interference posed by the reasonably foreseeable presence of the device during specific diagnostic investigations, evaluations, therapeutic treatment or other procedures such as electromagnetic interference emitted by the device affecting other equipment,
precautions related to materials incorporated into the device that contain or consist of CMR substances, or endocrine disrupting substances or that could result in sensitisation or an allergic reaction by the patient or user,
if the device is intended for single use, an indication of that fact. A manufacturer’s indication of single use shall be consistent across the Union,
if the device is reusable, information on the appropriate processes to allow reuse, including cleaning, disinfection, decontamination, packaging and, where appropriate, the validated method of re-sterilisation. Information shall be provided to identify when the device should no longer here used, such as signs of material degradation or the maximum number of allowable reuses
Any warnings and/or precautions related to potentially infectious material that is included in the device
Where relevant, requirements for special facilities, such as a clean room environment, or special training, such as on radiation safety, or particular qualifications of the intended user
Conditions for collection, handling, and preparation of the specimen
Details of any preparatory treatment or handling of the device before it is ready for use, such as sterilisation, final assembly, calibration, etc., for the device to be used as intended by the manufacturer
The information needed to verify whether the device is properly installed and is ready to perform safely and as intended by the manufacturer, together with, where relevant:
— details of the nature, and frequency, of preventive and regular maintenance, including cleaning and disinfection; — identification of any consumable components and how to replace them; — information on any necessary calibration to ensure that the device operates properly and safely during its intended lifetime; — methods for mitigating the risks encountered by persons involved in installing, calibrating or servicing devices.
Where applicable, recommendations for quality control procedures
The metrological traceability of values assigned to calibrators and control materials, including identification of applied reference materials and/or reference measurement procedures of higher order and information regarding maximum (self-allowed) batch to batch variation provided with relevant figures and units of measure
Assay procedure including calculations and interpretation of results and where relevant if any confirmatory testing shall be considered; where applicable, the instructions for use shall be accompanied by information regarding batch to batch variation provided with relevant figures and units of measure
Where relevant, clinical performance characteristics, such as threshold value, diagnostic sensitivity and diagnostic specificity, positive and negative predictive value
Where relevant, reference intervals in normal and affected populations
Information on interfering substances or limitations (e.g. visual evidence of hyperlipidaemia or haemolysis, age of specimen) that may affect the performance of the device
Warnings or precautions to be taken in order to facilitate the safe disposal of the device, its accessories, and the consumables used with it, if any. This information shall cover, where appropriate:
infection or microbial hazards, such as consumables contaminated with potentially infectious substances of human origin
environmental hazards such as batteries or materials that emit potentially hazardous levels of radiation)
physical hazards such as explosion
A notice to the user that any serious incident that has occurred in relation to the device shall be reported to the manufacturer and the competent authority of the Member State in which the user and/or the patient is established
Where device kits include individual reagents and articles that may be made available as separate devices, each of these devices shall comply with the instructions for use requirements contained in this Section and with the requirements of this Regulation
For devices that incorporate electronic programmable systems, including software, or software that are devices in themselves, minimum requirements concerning hardware, IT networks characteristics and IT security measures, including protection against unauthorised access, necessary to run the software as intended
In addition, the instructions for use for devices intended for self-testing shall comply with all of the following principles:
the information provided shall include a statement clearly directing that the user should not take any decision of medical relevance without first consulting the appropriate healthcare professional, information on disease effects and prevalence, and, where available, information specific to the Member State(s) where the device is placed on the market on where a user can obtain further advice such as national helplines, websites
for devices intended for self-testing used for the monitoring of a previously diagnosed existing disease or condition, the information shall specify that the patient should only adapt the treatment if he has received the appropriate training to do so
Symbols used on IVDR labels and IFUs
Please note: Symbols listed here are used in common for Medical Devices and IVDs
Manufacturing Information Symbols
Manufacturer Symbol to be accompanied with Manufacturer name and address adjacent to the symbol
EU Authorised Representative Symbol to be accompanied with Local EU authorised representative name and address. If the Authorised Representative is the Importer and Distributor, these details need not be duplicated.
Date of manufacture Format YYYY-MM- DD For a “Sterile” device, Manufacturing Date and Expiration Date symbols to be mentioned
Country of manufacture Indicates the country of manufacture of the medical device. In the application of this symbol, the “CC” shall be replaced by either the two-letter country code or the three-letter country code defined in ISO 3166-1.
Use by Date or Expiry Date Represents Expiration Date Can be used in place of “Date of manufacture” For a ‘Sterile’ device, Manufacturing Date and Expiration Date symbols to be mentioned
Information available on web Indicates that patient can get additional information on web about the product.
Importer Required to be provided with their name, registered trade mark and address Importer to add label to the device ensuring the label does not obscure any information on the label provided by the manufacturer
Distributor Required to be provided with their name, registered trade mark and address
CE marking (with notified body number) Symbol to indicate “CE” conformity XXXX not present for self-declaration devicesXXXX replaced with the respective notified body number that assessed the medical device
In-Vitro Diagnostic Medical Device To indicate the product is an In- Vitro Diagnostic Medical Device
For self-testing A lay person can use the device marked with this symbol even without professional medical experience.
Not for self-testing Indicates that devices must be used by trained professionals in an appropriate setting.
For near-patient testing Indicates that the device must be used by a trained professional in a near-patient setting.
Not for near-patient testing Indicates that device must be used by trained professional in laboratory setting.
Identification / Product Traceability Symbols
Batch code or Lot code Batch or Lot code to be mentioned adjacent to the symbol
Catalogue number Indicated catalogue number to be mentioned adjacent to the symbol
Serial Number Indicates manufacturer serial number to identify device (Mandatory for implantable devices)
Model number To identify the model number or type number of the product This symbol to be accompanied by the model number or catalogue number of the product, adjacent to the symbol
Unique Device Identifier Contains 2 parts UDI-DI – Device Identifier & UDI-PI – Production Identifier Symbol is not mandatory, can be indicated using Bar Code/RFID/QR Code
Patient Number Indicates a unique number associated with an individual patient NOTE # is part of the symbol. The patient number appears adjacent to the symbol.
Non-Sterile Indicates a medical device has not been subjected to a sterilisation process
DO NOT Re-sterilize Indicates the device should not be subjected to any re-sterilization
Sterile* Indicates the device has been subjected to sterilization process / methods
Sterilized using Aseptic techniques* Subject to sterilization using aseptic processing techniques
Sterilized using Ethylene dioxide* Subject to sterilization using Ethylene dioxide
Sterilized using irradiation* Subject to sterilization using irradiation
Sterilized using vaporized hydrogen peroxide* Subject to sterilization using vaporized hydrogen peroxide
Single Sterile Barrier Indicates a single sterile barrier system This symbol can be used in adjacent or in combination with Sterile* symbols
Double Sterile Barrier Indicates two sterile barrier systems This symbol can be used in adjacent or in combination with Sterile* symbols
Single Sterile with protective packaging inside Indicates a single sterile barrier system with protective packaging inside NOTE: The protective packaging located inside the sterile barrier system is designed to prevent damage to the contents or to help with aseptic presentation. It does not provide a microbial barrier to maintain sterility
Single Sterile with protective packaging outside Indicates a single sterile barrier system with protective packaging outside NOTE: The protective packaging located outside the sterile barrier system is designed to prevent damage to the sterile barrier system and the contents. The protection can be against physical hazards, particulate contamination or other environmental hazards, but it does not include a microbial barrier.
Cautions / Warning / Information to User
Cautions to use the device Indicates user to consult for important cautionary information such as warnings
Refer to Instructions for Use (IFU) or refer to electronic Instructions for Use (eIFU) Indicates need for the user to consult instructions for use to use the device appropriately and safe For eIFU mention web address alongside the IFU symbol
Translation To identify that the original medical device information has undergone a translation which supplements or replaces the original information This symbol shall be accompanied by the name and address of the entity that is responsible for the translation activity, adjacent to the symbol. If multiple symbols (i.e., Authorized Representative, Importer, Distributor, Translation, or Repackaging) identify the same responsible entity, the name and address need not be duplicated. This symbol should only be used when the translation activity was undertaken by someone other than the manufacturer.
Repackaging To identify that a modification to the original medical device packaging configuration has occurred. This symbol shall be accompanied by the name and address of the entity that is responsible for the repackaging activity, adjacent to the symbol If multiple symbols (i.e., Authorized Representative, Importer, Distributor, Translation, or Repackaging) identify the same responsible entity, the name and address need not be duplicated. This symbol should only be used when the repackaging activity was undertaken by someone other than the manufacturer.
Single Patient – multiple use Indicates a medical device that may be used multiple times or multiple procedures on a single patient
DO NOT Re-Use Device intended only for single use
Indicates do not use if package is damaged Also indicates, do not use device if sterile barrier or its packaging is compromised
Biological risks Indicates that there are potential biological risks associated with the medical device
Contains natural rubber latex Indicates the presence of natural rubber or dry latex as a material, within the construction of the device or in the packaging of the medical device
Device containing substances or incorporates
Contains human blood or plasma derivative Indicates a medical device that contains or incorporates human blood or plasma derivatives
Contains medicinal substance Indicates a medical device that contains or incorporates a medicinal substance
Contains tissues or cell derivatives of animal origin Indicates a medical device that contains or incorporates a medicinal substance
Contains tissues or cell derivatives of human origin Indicates a medical device that contains biological tissue, cells, or their derivatives, of human origin
Contains hazardous substances Indicates a medical device that contains substances that can be carcinogenic, mutagenic, reprotoxic (CMR), or substances with endocrine-disrupting properties
Contains nano materials Indicates a medical device that contains nano materials
Fragile, handle with care Indicates a medical device that can be broken or damaged if not handled carefully
Keep dry Indicates a medical device that needs to protected from moisture
Temperature Limit Indicates the temperature limits to which the medical device can be safely exposed
Humidity Limitation Indicates the humidity range to which the medical device can be safely exposed
Atmospheric pressure limitation Indicates the atmospheric pressure range to which the medical device can be safely exposed